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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 Diabetic peripheral neuropathy (DPN) is a diffuse disease and represents a broad term for the many kinds of nerve damage that often accompany diabetes mellitus. The consensus definition includes the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes

5 Pathogenesis of Diabetic Neuropathy

6 ~ 66% Diabetic Neuropathy
We know that diabetes has reached epidemic proportions with over 20 million people in the United States afflicted by this disease. Despite significant advances in technology and medications, the incidence of diabetes has worsened. (Pie Chart) Over the last 6 years, nearly half of patients with diabetes failed to reach national treatment goals as of December 2006. An analysis of 22.7 million HBA1C tests performed on 4.8 million patients with Diabetes revealed that as of December 2006, 55% of patients had reached the ADA treatment target of HBA1C levels less than 7%. We also know that people are being diagnosed with diabetes earlier in life and the #1 predictor of diabetes inflicted complications is duration of the disease. (Pie Chart) One of the most common complications of diabetes is peripheral nerve damage. Peripheral neuropathy affects approximately 66% of people with diabetes. 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. The impact of diabetic neuropathy is overwhelming. The predominant feature of DPN is sensory loss. Sensory loss is the number one predictor of foot ulceration and non-traumatic amputations in the United States. The cost of diabetes and the complications of neuropathy to the healthcare system are staggering and as previously mentioned diabetes is getting worse not better. Gordois et al. Diabetes Care 26: , 2003

8 Impact of Diabetic Neuropathy
LARGEST NUMBER OF DIABETES RELATED HOSPITAL BED-DAYS Most Common Proximate, Nontraumatic Cause of Amputations Of all the problems that diabetes patients have: stroke, heart attack, renal disease etc. Foot infections are the #1 reason for hospitilization (graphic). As a result of the numbness associated with neuropathy, this ends up happening (picture of amputated foot): DPN is much more than just “my feet are numb” or “my feet tingle”. You have to think to yourself-if you can control the glucose and treat the underlying pathology, then maybe this patient would have felt the problem before it got to this point. As previously mentioned most non-traumatic lower extremity ulcerations in the United States are preceded by diabetes induced neuropathy and ulceration. We have to begin thinking about how we can prevent this type of outcome resulting from diabetes. 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

9 Improved side effect profile
Clinical Unmet Needs in DPN Increasing level of importance 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 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. There are a wide range of treatments available neuropathic pain This prescribing pattern suggests that there is no one treatment that addresses all the factors. Some treatments have specific indications and some are off-label Datamonitor Research 2008

10 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. Results from the 2005 American Diabetes Association National Survey uncovered that: DPN is under diagnosed. Only 1 in 4 people surveyed have been diagnosed with diabetes induced nerve damage The majority of individuals experiencing symptoms are not acutely aware of the term DPN diabetic neuropathy Only 42% of respondents have been told that diabetes is the cause of their symptoms Clearly we have to do a better job at communicating with our patients regarding the various complications associated with diabetes, including peripheral neuropathy 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 •Along with the range of positive symptoms of neuropathic pain, loss of motor, sensory, or autonomic neuronal function (negative symptoms) may occur. •The nature of the symptoms depends on the functional system that has been affected. Spontaneous pain is the most frequent symptom of all painful neuropathies and presents with a burning quality, localized superficially, or an electric-shocklike pain for several seconds. •Although the terms have been used somewhat interchangeably, the International Association for the Study of Pain has defined dysesthesias as abnormal sensations that are unpleasant and paresthesias as abnormal sensations that are not unpleasant. Baron R. Clin J Pain. 2000;16(2 suppl):S12-S20.

13 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 Neuropathic symptoms affect simple everyday activities and significantly impacts the quality of life in a negative way. Obviously, quality of life is different for everyone and leads to other disease states such as anxiety and depression. As a result, the cost associated with treating these patients continues to increase. The National Initiative on Pain Control, Vileikyte et al, Diabetes Care 2005

14 Diabetic Neuropathy: Symptoms
Majority of symptomatic DPN patients are insensate Almost half of diabetics with neuropathy don’t even know they have it. The majority of diabetics with neuropathy have significant sensory loss which is a real problem. LOPS is the #1 predictor of lower extremity ulceration and amputation. A very small percentage of diabetics with neuropathy actually experience painful symptoms and an even smaller percentage of these patients receive treatment. 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 Cost DPN Painful Neuropathy Impairment Disability Handicap Sensory Loss Quality of Life Foot Ulcers Infection (skin, bone) Charcot Foot 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” Perform a comprehensive foot examination annually on patients with diabetes to identify risk factors predictive of ulcers and amputations. Perform a visual inspection of patients’ feet at each routine visit How many physicians actually perform yearly foot examinations. Specifically, how many primary care physicians are conducting this exam? If a patient is diabetic, they should be taking their shoes and socks off in the exam room. The earlier we can detect foot problems, the earlier we can treat the problem. As we have already mentioned, it isn’t the pain that is leading to ulceration, infection and amputation, it’s the SENSORY LOSS. 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  NCV, Regeneration, Structural damage
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 It looks a little more complicated, but the common final path in neuropathy may be endothelial dysfunction. And this is caused by several things including insulin resistance, including these metabolic abnormalities advanced glycation end products. But then this results in reduced capillary blood flow, nerve hypoxia and nerve dysfunction. So this seems to show that endothelial dysfunction seems to have primacy in diabetic neuropathy. In HIV treated patients, because of the drugs, they also have endothelial dysfunction and they have neuropathy that is clinically identical to diabetes, so it is sort of a proof of concept in what we are talking about. We are getting away from the blood sugar as a primary cause into a cardiovascular cause.

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, B6, and B12 deficient Other factors that may be involved in the etiology of Diabetic Neuropathy include: Oxidative Stress – Free radicals produced from advanced glycation end products may lead to damaged neurons. Oxidative stress can be relieved by improving blood flow to the nerve. Sorbitol Concentration – many patients with DPN have an excess accumulation of sorbitol within the nerve itself which causes it to absorb water and swell and it becomes problematic Myoinositol Depletion – Myoinositol is a substance that you find in nerves that helps nerves to conduct electricity. The potassium, sodium and calcium that cross nerve membranes is regulated in part by myoinositol. Neuropathic patients have less myoinositol compared to patients without neuropathy Neurotrophic Factors – neurotrophic factors play an important role in the development, maintenance, and survival of neuronal tissues. Diabetic nerves tend to lack neurotrophic factors. Many times these factors can be folate, B6 and B12 and we know that replacing these agents can be helpful in restoring function to those nerves 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 This is how we used to think of this disease, the pathophysiology. Stemming from hyperglycemia, where glucose is metabolized by the Polyol Pathway which includes Aldose Reductase, an enzyme that converts it to a non-metabolizable sorbitol. There is also nerve ischemia from microvascular disease. This increases oxidative stress in the nerve, loss of neurotrophic support, immune stimulation, altered protein synthesis. Sorbitol also depleted myoinositol from the membrain. All quite complex theories in the pathophysiology all stemming from hypergl ycemia.

24 Endothelial Dysfunction
Diabetes and Endothelial Dysfunction Endothelium: a biologically active organ Deranged nitric oxide pathways Multifactorial Hyperglycemia Insulin resistance FFA production / metabolism Endothelial dysfunction is important and is recognized that the endothelium is biologically active. The blood vessels are in line with grass (??), they are quite dynamic and in type 2 diabetes, the deranged nitric oxide pathways. This is multifactorial for Hyperglycemia but also for Insulin resistance and from abnormal free fatty acids production and metabolism. Those of you who do research looking at animal models and diabetes, the models should include more than just hyperglycemia. There is a lot more going on in diabetes than just hyperglycemia.

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 The ADA recently had an expert consensus to classify and treat neuropathies and generally have generalized symmetric neuropathies in diabetes and then they have focal and multifocal neuropathies. We will mostly be talking about chronic sensorimotor under generalized. This is the one that gets our patients into the most trouble. There is also autonomic, and then the cranial, truncal, proximal neuropathy which used to be called amyotrophy. There is also co-existing chronic (enzymatory Demylinating polyneuropathies ??) 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%) (38%) STJ mobility 1st MTP mobility Forefoot PP Rearfoot PP This is a paper by Dr. Veves and looking at predictors of foot ulceration, we have a neuropathy disability score, the vibratory perception threshold and the Semmes Weinstein monofilament, all pretty much came in as a tie. A nice trifector there. So, any of those modalities can make the diagnosis. Rich, Veves,Wounds,2000;12:82-87

27 Proximal Neuropathies
Phil Lowe at the Mayo Clinic has done the most work in proximal neuropathies. This is a heterogeneous group that present with weakness, but not very common. It could be amyotrophy, which is associated with severe weakness and weight loss. It is also associated with initiation of (something therapy??), chronic inflammatory demyelinating polyneuropathies seen in this group. The key here is that they are demyelinating. Diabetes itself is usually just axonal, (it’s not demyelinating??). And then you have the diabetic proximal neuropathies which are also uncommon and a little bit different to characterize. Pascoe et al, Mayo Clin Proc,1997;72:

28 Autonomic Neuropathy Heart rate abnormalities Postural hypotension
Abnormal sweating Gastroparesis Neuropathic diarrhea Impotence Retrograde ejaculation Autonomic neuropathic is the largest underappreciated area in this field of neuropathy. You get abnormal sweating, this affects the feet by the way, less sweat, which results in drier skin, impotence we know quite well and heart rate abnormalities.

29 Sensorimotor Neuropathy
Most common type of diabetic neuropathy Affects 30-50% of all diabetic population Most commonly involved in diabetic foot problems Sensorimotor neuropathy is most common and affects about 40% of people with diabetes.

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 The symptoms are progressive, it usually involves the longest nerves first then marches back inexorably year to year. The main symptoms are numbness, but the important symptom is loss of protective sensation.

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. It can be painful. It is in a stocking glove distribution, and characterized also by reduced reflexes and muscle atrophy. When there is motor involvement you can get foot deformities which result in increased pressure. Increased pressure in somebody with someone who cannot feel that is a bad recipe for foot ulcer.

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 The diagnosis is basically clinical, based on symptoms and signs. We do some documentation of the loss of sensation. Electrophysiology and nerve biopsies are rarely needed

33 Pharmacologic Therapies
Neuropathic Pain: Pharmacologic Therapies Gabapentin, carbamazepine, lamotrigine, and newerAEDs Antidepressants Opiod analgesics Lidocaine (transdermal, intravenous [IV]), mexiletine Alpha-2 adrenergic agonists So with neuroprotection, we are not quite there yet but have seen some interesting things. We have started a study using Metanx as a neuroprotective agent and going to use the vibratory perception threshold as the end point, that study is under way. Tulane University is one site in New Orleans, LA. For neuropathic pain, we do have some treatment options.

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 The best evidence for antidepressants are the trycyclics, amitriptyline, and it does work. There are some side effects, not safety issues but tolerability issues. The SSRI’s have not been shown to be effective but I will talk about duloxetine or Cymbalta which is not FDA approved which is the first serotonin, norepinephrine inhibitor approved for neuropathic pain. *Kunz NR et al ADA, San Antonio, 2000

35 Only Target Positive (Painful) Symptoms
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 There are various alternatives in treating the Positive symptoms of DPN. Obviously, these drug therapies have distinct side effects and we have to measure risk vs. benefit to decide on the correct therapy. Twenty-five percent of patients who present to their physicians complaining about symptomatic diabetic neuropathy receive no treatment at all. About 54% of patients who are being treated for symptomatic neuropathy are being treated with opioids. About 40% of patients receive anti-inflammatory medications, though NSAIDS have no role in the treatment of symptomatic diabetic neuropathy. Tricyclic antidepressants and anti-convulsants are the two categories of pharmaceuticals that have the most literature support for the treatment of diabetic neuropathy, but combined these are prescribed by physicians who treat symptomatic diabetic neuropathy less than there are patients who are untreated. (Graphic) The majority of these patients are on opioids which can lead to addiction. None of these therapies manipulate the underlying disease state. They simply treat the positive symptoms only 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 Treatment of diabetic neuropathy depends on the symptoms and on the patients themselves. It is best to tell patients not to expect 100% relief of symptomatic neuropathic pain. Although that is the goal of treatment, patients need to understand that to control their diabetes, they need to control a number of factors, but in general, they can expect between 30% and 50% relief of pain. Most patients with symptomatic diabetic neuropathy need two drugs to get closer to 100% improvement. The average patient spends $1,000 a year on medication for symptomatic diabetic neuropathy when taking 1 drug. The average patient in the United States spends $1,600 taking 2 drugs for the treatment of symptomatic diabetic neuropathy and as you can see, there are a number of treatments to choose from: Tricyclic antidepressants have been the standard for a long time. When using these, it is important to get a baseline EKG and they are probably not a good treatment for certain types of patients, such as patients with glaucoma. Patients also need to be warned about weight gain, fluid retention, and anti-cholinergic side effects. Amitriptyline is the most effective of the tricyclics, however, it also has the highest side effect profile. Duloxetine HCl (Eli Lilly and Company, Indianapolis, IN) cannot be used in patients with any kind of significant hepatic disease at all. Duloxetine HCl is a selective serotonin, norepinephrine inhibitor, used for treating depression, plus it is FDA-approved for treating symptomatic diabetic neuropathy. It has less side effects than the tricyclic antidepressants, but it is also less effective than the tricyclic antidepressants in head-to-head evaluations. Pregabalin Pfizer, New York, NY) is the newest, FDA-approved agent in its class. Generally, start patients at 50 mg 3 times a day or 75 mg twice a day for 1 to 2 weeks. It has a rapid onset of action and if the patients are doing well, 100 mg 3 times a day seems to be an adequate dose. Tramadol TCA Gabapentin Pregabalin Duloxetine Chen H, Lamer TH, Rho RH et al. Mayo Clin Proceed. 79; 2004

37 Symptomatic Palliative DPNP Therapies
FDA Approved Drugs for the Treatment of DPNP Pregabalin (Lyrica®) Duloxetine (Cymbalta®) FDA has approved 2 drugs for neuropathic pain, one is duloxetine known as Cymbalta and the other is pregabalin which is known as Lyrica.

Fibromyalgia Post herpetic neuralgia Adjunctive seizure medication DOSAGE Start at 50mg tid and may increase to 100mg tid within one week 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
It works on the alpha 2 delta subunit of the calcium channels. It seems to only work on excited nerves, so the alpha 2 delta subunit is (over expressed??) in what they call excited nerves, hyper-excited neurons, so it seems to be a membrane stabilizer and that is probably how it reduces neurotransmitter release and helps with pain. 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:

40 Pregabalin Effect on Mean Weekly pain Scores in Painful DPN
A pain score from 6 to 4, an almost identical profile. Rosenstock et al. Pain 2004; 110:

41 Pregabalin: Percentage of Patients with >
50% Reduction in Pain in Painful DPN* Those who had a greater than 50% reduction was over 40%, nobody gets 100%, so don’t have that expectation for yourself or your patients. But it is a good 50%, they can sleep at night. 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. 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 This is duloxetine phase 2 trial, improving pain by as many as 3 points on the scale.

45 Duloxetine Phase 2 This is the average dose of opiates required so you can see the patients with a higher dosage of duloxetine required less other analgesics. Goldstein et al. PAIN 2005

46 Anticonvulsant Drugs Carbamazepine 600mg/day Phenytoin 300mg/day
Valporate mg/kg/day Gabapentin mg/day Topiramate mg/day Lamotrigine mg/day Felbamate mg/day Anticonvulsant drugs probably work as a class although right now it is only pregabalin that’s approved. Carbamazepine, known as tegretol, was used a lot back in the day, clinically this seems to help especially with this lancenating electric shock kind of pain. There is some literature on topiramate (Tompamax) and lamotrigine (Lamictal???).

47 New Therapeutic Approaches to
Diabetic Neuropathy Aldose reductase inhibitors Ineffective Anti-oxidants (a-lipoic acid) Effective Nerve growth factors Ineffective Gamma linolenic acid Ineffective Aldose reductase inhibitors are ineffective, some use alpha lipoic acid. Mostly studies have been negative, a few have suggested an improvement. It’s not harmful and not a bad thing for patients to try, they can get it at a health store. Nerve growth factor, major study from (???), the placebo did better than the treated group. Gamma linolenic acid has also shown to be ineffective.

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

49 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)

50 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

51 METANX® L-methylfolate Methylcobalamin Pyridoxal 5’-phosphate
L-Methylfolate 2.8mg Methylcobalamin mg Pyridoxal 5’ –phosphate mg METANX® L-methylfolate Active form of folate necessary for neural function Works with MethylB12 to activate protein, DNA / RNA synthesis Increase nitric oxide synthesis Methylcobalamin Neurologically active form of B12 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 B6, Necessary for neural function May inhibit effects of advanced glycation endproducts B12 as a methyldonor in DNA metabolism, up-regulate gene transcription which may in turn increase protein synthesis for nerve regeneration

52 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

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 VAS of 35.28% compared to the active control group of 11.73% reduction in VAS 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) Objective Determine the effects of L-methylfolate, Me-Cbl, and P-5-P on burning paresthesias in patients with DPNP who had obtained partial symptoms resolution with pregabalin. Methodology 24 consecutive patients who received pregabalin > 4 months with partial (<50% NPS reduction) resolution of paresthesias were enrolled. Study group (n=16) continued the pretrial pregabalin dose to which oral L-methylfolate, Me-Cbl, and P-5-P was added twice daily. Control group (n=8) maintained pregabalin therapy. A numeric pain scale (0-10) was evaluated at baseline and 20 weeks. Jacobs AM. NCVH Oral Presentations 2008.

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 Medial Heel Great Toe Pulp Left / Right 1 & 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 The Pharmacological Management of Diabetic Small Fiber Neuropathy Utilizing Metanx as a Neurotrophic Agent Epidermal Nerve Fiber Density ENFD/mm 11 patients symptomatic DPN patients Baseline / 6 month skin biopsies (n=22) Metanx B.I.D. for 6 months demonstrated 97% ↑ ENFD P=0.004 82% of study participants experienced reduced frequency and intensity of paresthesias and dysesthesias with Metanx Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

58 Clinical Case Outcome I
Baseline 6 months Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC

59 Clinical Case Outcome II
Baseline 6 Months Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC

60 New Therapeutic Approaches to Diabetic Neuropathy
Treatments to Improve Nerve Hypoxia ACE inhibitors Effective VEGF gene Under Study VEGF zinc finger protein Under Study Ruboxistaurin Under Study Benfotiamine Under Study Pyridoxamine Under Study ACE inhibitors have been shown to be effective in one trial. This supports the idea that if we can improve endothelial function and nerve flow, that it would be effective. Couple of early stuff, phase I on VEGF gene and VEGF zinc finger protein to try to stimulate angiogenesis to the nerve. In animal studies preclinical's, it has worked as a neuroprotective effect. Ruboxistaurin is a protein (???) data isoform inhibitor, this is Lily’s drug, did not seem to be effective and is no longer in trial. Benfotiamine also improves endothelial function, it’s a (thinine???) derivative, it seems to help with complications in diabetes in general, in an animal study, it did show to be effective. Pyridoxamine is a B6 (analog???), it prevents the formation of advanced glycation end products and has also shown to be effective in an animal model. Metanx is a medical food…(starts talking about how Pamlab is the sponsor of this symposium…)

61 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

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 Most patients with peripheral neuropathy experience numbness NOT Pain. It’s the loss of sensation that leads to further complications such as lower-extremity ulcerations and amputations. Most therapies that target neuropathy simply treat the acute pain in an effort to improve quality of life which is important. We need to look for therapies to address the underlying pathology of neuropathy.

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