diabetic peripheral neuropathy optimal assessment and management

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Diabetic Peripheral Neuropathy Optimal Assessment and Management Slide 2 Presentation Objectives Understand the clinical impact of DPNUnderstand the clinical impact of DPN Distinguish between symptoms and signs DPNDistinguish between symptoms and signs DPN Describe the proposed etiology of diabetic neuropathyDescribe the proposed etiology of diabetic neuropathy Understand the potential MOA of currently used medications in the management of DPN SymptomsUnderstand the potential MOA of currently used medications in the management of DPN Symptoms Slide 3 Chronic Diabetes Complications Chronic Diabetes Complications Stroke Retinopathy Cardiovascular Disease (CVD) Hypertension Nephropathy Peripheral Vascular Disease (PVD) Peripheral Neuropathy most common complication 50% to 90% of diabetes patients depending upon criteria used for diagnosis Tavakoli M, et al. Current Pain and Headache Reports. 2008;12:192-197. Slide 4 Diabetes StatisticsDid you know? Up to 70% of those with diabetes will lose sensation in their feet Peripheral sensory neuropathy is the leading factor to diabetic foot ulcerations Approximately 25% of those with diabetes will develop a foot ulcer More than half of all foot ulcers will become infected, requiring hospitalization and 1 in 5 will require an amputation After a major amputation, 30% of patients will have their other limb amputated within 3 years 5-year mortality rate after limb amputation is reported as high as 74%, when compared to cancer- it is greater than colorectal, breast, and prostate cancer Dyck et al. Diabetic Neuropathy 1999; Singh et al. J Amer Med Assoc 2005; Robbins, et al. J Am Podiatr Med Assoc 2008. Slide 5 Diabetic Peripheral Neuropathy: What is it? Nerve damage and dysfunction secondary to diabetes mellitus type 1 or 2Nerve damage and dysfunction secondary to diabetes mellitus type 1 or 2 Consensus definition: the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes Consensus definition: the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes Tavakoli M, et al. Current Pain and Headache Reports. 2008;12:192-197. Slide 6 Impact of Diabetic Neuropathy 60-70% of foot ulcers are preceded by neuropathy60-70% of foot ulcers are preceded by neuropathy 85% of diabetes related lower limb amputations are preceded by a foot ulcer85% of diabetes related lower limb amputations are preceded by a foot ulcer Most Common Proximate, Nontraumatic Cause of AmputationsMost Common Proximate, Nontraumatic Cause of Amputations Largest number of diabetes related hospital bed-daysLargest number of diabetes related hospital bed-days Gordois et al. Diabetes Care. 2003;26:1790-1795. Reiber G, et al. Diabetes in America. 1995; 2nd ed:409-428. Reiber GE, Vilekyte L, Bokyo EJ et al. Diabetes Care.1999;22. Pecoraro RE, Reiber GE, Burgess EM. Diabetes Care. 1990;13. Frykberg R, et al. Journ of Foot and Ankle Surgery 2006;45(5):S2-S8. Slide 7 Clinical Unmet Needs in DPN There are a wide range of treatments available for neuropathic painThere are a wide range of treatments available for neuropathic pain This prescribing pattern suggests that there is no one treatment that addresses all the factorsThis prescribing pattern suggests that there is no one treatment that addresses all the factors Despite a spectrum of drugs available with different modes of action, many patients remain inadequately treated in several aspects of the diseaseDespite a spectrum of drugs available with different modes of action, many patients remain inadequately treated in several aspects of the disease Datamonitor Research 2008. Increasing level of importance Improved efficacy Improved side effect profile Reduced time to onset of action Fewer drug-drug interactions Reduced pill burden Slide 8 Peripheral Nervous System Vinik et al. Nature Clinical Practice Endocrinology & Metabolism 2006. Slide 9 Diagnostic Tools for DPN: Large Fiber 5.07 Semmes-Weinstein Monofilament5.07 Semmes-Weinstein Monofilament Biosthesiometer Biosthesiometer Calibrated Tuning ForkCalibrated Tuning Fork Nerve Conduction VelocityNerve Conduction Velocity Quatrini C, Boulton A, et al. Diabetologia. 2008;51(6):1046-1050. Boulton AJ, et al. Diabetes Care. 2004;27(6):1458-1486. Boulton AJ, et al. Prev and Treatment of Diab and its Compli. 1998;82(4):909-919. Barber MA, et al. J Am Podiatr Med Assoc. 2001;91(10):508-514. Kiso T, et al. Journ of Pharmaco and Experi Therap. 2001;297(1):352-356. Slide 10 TAVEE J, ZHOU L Cleveland Clinic Journal of Medicine 2009;76:297-305 Normal Skin Biopsy Small Fiber Neuropathy Biopsy Normal innervation with small nerve fibers seen in the epidermis (arrows). Skin biopsy specimens with protein gene product 9.5 immunostaining. A specimen from a patient with small fiber neuropathy shows denervation with no small nerve fibers seen in the epidermis Diabetic Neuropathy: A Small Fiber Disease Slide 11 Symptoms and Signs of Diabetic Peripheral Neuropathy Symptoms Small Fiber Numbness or loss of feeling (asleep or bunched up sock under toes sensation)Numbness or loss of feeling (asleep or bunched up sock under toes sensation) Prickling/TinglingPrickling/Tingling Aching PainAching Pain Burning PainBurning Pain Lancinating PainLancinating Pain AllodyniaAllodynia Defective Thermal SensationDefective Thermal Sensation Decreased SweatingDecreased Sweating Signs Large Fiber Diminished vibratory perceptionDiminished vibratory perception Decreased knee and ankle reflexesDecreased knee and ankle reflexes Reduced protective sensation such as pressure, hot and cold, painReduced protective sensation such as pressure, hot and cold, pain Diminished ability to sense position of toes and feetDiminished ability to sense position of toes and feet Pain is deep, aching or crampingPain is deep, aching or cramping Symptoms and signs progress from distal to proximal over time Boulton AJ, et al. Diabetes Care. 2005 April; 28(4):956-62. Slide 12 Hyperglycemi a Metabolic Abnormalities AGEs Oxidative Stress Polyols EFA Endothelial Abnormalities ET A II NO PGI 2 Microvascular Insufficiency Neuronal and Schwann Cell Dysfunction Endothelial Dysfunction in DPN: Endothelium: a biologically active organ Endothelium: a biologically active organ Deranged nitric oxide pathways Deranged nitric oxide pathways Vinik A. The Amer Journal of Med. August 1999 Etiology of DPN Slide 13 A consequence of low nitric oxide levels Endothelial Dysfunction in the Diabetic Foot Moncada S., Higgs A.N Engl J Med 1993; 329:2002-2012. Schffer M, et al. Nitric Oxide Regulates Wound Healing. J Surg Res 1996; 63:237-240. Schwentker A, et al. Nitric Oxide and Wound Repair. Surg Clin N Am 2003; 83:521-530. poor microcirculation loss of protective sensation foot ulceration DPN pain Slide 14 HyperglycemiaHyperglycemia Endoneurial Ischemia Progressive Diabetic Peripheral Neuropathy Progressive Diabetic Peripheral Neuropathy Neuronal Injury Putative Pathogenic Sequence Impaired Neuronal Regeneration Slide 15 Clinical Impact of DPN TOTAL Symptoms DPN Boulton A. NCVH. Oral Presentations. 2007. Mortality Cost ImpairmentDisabilityHandicap Infection (skin, bone) CharcotFoot Foot Ulcers PainfulNeuropathy Quality of Life Sensory Loss Surgery,Amputation Slide 16 Microvascular Damage Leads to DPN Examination of tissues from patients with diabetes reveals capillary damage, including occlusion in the vasa nervorumExamination of tissues from patients with diabetes reveals capillary damage, including occlusion in the vasa nervorum Reduced blood supply to the neural tissue results in impairments in nerve signaling that affect both sensory and motor functionReduced blood supply to the neural tissue results in impairments in nerve signaling that affect both sensory and motor function Dyck PJ, Giannini C. J Neuropathol Exp Neurol. 1996;55:1181-1193. Sheetz MJ, King GL. JAMA. 2002;288:2579-2588. Normal nerve Damaged nerve Occluded vasa nervorum Damage to myelinated and unmyelinated nerve fibers Slide 17 Progression of Symptomatic DPN DPN patients are labor intensive and require multiple therapies to mask pain as disease continues progressing Tavakoli M, et al. Current Pain and Headache Reports 2008. Tavakoli M and Malik RA. Expert opin Pharmacother 2008. Argoff CE, et al. Mayo Clin Proc 2006. Slide 18 Association of Metformin and Clinically Worsened DPN A prospective study of 122 symptomatic DPN patients compared those who had > 6 months of metformin to those without metforminA prospective study of 122 symptomatic DPN patients compared those who had > 6 months of metformin to those without metformin Results demonstrate that metformin contributes to the severity of DPN (P

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