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
~ 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 LARGEST NUMBER OF DIABETES RELATED HOSPITAL BED-DAYS 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 Reiber GE. Diab. Med 13 (SUPPL 1) 1996
Improved efficacy Improved side effect profile Increasing level of importance 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
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 • Boulton AJ, et al. Diabetes Care. 2005;28(4):956-962. • SYMPTOMS • Numbness, loss of feeling, prickling, • tingling • Aching pain • Burning pain • Lancinating pain • Unusual sensitivity or tenderness • when feet are touched (allodynia)
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 Impairment Disability Handicap Sensory Loss Mortality Foot Ulcers Cost Quality of Life Infection (skin, bone) Charcot Foot Surgery, Amputation Boulton A. NCVH. Oral Presentations 2007.
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 Impaired n-6 fatty acid metabolism Polyol pathway Sugar autoxidation Advanced glycation Triglycerides LDL 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, B6, and B12 deficient Vinik A. The Amer. Journal of Med. August 1999.
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 2.1 + 2.4 2.7 + 2.8 0.297 NDS 13 + 8 18 + 5 0.0001 VPT (volts) 38 + 15 46 + 6 0.0001 SWMF 5.90+1.20 6.63+0.74 0.0001 NP Pedal Pulse 28 (22%) 20 (38%) 0.035 STJ mobility 22 + 7 22 + 11 0.784 1st MTP mobility 71 +18 61 + 20 0.002 Forefoot PP 6.6 + 2.8 8.2 + 4.3 0.005 Rearfoot PP 3.1 + 1.5 3.4 + 1.8 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 • 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
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
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 α2-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 Phase 2 Goldstein et al. PAIN 2005
Anticonvulsant Drugs • Carbamazepine 600mg/day • Phenytoin 300mg/day • Valporate 15-60mg/kg/day • Gabapentin 900-1800mg/day • Topiramate 50-400mg/day • Lamotrigine 300-500mg/day • Felbamate 1200-3600mg/day
New Therapeutic Approaches to Diabetic Neuropathy • Aldose reductase inhibitors Ineffective • Anti-oxidants (a-lipoic acid) Effective • Nerve growth factors Ineffective • Gamma linolenic acid Ineffective
Potential Disease State Modifying Therapies • Control Diabetes (blood sugar) • Alpha Lipoic Acid • L-Methylfolate, Me-Cbl, P-5-P (Metanx®)
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
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