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Silence of the Limbs Bruce Trippe, M.D., F.A.C.E. Montgomery, AL.

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Presentation on theme: "Silence of the Limbs Bruce Trippe, M.D., F.A.C.E. Montgomery, AL."— Presentation transcript:

1 Silence of the Limbs Bruce Trippe, M.D., F.A.C.E. Montgomery, AL

2 “I marvel that society would pay a surgeon a large sum of money to remove a person’s leg- but nothing to save it.” - George Bernard Shaw

3 Presentation Objectives  Understand the economic and social impact of diabetic peripheral neuropathy  Distinguish between positive and negative symptoms of diabetic peripheral neuropathy  Describe remittive vs. palliative therapy in the management of diabetic peripheral neuropathy  Understand the potential mechanism of action of diabetic peripheral neuropathy prescribed therapies

4 Diabetic Peripheral Neuropathy: What is it? Nerve 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” A leading cause of neuropathic pain A very common complication of diabetes

5 Pathogenesis of Diabetic Neuropathy

6 ~ 66% Diabetic Neuropathy Chen H, Lamer TH, Rho RH et al. Mayo Clin Proceed. 79; 2004 Boulton AJM, Mailik RA, ArezzoJC, Sosenko JM. Diab.Care 27, 2004 Wendling Patrice. 45% of Diabetic Patients Not Reaching HbA1C Target. Internal Medicine News. July ;40(No.14):1, 20.

7 Impact of Diabetic Neuropathy 15% of diabetics will develop an ulcer. One in six of those with ulcers will have an amputation. Half of those will have an ulcer on the opposite foot within three years. Gordois et al. Diabetes Care 26: , 2003

8 Impact of Diabetic Neuropathy LARGEST NUMBER OF DIABETES RELATED HOSPITAL BED-DAYS Reiber GE. Diab. Med 13 (SUPPL 1) 1996 Most Common Proximate, Nontraumatic Cause of Amputations Reiber GE, Vilekyte L, Bokyo EJ et al. Diabetes Care 22, 1999 Pecoraro RE, Reiber GE, Burgess EM. Diabetes Care 13, 1990

9 Increasing level of importance Improved efficacy Improved side effect profile Reduced time to onset of action Fewer drug-drug interactions Reduced pill burden Clinical Unmet Needs in DPN There are a wide range of treatments available for neuropathic pain This 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, may patients remain inadequately treated in several aspects of the disease. Datamonitor Research 2008

10 Results of the 2005 ADA National Survey Only one in four survey respondents who experience symptoms of diabetic neuropathy have been diagnosed with the condition. The majority of respondents who experience symptoms (56%) remain unaware of the term diabetic neuropathy. 62% believe that their symptoms are associated with their diabetes, but only 42% have been told by their physician that diabetes is the cause. Approximately one in seven people who said they talked to their doctor about their symptoms and pain reported that no cause was mentioned. Diabetic Neuropathy: The Forgotten Complication May 10, 2005 /PR Newswire via COMTEX

11 Signs and Symptoms of Diabetic Peripheral Neuropathy Distal symmetrical sensorimotor polyneuropathy is the most common form of DPN. Signs and symptoms may progress from distal to proximal over time. SIGNS Diminished vibratory perception Decreased knee and ankle reflexes Reduced protective sensation, such as pressure, hot and cold, pain Diminished ability to sense position of toes and feet Boulton AJ, et al. Diabetes Care. 2005;28(4): SYMPTOMS Numbness, loss of feeling, prickling, tingling Aching pain Burning pain Lancinating pain Unusual sensitivity or tenderness when feet are touched (allodynia)

12 DPN Produces Positive and Negative Symptoms Positive Symptoms –Spontaneous Pain –Dysesthesias C-Fibers Unpleasant –Parasthesias A-Fibers Not Unpleasant Negative Symptoms –Loss/impairment of sensory quality –Numbness –Dry skin –Erectile dysfunction –Incontinence –Gait instability and fall risk Baron R. Clin J Pain. 2000;16(2 suppl):S12-S20.

13 Positive and negative symptoms have an impact on functioning, activities of daily living (ADL) and QOL QOL is an unique, individual experience – how persons perceive and react to their health status Psychosocial Morbidity – Depression – Anxiety – Anger – Loss of Self-Esteem Societal Consequences – Social isolation – Strained relationships with family and friends – Effects upon intimacy/sexual activity Neuropathic Symptoms and Quality of Life The National Initiative on Pain Control, 2002 Vileikyte et al, Diabetes Care 2005

14 Diabetic Neuropathy: Symptoms Majority of symptomatic DPN patients are insensate Argoff et al. Mayo Clin. Proc. 2006:81 (S4) Boulton AJM et al. Diab. Care 27, 2004 M. Clin. Diab. 23, 2005

15 Clinical Impact of Positive and Negative DPN Symptoms Mortality CostDPNPainfulNeuropathyImpairmentDisabilityHandicap Sensory Loss Quality of Life Foot Ulcers Infection (skin, bone) CharcotFoot Surgery,Amputation Boulton A. NCVH. Oral Presentations 2007.

16 ADA Consensus Statement “The effort to optimize foot care for patients with diabetes led to the American Diabetes Association consensus statement on foot care, which recommended that the cutaneous pressure threshold be measured at least once a year” “The goal of this recommendation is to reduce the risk of ulceration, infection and amputation due to sensory loss that can occur through progressive neuropathy” American Diabetes Association: Foot care guidelines. Diabetes Care 2355;2000

17 Diagnostic Tests for DPNP NCS/EMG – Measures the speed and amplitude of sensory and motor conduction – Objective, parametric, non-invasive – Insensitive in acute and small-fiber neuropathy – > 50% False Negative for Tarsal Tunnel Syndrome QST – Detects sensory thresholds for vibration, heat and pain – Useful in tracking the progression of neuropathy in large cohorts and the efficacy of treatment end points in multicenter clinical trials Skin Biopsy (IENFD) – Measures density of intraepidermal nerve fiber at various sites in the leg – Loss of nerve fibers is associated with increased neuropathic pain – Although the test is invasive, it requires a 3mm skin biopsy specimen and enables a direct study of small nerve fibers Pathways: Perspectives in Modern Neurology and Pain Management. Vol 3. July 2007; Page 6

18 Skin Biopsy Sensitivity of skin biopsy in diagnosing small fiber neuropathy is 88.4%, with a specificity of 95% to 97%. Skin specimens are routinely obtained by punch biopsy at the foot, calf, and/or thigh, under local anesthesia. The ENFD at the calf-foot/ankle is routinely compared to that at the thigh, to help differentiate between distal neuropathy and neuronopathy or multifocal neuropathy. Skin biopsy specimens are routinely obtained for analysis, using a 3 mm punch biopsy. Patients with small fiber neuropathy exhibit a reduction is the epidermal nerve fiber density, or structural abnormalities that are indicative of neuropathy.

19 Skin Biopsy This image demonstrates skin with normal nerve fiber density (Epidermal Nerve Fiber Density). Arrow points to the small nerve fiber in the epidermal layer of skin, arrowhead points to the basement membrane that separates the dermis from the epidermis. Skin with low normal nerve fibers, consistent with small fiber neuropathy. The arrow points to the basement membrane of the epidermis.

20 Other Diagnostic Tools for Detection of DPN 5.07 Semmes-Weinstein Monofilament Biosthesiometer ® Calibrated Tuning Fork Diskcriminator for 2 Point Spacing Neurometer CPT ® (A-beta,A-delta,C fibers) PSSD ® (Earliest detection of pathology of A-beta skin surface/touch fibers Neuropad (correlates with IENFD, p=0.04)* * The Neuropad test: a visual indicator test for human diabetic neuropathy. Quatrini C, Boulton A, et al. 22 Feb Diabetologia.

21 DIABETES Hyperglycemia  DAG  PKC Impaired n-6 fatty acid metabolism Polyol pathway Sugar autoxidation Advanced glycation OXIDATIVE STRESS ENDOTHELIAL DYSFUNCTION  capillary blood flow  endoneurial hypoxia NERVE DYSFUNCTION  NCV,  Regeneration, Structural damage  Triglycerides  LDL

22 Etiology of Diabetic Neuropathy Hyperglycemia Microvascular Disease Oxidative Stress –Free radicals produced from an advanced glycation lead to damaged neurons –Relieved by improving blood flow Sorbitol Concentration –Excess sorbitol within the nerve causes it to retain water and nerve edema/compression Myoinositol Depletion –Myoinositol helps nerves conduct electricity –K +, Na +, and Ca + are regulated by Myoinositol Neurotrophic Factors –Diabetic nerves are folate, B 6, and B 12 deficient Vinik A. The Amer. Journal of Med. August 1999.

23 Pathophysiology HYPERGLYCEMIA Microvascular Ischemia Polyol Pathway Oxidative Stress Loss of Neurotrophic Support Immune Mechanisms Altered Protein Synthesis

24 Diabetes and Endothelial Dysfunction Endothelium: Endothelium: a biologically active organ Deranged nitric oxide pathways Multifactorial Hyperglycemia Insulin resistance FFA production / metabolism

25 ADA Statement Diabetic Neuropathies Classification of Neuropathies Generalized symmetric polyneuropathies Acute sensorimotor Chronic sensorimotor Autonomic Focal and multifocal neuropathies Cranial Truncal Focal limb Proximal (Amyotrophy) Co-existing CIDP Boulton, et al. Diabetes Care; April 2005

26 Predictors of Foot Ulceration Variable No Ulcer (127) Ulcer (53) p-value NSS NDS VPT (volts) SWMF NP Pedal Pulse 28 (22%) 20 (38%)0.035 STJ mobility st MTP mobility Forefoot PP Rearfoot PP Rich, Veves,Wounds,2000;12:82-87

27 Proximal Neuropathies Pascoe et al, Mayo Clin Proc,1997;72:

28 Autonomic Neuropathy Heart rate abnormalities Postural hypotension Abnormal sweating Gastroparesis Neuropathic diarrhea Impotence Retrograde ejaculation

29 Sensorimotor Neuropathy Most common type of diabetic neuropathy Affects 30-50% of all diabetic population Most commonly involved in diabetic foot problems

30 Sensorimotor Neuropathy Symptoms Development progressive, initially involving more distal parts Main symptoms are numbness of the legs and feet, muscular cramps, pins and needles, shooting, deep aching and burning pain. Nocturnal exacerbation characteristic. Symptoms may be absent or present either in the early or late stages

31 Sensorimotor Neuropathy Clinical Signs Reduced or absent sensation to pain, touch, cold, hot and vibration in a stocking-glove distribution most common signs of sensory neuropathy. Reduced or absent ankle reflexes, muscle weakness, small muscle atrophy and prominence of the metatarsal heads main signs of motor neuropathy.

32 Sensorimotor Neuropathy Diagnosis Should be based on: clinical symptoms clinical signs quantitative sensory testing electrophysiology sural nerve biopsies Not all methods necessary on a daily clinical base Simple tests can identify the at risk patient

33 Neuropathic Pain: Pharmacologic Therapies Gabapentin, carbamazepine, lamotrigine, and newerAEDs Antidepressants Opiod analgesics Lidocaine (transdermal, intravenous [IV]), mexiletine Alpha-2 adrenergic agonists

34 Adjuvant Analgesics: Antidepressants Best evidence: 30 amine TCAs (e.g., amitriptyline) 20 amine TCAs (desipramine, nortiptyline) better tolerated and also analgesic. Some evidence for SSRI / SSNRIs / atypical antidepressants (e.g., paroxetine, venlafaxine*, maprotiline, bupropion, others) and these are better tolerated yet. Duloxetine SSRI /SNRI now FDA approved *Kunz NR et al ADA, San Antonio, 2000

35 Diabetic Neuropathy: Current Treatments 25% NO TREATMENT 53.9% OPIOIDS 39.7% NSAIDS 21.1% SSRI’s 11.3% TCA’s 11.1% ANTICONVULSANTS Only Target Positive (Painful) Symptoms Berger A, Dukes EM, Oster G; J. Pain 5; 2004

36 Current Palliative Treatments Distal Neuropathy C-fibers (dysesthesias, allodynia, burning) A-fibers (paresthesias, radiating, night cramps) Capsaicin cream Clonidine Lidocaine Insulin Infusion Carbamazepine Lidocaine Muscle relaxant NSAID’s Tramadol TCA Gabapentin Pregabalin Duloxetine Chen H, Lamer TH, Rho RH et al. Mayo Clin Proceed. 79; 2004

37 Symptomatic Palliative DPNP Therapies  Pregabalin (Lyrica®)  Duloxetine (Cymbalta®) FDA Approved Drugs for the Treatment of DPNP

38 Pregabalin INDICATIONS – DPNP – Fibromyalgia – Post herpetic neuralgia – Adjunctive seizure medication DOSAGE – DPNP Start at 50mg tid and may increase to 100mg tid within one week – Fibromyalgia 150mg tid – Post-herpetic neuralgia 200mg tid SIDE EFFECTS – Dizziness, drowsiness, dry mouth, edema DRUG INTERACTIONS – Alcohol and drugs that cause sedation may increase the sedative effects of those agents. – No pharmacokinetic interactions have been demonstrated in vivo.

39 Subunit of Voltage-Gated Ca2+ Channels in the Central Nervous System Pregabalin selectively binds to α 2 -δ subunit of calcium channels Modulates calcium influx in hyperexcited neurons Reduces neurotransmitter release Pharmacologic effect requires binding at this site The clinical significance of these observations in humans is currently unknown Taylor. CNS Drug Rev. 2004;10:

40 Pregabalin Effect on Mean Weekly pain Scores in Painful DPN Rosenstock et al. Pain 2004; 110:

41 Pregabalin: Percentage of Patients with > 50% Reduction in Pain in Painful DPN* Rosenstock et al. Pain 2004; 110:

42 Duloxetine INDICATIONS – Depression – Generalized anxiety disorder – DPNP – Fibromyalgia DOSAGE – Treatment should begin at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. – Some patients may respond to the starting dose. – There is no evidence that doses greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions.higher doses are associated with a higher rate of adverse reactions SIDE EFFECTS – Duloxetine can cause hepatotoxicity in the form of transaminase elevations. – It may also be a factor in causing more severe liver injury, but there are no cases in the NDA database that clearly demonstrate this. – Use of duloxetine in the presence of ethanol may potentiate the deleterious effect of ethanol on the liver. DRUG INTERACTIONS – Diet drugs like Redux, Adipex, Meridia, fenfluramine – MAOIs like Carbex/Eldepryl, Marplan, Nardil, and Parnate – The chemotherapy drug, Matulane (procarbazine) – SSRIs like Celexa, Lexapro, Prozac, Luvox, Paxil, Zoloft – St. John's Wort – Thioridazine – Tryptophan – Effexor XR

43 Duloxetine Proposed MOA

44 Duloxetine Phase 2

45 Goldstein et al. PAIN 2005

46 Anticonvulsant Drugs Carbamazepine600mg/day Phenytoin300mg/day Valporate15-60mg/kg/day Gabapentin mg/day Topiramate50-400mg/day Lamotrigine mg/day Felbamate mg/day

47 New Therapeutic Approaches to Diabetic Neuropathy Aldose reductase inhibitorsIneffective Anti-oxidants (a-lipoic acid)Effective Nerve growth factorsIneffective Gamma linolenic acidIneffective

48 Potential Disease State Modifying Therapies Control Diabetes (blood sugar) Alpha Lipoic Acid L-Methylfolate, Me-Cbl, P-5-P (Metanx®)

49  1988 via amendments to the Federal Food, Drug and Cosmetic Act: Active ingredient: present in / derived from a food (e.g. folate)  Oral dosage form  Addresses distinct nutritional requirements of patients with specific diagnosed diseases or conditions (e.g. low plasma / RBC folate, hyperhomocysteinemia, endothelial dysfunction)  Efficacy/dosing must be proven in peer-reviewed scientific literature  Only under care of M.D. (Rx Only) MEDICAL FOOD

50 13 Studies / 741 Patients 2 Studies No Short-Term Pain Reduction 1 Study Vibration Detection Improved Higher Doses Improved Paresthesias, Pain, Temperature, Vibration, Numbness Still Limited Data ANG, C.D., ALVIAR, M.J.M., DANS, A.L., BAUTISTA-VELEZ, G.G.P., ET AL COCHRANE DATABASE OF SYSTEMATIC REVIEWS ISSUE 3, ARTICLE #CD004573, 2008 Vitamin B for Peripheral Neuropathy: Cochrane Database

51 L-methylfolate Active form of folate necessary for neural function Works with MethylB 12 to activate protein, DNA / RNA synthesis Increase nitric oxide synthesis Methylcobalamin Neurologically active form of B 12 Methyl donor in DNA metabolism, Up-regulate gene transcription for peripheral nerve repair & regeneration Enhance protein metabolism in Schwann Cells Pyridoxal 5’-phosphate Active form of B 6, Necessary for neural function May inhibit effects of advanced glycation endproducts L-Methylfolate2.8mg Methylcobalamin 2mg Pyridoxal 5’ –phosphate 25mg METANX ®

52 Subjective VAS Study as isolated therapy Subjective VAS study combined with palliative agent Quantitative Sensory Testing Intraepidermal Nerve Fiber Density Testing L-methylfolate, Me-Cbl, P-5-P: Correlative Data

53 Orally Administered L-methylfolate, Me-Cbl, and P-5-P Reduces DPNP Results from a 20 week, randomized, controlled study of 97 patients to evaluate Metanx in patients with DPNP. The average absolute pain reduction after 20 weeks in the study group was 1.73 compared to.44 in the active group (p<0.008) Compared to baseline, after 10 weeks the study group demonstrated a reduction in VAS of 32.92% compared to the active control group of 11.57% reduction in VAS (P<0.01) Compared to baseline, after 20 weeks the study group demonstrated a reduction in VAS of 35.28% compared to the active control group of 11.73% reduction in VAS (P<0.01) Jacobs AM. NCVH Oral Presentations 2008.

54 L-Methylfolate, Me-Cbl, and P-5-P Supplementation to Pregabalin Partial-Responders for Management of DPNP Results from a 20 week, open trial of 24 patients to evaluate Metanx. The average absolute pain reduction after 20 weeks in the study group was 3.0 compared to.25 in the active control group (p<0.001) After 20 weeks, the study group experienced greater pain relief compared to the active control group, 87.5% vs. 25.0% reduction in NPS respectively (p=0.005) Jacobs AM. NCVH Oral Presentations 2008.

55 RESTORATION OF CUTANEOUS SENSORUM 16 consecutive DPN patients with established sensory loss were quantified utilizing the PSSD. Study outcomes were measured at baseline, 6 months and 1 year after L-methylfolate, Me-Cbl, P-5-P for all 8 measurements. Eight Outcome Measurements: FootMedial HeelGreat Toe Pulp Left / Right1 & 2 point static touch Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

56 Restoration of Cutaneous Sensorum Baseline, 6 month, & 1 year follow up Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

57 11 patients symptomatic DPN patients Baseline / 6 month skin biopsies (n=22) Metanx B.I.D. for 6 months demonstrated 97% ↑ ENFD The Pharmacological Management of Diabetic Small Fiber Neuropathy Utilizing Metanx as a Neurotrophic Agent Epidermal Nerve Fiber Density ENFD/mm P=0.004 Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

58 Baseline6 months Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC Clinical Case Outcome I

59 Baseline6 Months Clinical Case Outcome II Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC

60 New Therapeutic Approaches to Diabetic Neuropathy Treatments to Improve Nerve Hypoxia ACE inhibitorsEffective VEGF geneUnder Study VEGF zinc finger proteinUnder Study RuboxistaurinUnder Study BenfotiamineUnder Study PyridoxamineUnder Study

61 Identification Statement Metanx is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy The distinct nutritional requirements of patients with endothelial dysfunction: who present with loss of protective sensation and neuropathic pain associated with diabetic peripheral neuropathy. Dosage 1 tablet twice daily Metanx Indication and Dosage

62 Ongoing Clinical Trial Effects of L-methylfolate, Me-Cbl, P5P in Subjects with DPN Randomized, Double-Blind, Placebo-controlled trial studying 216 patients with definite sensorimotor DPN Primary End Point » To determine if Metanx improves VPT in DPN patients Principle Investigators » Vivian Fonseca, MD - Tulane Medical » Julio Rosenstock, MD – Dallas Diabetes and Endocrine Center » Lawrence Lavery, DPM –Texas A&M University Health Sciences Center » Cyrus Desouza, MD – Omaha VA Medical Center » Douglas Denham, MD – DgD Research, Inc. » Fernando Ovalle, MD – University of Alabama School of Medicine Expected Completion Date: February 2010

63 SUMMARY Most Patients with DPN experience Loss of Protective Sensation Etiology of DPN may primarily be microvascular insufficiency Treatment should be based upon individual patient factors Need to focus on disease modifying agents to manipulate underlying pathophysiology of DPN

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