Silence of the Limbs

Bruce Trippe, M.D., F.A.C.E.

Montgomery, AL

“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

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

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

Pathogenesis of Diabetic Neuropathy

~ 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 15 2007;40(No.14):1, 20.

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 26:1790-1795, 2003

Impact of Diabetic Neuropathy

Reiber GE. Diab. Med 13 (SUPPL 1) 1996 Pecoraro RE, Reiber GE, Burgess EM. Diabetes Care 13, 1990

Clinical Unmet Needs in DPN

Improved efficacy Improved side effect profile Reduced time to onset of action Fewer drug-drug interactions Reduced pill burden

• There are a wide range of treatments available for neuropathic pain

Increasing level of importance

• 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

Diabetic Neuropathy:

The Forgotten Complication

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.

May 10, 2005 /PR Newswire via COMTEX

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

SYMPTOMS

• Numbness, loss of feeling, prickling, tingling • Aching pain • Burning pain • Lancinating pain • Unusual sensitivity or tenderness when feet are touched (allodynia) Boulton AJ, et al. Diabetes Care. 2005;28(4):956-962.

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.

Neuropathic Symptoms and Quality of Life

• 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 The National Initiative on Pain Control, 2002 Vileikyte et al, Diabetes Care 2005

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

Clinical Impact of Positive and Negative DPN Symptoms

DPN Painful Neuropathy Quality of Life

Boulton A. NCVH. Oral Presentations 2007.

Impairment Disability Handicap Sensory Loss Foot Ulcers Infection (skin, bone) Mortality Cost Charcot Foot Surgery, Amputation

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

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

•

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.

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.

• • • • • • •

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 2008. Diabetologia.

DIABETES

Hyperglycemia  DAG  PKC  Triglycerides  LDL 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

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.

Pathophysiology

HYPERGLYCEMIA

Microvascular Ischemia Loss of Neurotrophic Support

Oxidative Stress

Immune Mechanisms Polyol Pathway Altered Protein Synthesis

Diabetes and Endothelial Dysfunction

• Endothelium: a biologically active organ • Deranged nitric oxide pathways • Multifactorial    Hyperglycemia Insulin resistance FFA production / metabolism

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

Predictors of Foot Ulceration

Variable No Ulcer (127) Ulcer (53) p-value

NSS NDS VPT (volts) SWMF NP Pedal Pulse STJ mobility 1 st MTP mobility Forefoot PP Rearfoot PP 2.1 + 2.4

13 + 8 38 + 15 5.90+1.20

28 (22%) 22 + 7 71 +18 6.6 + 2.8

3.1 + 1.5

2.7 + 2.8

18 + 5 46 + 6 6.63+0.74

20 (38%) 22 + 11 61 + 20 8.2 + 4.3

3.4 + 1.8

0.297

0.0001

0.0001

0.0001

0.035

0.784

0.002

0.005

0.37

Rich, Veves,Wounds,2000;12:82-87

Proximal Neuropathies

Pascoe et al, Mayo Clin Proc,1997;72:1123-1132

Autonomic Neuropathy

• • • • • • • Heart rate abnormalities Postural hypotension Abnormal sweating Gastroparesis Neuropathic diarrhea Impotence Retrograde ejaculation

Sensorimotor Neuropathy

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

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

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.

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

Neuropathic Pain: Pharmacologic Therapies

• Gabapentin, carbamazepine, lamotrigine, and newerAEDs • Antidepressants • Opiod analgesics • Lidocaine (transdermal, intravenous [IV]), mexiletine • Alpha-2 adrenergic agonists

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

Diabetic Neuropathy: Current Treatments

• 25% NO TREATMENT • 53.9% OPIOIDS • 39.7% NSAIDS

Only Target Positive (Painful)

• 21.1% SSRI’s

Symptoms

• 11.3% TCA’s • 11.1% ANTICONVULSANTS Berger A, Dukes EM, Oster G; J. Pain 5; 2004

Current Palliative Treatments

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

Symptomatic Palliative DPNP Therapies

FDA Approved Drugs for the Treatment of DPNP



Pregabalin (Lyrica®)



Duloxetine (Cymbalta®)

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.

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;10:183-188.

Pregabalin Effect on Mean Weekly pain Scores in Painful DPN

Rosenstock et al. Pain 2004; 110:628-638.

Pregabalin: Percentage of Patients with > 50% Reduction in Pain in Painful DPN*

Rosenstock et al. Pain 2004; 110:628-638.

Duloxetine

• • • • •

InsideCymbalta.com

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 .

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

Duloxetine Proposed MOA

Duloxetine Phase 2

Duloxetine Phase 2

Goldstein et al. PAIN 2005

Anticonvulsant Drugs

• • • Carbamazepine Phenytoin Valporate • • • • Gabapentin Topiramate Lamotrigine Felbamate 600mg/day 300mg/day 15-60mg/kg/day 900-1800mg/day 50-400mg/day 300-500mg/day 1200-3600mg/day

New Therapeutic Approaches to Diabetic Neuropathy

• Aldose reductase inhibitors • Anti-oxidants (a-lipoic acid) • Nerve growth factors • Gamma linolenic acid Ineffective Effective Ineffective Ineffective

Potential Disease State Modifying Therapies

•

Control Diabetes (blood sugar)

•

Alpha Lipoic Acid

•

L-Methylfolate, Me-Cbl, P-5-P (Metanx®)

MEDICAL FOOD

 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)

Vitamin B for Peripheral Neuropathy: Cochrane Database • • • • • 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

METANX

®

L-Methylfolate Methylcobalamin 2.8mg

2mg Pyridoxal 5’ –phosphate 25mg

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-methylfolate, Me-Cbl, P-5-P:

Correlative Data

• • • • Subjective VAS Study as isolated therapy Subjective VAS study combined with palliative agent Quantitative Sensory Testing Intraepidermal Nerve Fiber Density Testing

0 -0,2 -0,4 -0,6 -0,8 -1 -1,2 -1,4 -1,6 -1,8 -2 0 Orally Administered L-methylfolate, Me Cbl, and P-5-P Reduces DPNP

Mean Pain Reduction From Baseline

* p <0.01

10 • Results from a 20 week, randomized, controlled study of 97 patients to evaluate Metanx in patients with DPNP.

** p = 0.008

Acetaminophen L-methylfolate, Me Cbl, P-5-P •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) 20

Weeks

* L-methylfolate,Me-Cbl, P-5-P vs. Acetaminophen at 10 weeks ** L-methylfolate, Me-Cbl, P-5-P vs. Acetaminophen at 20 weeks Jacobs AM. NCVH Oral Presentations 2008.

0 -0,5 -1 -1,5 -2 -2,5 -3 -3,5 0

L-Methylfolate, Me-Cbl, and P-5-P Supplementation to Pregabalin Partial-Responders for Management of DPNP

Mean Pain Reduction from Baseline Weeks

P<0.001

20 Pregabalin L-methylfolate, Me Cbl, P-5-P/Pregabalin •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.

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: Foot

Left / Right

Medial Heel

1 & 2 point static touch

Great Toe Pulp

1 & 2 point static touch Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

Restoration of Cutaneous Sensorum Baseline, 6 month, & 1 year follow up

Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

The Pharmacological Management of Diabetic Small Fiber Neuropathy Utilizing Metanx as a Neurotrophic Agent

Epidermal Nerve Fiber Density

P=0.004

• 11 patients symptomatic DPN patients • Baseline / 6 month skin biopsies (n=22) • Metanx B.I.D. for 6 months demonstrated 97% ↑ ENFD Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

Baseline

Clinical Case Outcome I

6 months Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC

Clinical Case Outcome II

Baseline 6 Months Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC

New Therapeutic Approaches to Diabetic Neuropathy

Treatments to Improve Nerve Hypoxia

• • • • • • ACE inhibitors VEGF gene VEGF zinc finger protein Ruboxistaurin Benfotiamine Pyridoxamine Effective Under Study Under Study Under Study Under Study Under Study

Metanx Indication and Dosage

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

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

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