pathways-perspectives in modern neurology and pain management

8/14/2019 Pathways-Perspectives in Modern Neurology and Pain Management

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perspectives in modern neurology and pain management

volume [3] july 07

feature articleDiagnostic Tools for DPNP

David M. Simpson, MDAlejandra Gonzalez-Duarte, MD


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Dear Colleague:

Welcome back to Pathways, a journal for physicians who specialize in pain management. In this edition, DavidM. Simpson, MD, Director of the Clinical Neurophysiology Laboratories and Neuro-AIDS Program at MountSinai School of Medicine, and Alejandra Gonzalez-Duarte, MD, Neurologist, Mount Sinai School of Medicine,discuss the clinical features of diabetic peripheral neuropathic pain (DPNP) and the tools that can aid physiciansin the diagnosis of this condition. The authors present an overview of simple diagnostic tools, such as a tuningfork, as well as more complicated and recently developed tests, such as nerve conduction studies and skin biopsy,that may be required in patients with atypical presentations of DPNP. In addition, the authors list key questionsthat physicians should ask when evaluating patients with suspected DPNP.

In the accompanying case study, the authors present a patient with symptoms indicative of DPNP. The authors walk through the examination findings that lead to the diagnosis of DPNP and describe an appropriatetreatment strategy.

We hope that you will find this information to be clinically relevant to your practice as you strive to improve thepain and overall functioning of your patients with DPNP. Please send us your feedback on the enclosed reply card.

Sincerely,Doug Williamson, MD

Associate Medical DirectorUS Neurosciences

Eli Lilly and Company

introduction

contents

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Feature Article Diagnostic Tools for DPNP

Case Study Diagnosis of DPNP


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feature article

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Diagnostic Tools for DPNP

Diabetic peripheral neuropathic pain (DPNP) is a debilitating complication of diabetes, affecting 10% to20% of patients with this disease.1 The prevalence of peripheral neuropathy approaches 50% in patients

who have had diabetes for more than 25 years.2,3 Neuropathic pain is often described as aching, burning,stabbing, or shooting sensations in the feet.1,4 It is variable in severity and is often worst at night.1,4,5

DPNP can dramatically impact quality of life.5 Painful symptoms have been linked to worsening physical andpsychosocial functioning.5 DPNP also predisposes patients to foot ulceration, burns, infections,gangrene,andCharcots neuroarthropathy.6 Thus, early diagnosis and treatment are essential to the care of patients withDPNP. Key questions in the diagnosis of DPNP are listed in Table 1.

continued on page 3

Alejandra Gonzalez-Duarte, MDNeurologistMount Sinai School of Medicine,New York City

David M. Simpson, MDProfessor of NeurologyDirector, Clinical NeurophysiologyLaboratoriesDirector, Neuro-AIDS ProgramMount Sinai School of Medicine,New York City

Table 1. Key Questions for the Diagnosis of DPNP

1. Is the patient diabetic?

2. Does the patient have burning pain in his or her feet?

3. Is the pain associated with tingling, pinprick sensations, or numbness?

4. Are the symptoms distributed symmetrically?

5. Are the examination findings consistent with distal peripheral neuropathy (ie, decreased or absent anklereflexes, decreased sensation of temperature or vibration, decreased propioception)?

6. Have other, nondiabetic causes of neuropathy been ruled out (eg, neoplasm, infection, toxic substance abuse)?


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Features of DPNP

Neuropathic pain is defined as spontaneous pain or hypersensitivity to sensory stimuli in association withdamage to or a lesion of the nervous system.7 It is often chronic and unrelenting, and it does not respondto treatment with common analgesics.8 Neuropathic pain can be diagnosed clinically on the basis ofdistinct features that help differentiate it from other types of pain (Table 2).1,6,8

The pathogenesis of diabetic neuropathy is complex. In hyperglycemia, elevated intracellular levels ofglucose drive secondary pathologic mechanisms, such as oxidative stress and protein glycation, in vascularand nervous tissues.9 Diabetic neuropathy can affect both large and small nerve fibers to varying degrees,resulting in mixed symptoms and sensory loss.10,11 More commonly, small-fiber neuropathy predominatesover large-fiber neuropathy. Large afferent nerve fibers transmit propioception (ie, spatial limb location)and sensations of cold and vibration.10,12 Small afferent fibers conduct nociceptive stimuli and sensationsof touch and warmth.10,12,13

The diagnosis of DPNP is usually made based on the patients history and results of a physical andneurologic examination. Neuropathic symptoms are often difficult for patients to describe. They may

consist of severe burning pain, paresthesias, and numbness and can fluctuate in intensity from milddiscomfort to severe pain. The classic presentation of DPNP is pain in the feet, often described asburning, shooting, or throbbing. The pain may be spontaneous or stimulus-evoked and may beassociated with allodynia (pain resulting from a stimulus that ordinarily does not elicit a painful response,such as contact with bedclothes, shoes, and socks) or with hyperalgesia (increased sensitivity to a painfulstimulus, such as pinprick).8,12 Tingling or pins and needles sensations are common. In addition to the

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Table 2. Features of Neuropathic and Nociceptive Pain1,6,8

Neuropathic pain Nociceptive pain

Time course Chronic, unrelenting, and not self-limited; Usually acute and self-limitedcan persist for years

Symptoms Sensations of burning or of electric, Sharp, aching, throbbing, or gnawing paintingling, or shooting pain

Treatment response Poor response to NSAIDS; usually responds Usually responds to nonspecific analgesics,to anticonvulsants, antidepressants, opioids, NSAIDS, and opioidsand topical agents

Pathophysiology Produced by damage to or pathologic Caused by the stimulation of A- andchanges in the peripheral or central C-polymodal pain receptors and bynervous system algogenic substances (eg, histamine,

bradykinin, substance P)

Source of pain Injury or malfunction in the peripheral or Protective biological function to warn ofcentral nervous system ongoing tissue damage

Examples Radiculopathy, t rigeminal neuralgia, Postoperative pain, pain associated withpostherpetic neuralgia, phantom limb pain, trauma or arthritiscomplex regional pain syndrome,polyneuropathies (ie, DPNP, HIV infection)

DPNP, diabetic peripheral neuropathic pain; HIV, human immunodeficiency virus; NSAIDs, nonsteroidal anti-inflammatory drugs


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painful (positive) symptoms of neuropathy, patients may experience nonpainful (negative) symptoms.These include numbness, often described as an area that is dead or asleep. Other negative symptomsinclude gait unsteadiness (ataxia) and, in late stages, distal muscle weakness.1,12,14 Patients often compare

this sensation to one of walking through sponges that make it impossible to feel the ground normally.Excruciating pain is the most common identified symptom of diabetic neuropathy; however, the damagetypically develops insidiously as loss or changes of sensation that may be detected only by clinical tests.1,4

Typically, DPNP first affects the feet and lower limbs symmetrically and affects the upper extremities onlyin late stages.1,12 The distribution resembles a stocking and glove pattern (Figure).12,15 Proximal motor

weakness or an asymmetric distribution should suggest other types of neuropathy.1,16

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Figure. Neuropathies can be distinguished by signs, symptoms, and areas of the body that are affected.15

From Wulff EA, Simpson DM. HIV-associated peripheral nervous system complications.NeuroAIDS. 1999;2.Reprinted with permission from the American Association for the Advancement of Science.

Distal symmetricpolyneuropathy

1 Hyperesthesia

2 Normal strength

3 Pain, paresthesia

4 Decreased ankle reflexes

5 Decreased response topinprick, temperature;increased vibratorythresholds

6 Contact sensitivity

Inflammatorydemyelinating

polyneuropathy

1 Facial nerve paresis

2 Ascending weakness

3 Generalized areflexia

4 Mild sensory involvement

Progressivepolyradiculopathy

1 Radiating pain in caudaequina distribution

2 Flaccid paraparesis

3 Mild sensory loss

4 Areflexia

5 Sphincter dysfuntion

Mononeuritismultiplex

1 Cranial nerve involvement(eg, facial palsy); multipleperipheral nerveinvolvement

2 Medial nerve involvement

3 Meralgia paresthetica

4 Peroneal nerveinvolvement

5 Ulnar nerve involvement


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continued...

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Clinical Examination

Neurologic examination in DPNP reveals absent or depressed ankle reflexes relative to knee reflexes.

Because of the anatomic position of the Achilles tendon, assessment of the ankle reflex (S1 innervation) isat times difficult to perform correctly. To obtain the Achilles tendon reflex, the foot should be flexedupward to stretch the tendon. The tendon on the back of the leg at the height of the ankle bone is tapped,and if the reflex is present, the foot will extend. Most physicians have experience with the knee reflex (L3innervation) because it is accessible and easily palpated. However, to obtain this reflex, it is necessary tobend the knee to stretch the patellar tendon and ensure that the leg is relaxed. The tendon must bepalpated to verify the location. When reflexes are present, the leg will extend when tapped. Normalreflexes are usually graded as 2+. Hyperactive reflexes are graded 3+ and 4+, depending on the presenceof clonus (the rhythmic contraction and relaxation of a muscle group). Hypoactive reflexes are graded 1+and absent reflexes 0.

Results of sensory examination are commonly abnormal in patients with DPNP. Proprioception andsensations of light touch, vibration, and temperature are decreased or absent. A relative loss of

discrimination of sharp touch is noted over the distal lower extremities, and an area of gradual transitionwhere normal sensation returns. A broken tongue depressor is commonly used to test for sharp sensation, 8

although more specific commercial sterile examination pins and nylon monofilaments are available.Vibratory sensation is assessed by placing a 128-Hz tuning fork over the bony surface of the malleolus orfirst distal phalanx. The threshold to vibratory sensation is usually elevated in the feet compared with thatin the knees. Data from one study suggest that the predictive value of testing with a 128-Hz tuning forkin the diagnosis of DPNP is similar to that of national and international scoring systems. 17 The studyauthors concluded that the tuning fork should play a central role in the diagnosis of DPNP. 17 Temperaturesensation may be assessed with a cool tuning fork or with test tubes that contain warm or cold water. 8 Likethe thresholds to vibratory sensation, altered thresholds to thermal sensation have been well documentedin patients with DPNP, and their elevation has been associated with progression of neuropathy.1,18 Loss ofproprioception can impair gait and balance.1,14

Because the diagnosis of DPNP is usually evident based on results of the bedside examination, furtherneurologic testing is unnecessary in most patients.8,19 However, other diagnostic tests may be helpful inpatients with atypical clinical presentations, or in the research setting. Several methods to assessperipheral nerve function are available (Table 3):

Nerve conduction studies (NCS) and electromyography (EMG) have long been considered the goldstandard for the assessment of peripheral neuropathy. However, in DPNP, which may affectpredominantly small nerve fibers, NCS and EMG may yield normal results or show only minorabnormalities. NCS may differentiate DPNP from other neuropathies.4,8,20 Abnormal NCS resultsfrequently indicate more severe involvement, a less benign course, and a less favorable diagnosis. Theprogressive loss of distal axons is the pathologic hallmark of peripheral neuropathies. This loss isreflected in NCS by prolonged distal latencies, reduction in evoked potential amplitudes, and secondaryslowing of conduction velocity.

Quantitative sensory tests (QSTs) are used mostly for research purposes, although they may also beapplied in the clinical setting. They are performed with devices, often computer-assisted, that make itpossible to assess somatosensory function, including the perception of vibration, temperature, lighttouch, and pain.8,12,20 QSTs can be used to identify the sensory modalities affected and to estimate themagnitude of the deficit. In patients with diabetes, QSTs have proved valuable in the detection ofsubclinical neuropathy.1,12


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Skin biopsy is a newer technique that is sensitive in the detection of small-fiber neuropathies.12,21 A skinbiopsy is a procedure in which a small piece of the patients skin is removed for examination under amicroscope. It is a useful tool that requires basic medical skills and is easy to learn. Specimens areobtained by performing skin-punch biopsies at various sites in the leg, usually in the distal portion of theleg above the ankle and in the thigh. Full-thickness skin specimens are needed. After sterilizing andnumbing the area, a circular blade is rotated down through the epidermis and dermis and into thesubcutaneous fat, yielding a 3 to 4 mm cylindrical core of tissue. Samples are fixed and sent to thepathology laboratory, where morphometric and immunohistochemical methods are used to examine thethinly myelinated and unmyelinated nerve fibers. Integrity, density, and distribution of these fibers isassessed. Skin biopsy is the most sensitive measure of neuropathic changes. Significant inversecorrelations between the density of nerve fibers and the severity of neuropathy have been documented.21

Moreover, changes in nerve fiber density over time correlates with decreased neuropathic pain.22

The first step in the approach to diabetic patients with pain is to establish the diagnosis of neuropathicpain and determine the form of neuropathy. A simple key question to ask patients with diabetes might be,Do you feel burning pain, tingling, or numbness on your feet?8 If the answer is positive, the distributionmay differentiate DPNP from other conditions. A distal and symmetric distribution of symptoms andsigns is suggestive of DPNP.1,8 A nerve root distribution suggests radiculopathy, whereas a nerve trunkdistribution may indicate mononeuropathy simplex or multiplex. Sensory function should be assessed onboth sides of the feet and hands to distinguish DPNP from entrapment syndromes (eg, carpal or tarsaltunnel syndrome). Additional symptoms such as weakness are more suggestive of large-fiber dysfunction,such as diabetic amyotrophy or motor neuropathies. The diagnostic studies previously discussed provide

valuable data in differentiating these forms of neuropathy.

Conclusion

DPNP is predominantly a clinical diagnosis. Patients usually present with burning pain, tingling, andnumbness in a symmetrical distribution over the feet and occasionally the hands. Physical examinationreveals decreased or absent ankle reflexes, sensations of pinprick and vibration, and propioception. NCS,QSTs, and skin biopsy are helpful in differentiating DPNP from other forms of neuropathy and inassessing the progression of neuropathy over time.

Table 3. Diagnostic Tests for Diabetic Peripheral Neuropathic Pain

NCS/EMG Measures the speed and amplitude of Objective, parametric, noninvasive, and

sensory and motor conduction reproducibleInsensitive in acute and small-fiber neuropathy

QST Detects sensory thresholds for vibration, Useful in tracking the progression of neuropathyheat, and pain in large cohorts and efficacy of treatment end

points in multicenter clinical trials

Skin biopsy Measures density of intraepidermal nerve Loss of nerve fibers is associated with increasedfiber at various sites in the leg neuropathic pain

Although test is invasive, it requires only a 3-mmskin biopsy specimen and enables a direct studyof small nerve fibers

NCS/EMG, nerve conduction studies/electromyography; QST, quantitative sensory tests


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A 50-year-old woman with type 2 diabetes is referred with a 6-month history of burning pain and a pinsand needles sensation in her feet. The symptoms have progressed such that she is finding it difficult to

walk because of pain and has required a cane for 2 months. She is kept awake for much of the night withpain. She rates her average pain intensity at an 8 (on a scale of 0-10) during the day,with a worst pain scoreof 10 at night. She has been taking naproxen 250 mg every 6 to 8 hours as needed without anyimprovement during the previous 3 months. She has no significant past medical history or family historyof neurologic disease. She was formerly an avid golfer but can no longer play, and she does not engage inthe physical activities she once enjoyed. She has difficulty sleeping, feelsfrustrated, and wants something that can help her promptly.

Examination

Examination reveals shiny skin of the distal lower extremities.Her feet are cool to touch. Strength is normal. Deep tendonreflexes are diminished at the ankles (1 on a scale of 0-4)relative to the knees (2/4) bilaterally. Distal reduction inpinprick and temperature sensation is noted bilaterally in astocking distribution. Vibration sensation is reduced in thefeet. Results of nerve conduction studies are normal, as areresults of the rest of her neurologic and general examination.

Diagnosis and Treatment

Fasting serum glucose is 240 mg/dL, and the patient is diagnosed withdiabetic peripheral neuropathic pain (DPNP). Naproxen is stopped, and

Cymbalta (duloxetine HCl) 60 mg once daily is started. The patient is instructed to take the medicationat night and to monitor her symptoms daily using a pain diary. She experiences minor nausea anddizziness for the first 3 days, but these symptoms then abate. At her next visit, her pain diary indicates animprovement in painful symptoms beginning at 1 week. Her average pain score has dropped to 4, and her

worst pain score to 6. She is able to play golf again and no longer is kept awake at night because of pain.She starts a diet and exercise program after consulting a physician, and follow-up with a nutritionist andan endocrinologist is arranged.

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case studyDiagnosis of DPNP Alejandra Gonzalez-Duarte, MD

NeurologistMount Sinai School of Medicine,New York City

David M. Simpson, MDProfessor of NeurologyDirector, Clinical NeurophysiologyLaboratoriesDirector, Neuro-AIDS ProgramMount Sinai School of Medicine,New York City


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See Important Safety Information, including Boxed Warning, on page 9 and full PrescribingInformation enclosed.

Important Safety Information for Cymbalta:

Antidepressants increased the risk of suicidal thinking and behavior(suicidality) in short-term studies in children, adolescents, and youngadults with major depressive disorder (MDD) and other psychiatricdisorders.

Patients of all ages started on therapy should be monitoredappropriately and observed closely for clinical worsening, suicidality,or unusual changes in behavior.

Cymbalta is not approved for use in pediatric patients.

Discussion

This patient has classic signs and symptoms of a painful peripheral neuropathy. The symptoms of DPNPoften appear after periods of poor metabolic control or sudden changes in glycemic control. 1-3 Nerveconduction studies can yield normal results or show only minor abnormalities because small nerve fibersare more frequently damaged in sensory neuropathies. DPNP does not generally respond to the treatmentseffectively used for inflammatory pain, such as nonsteroidal anti-inflammatory drugs.1

The patient experienced a significant reduction of pain as a result of treatment with the dual serotonin andnorepinephrine reuptake inhibitor Cymbalta. Side effects developed in this patient but fortunately these

were mild and resolved within several days.

Diabetic neuropathy is a common complication of diabetes and is a leading risk factor for nontraumaticamputation.4,5 Therefore, measurement of the fasting serum glucose or a glucose tolerance test is indicatedin patients with a new onset of distal neuropathic pain. On the other hand, many patients with diabetes donot report symptoms of neuropathy until the complications are severe. These patients may benefit from acomplete neurologic examination despite being asymptomatic. The examination can reveal distal areas ofnumbness or decreased sensibility to pinprick or light touch. Abnormal ankle reflexes with diminished

vibration and temperature sensation fulfill the diagnosis of diabetic neuropathy. In this setting, rigorousglycemic control may halt the progression of neuropathy.6

Conclusion

DPNP primarily affects small nerve fibers and accounts for decreased perception of temperature andvibration and for paresthesias. Early institution of optimal glycemic control is the only method that hasbeen shown to prevent or slow the progression of diabetic neuropathy.6


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[9]

Important Safety Information on Cymbalta (duloxetine HCl)

Cymbalta is indicated in adults for: The treatment of major depressive disorder (MDD) The management of diabetic peripheral neuropathic pain (DPNP) The treatment of generalized anxiety disorder (GAD)

Suicidality and Antidepressant DrugsAntidepressants increased the risk compared to placebo of suicidal thinking andbehavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD)and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child,adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase inthe risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk

with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders

are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressanttherapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes inbehavior. Families and caregivers should be advised of the need for close observation and communication with theprescriber. Cymbalta is not approved for use in pediatric patients.

Contraindications

Cymbalta is contraindicated in patients with a knownhypersensitivity to duloxetine or any of the inactiveingredients.

Cymbalta should not be used in combination with MAOIs andis contraindicated for at least 14 days after discontinuation ofan MAOI. After stopping therapy on Cymbalta, at least 5 daysshould be allowed before starting an MAOI.

Cymbalta was associated with an increased risk of mydriasis;therefore, it should not be used in patients with uncontrollednarrow-angle glaucoma and used cautiously in patients withcontrolled narrow-angle glaucoma.

Warnings

Clinical Worsening and Suicide Risk

All patients being treated with antidepressants forany indication should be monitored appropriately andobserved closely for clinical worsening, suicidality, andunusual changes in behavior, especially when initiatingdrug therapy and when increasing or decreasing the dose.Consider changing the therapeutic regimen, including possiblydiscontinuing the medication in patients whose depression ispersistently worse or includes symptoms of anxiety, agitation,panic attacks, insomnia, irritability, hostility, aggressiveness,impulsivity, akathisia (psychomotor restlessness), hypomania,mania, or suicidality that are severe, abrupt in onset, or werenot part of the patients presenting symptoms.

If discontinuing treatment, the medication should be tapered.

Development of a potentially life-threatening serotoninsyndrome may occur with SNRIs and SSRIs, includingCymbalta treatment, particularly with concomitant use ofserotonergic drugs, including triptans. Concomitant use is notrecommended.

Precautions

Cymbalta and thioridazine should not be co-administered.

Cymbalta should not be administered to patients with anyhepatic insufficiency or patients with end-stage renal disease(requiring dialysis) or severe renal impairment (creatinineclearance


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REFERENCES: FEATURE ARTICLE

1. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care. 2004;27:1458-1486.

2. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973 (3rd and lastpart).Diabetes Metab. 1977;3:245-256.

3. Cabezas-Cerrato J. The prevalence of clinical diabetic polyneuropathy in Spain: a study in primary care and hospital clinic groups. Neuropathy SpanishStudy Group of the Spanish Diabetes Society (SDS).Diabetologia. 1998;41:1263-1269.

4. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956-962.

5. Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain. 2006;18:350-354.

6. Aring AM, Jones DE, Falko JM. Evaluation and prevention of diabetic neuropathy.Am Fam Physician. 2005;71:2123-2128.

7. Merskey H. Bogduk N, eds. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, Second Edition. Seattle,Wash: IASP Press; 1994:209-214.

8. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain: clinical and quality-of-life issues. Mayo Clin Proc. 2006;81:S3-S11.

9. Duby JJ, Campbell RK, Setter SM, White JR, Rasmussen KA. Diabetic neuropathy: an intensive review. Am J Health Syst Pharm. 2004;61:160-176.

10. Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies.Diabetologia. 2000;43:957-973.

11. Bird SJ, Brown MJ. The clinical spectrum of diabetic neuropathy. Semin Neurol. 1996;16:115122.

12. Barbano R, Hart-Gouleau S, Pennella-Vaughan J, Dworkin RH. Pharmacotherapy of painful diabetic neuropathy. Curr Pain Headache Rep. 2003;7:169-177.

13. Vinik AI, Holland MT, LeBeau JM, Liuzzi FJ, Stansberry KB, Colen LB. Diabetic neuropathies.Diabetes Care. 1992;15:1926-1975.

14. van Deursen RW, Sanchez MM, Ulbrecht JS, Cavanagh PR. The role of muscle spindles in ankle movement perception in human subjects with diabeticneuropathy.Exp Brain Res. 1998;120:1-8.

15. Wulff EA, Simpson DM. HIV-associated peripheral nervous system complications. NeuroAIDS. 1999;2.

16. Dyck PJ, Karnes JL, OBrien PC, Litchy WJ, Low PA, Meltton LJ. The Rochester Diabetic Neuropathy Study: Reassessment of tests and criteria fordiagnosis and staged severity.Neurology. 1992;42:1164-1170.

17. Meijer JW Smit AJ, Lefrandt JD, van der Hoeven JH, Hoogenberg K. Back to basics in diagnosing diabetic polyneuropathy with the tuning fork!DiabetesCare. 2005;28:2201-2205.

18. Sosenko JM, Kato M, Soto R, Bild DE. Comparison of quantitative sensory-threshold measures for their association with foot ulceration in diabeticpatients.Diabetes Care. 1990;13:1057-1061.

19. Pascuzzi RM. Peripheral neuropathies in clinical practice.Med Clin North Am. 2003;87:697-724.

20. Vinik AI, Mehrabyan A. Diabetic neuropathies.Med Clin North Am. 2004;88:947-999.

21. Sorensen L, Molyneaux L, Yue DK. The relationship among pain, sensory loss, and small nerve fibers in diabetes.Diabetes Care. 2006;29:883-887.

22. Boulton AJ. Clinical trials report. Curr Diab Rep. 2006;6:415-416.

REFERENCES: CASE STUDY

1. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain: clinical and quality-of-life issues. Mayo Clin Proc. 2006;81:S3-11.

2. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956-962.

3. Oyibo SO, Prasad YD, Jackson NJ, Jude EB, Boulton AJ. The relationship between blood glucose excursions and painful diabetic peripheral neuropathy:a pilot stud.Diabet Med. 2002;19:870-873.

4. Duby JJ, Campbell RK, Setter SM, White JR, Rasmussen KA. Diabetic neuropathy: an intensive review. Am J Health Syst Pharm. 2004;61:160-176.

5. American Diabetes Association. Preventive foot care in diabetes.Diabetes Care. 2004;27:S63-S64.

6. Boucek P. Advanced diabetic neuropathy: a point of no return?Rev Diabet Stud. 2006;3:143-150.

DD44590 0707 PRINTED IN USA.

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Cymbalta is a registered trademark of Eli Lilly and Company.


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