Presentation on theme: "Silence of the Limbs Bruce Trippe, M.D., F.A.C.E. Montgomery, AL."— Presentation transcript:
1Silence of the LimbsBruce 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
3Presentation Objectives Understand the economic and social impact of diabeticperipheral neuropathyDistinguish between positive and negative symptoms ofdiabetic peripheral neuropathyDescribe remittive vs. palliative therapy in the managementof diabetic peripheral neuropathyUnderstand the potential mechanism of action of diabeticperipheral neuropathy prescribed therapies
4Diabetic Peripheral Neuropathy: What is it?Nerve damage and dysfunction secondary todiabetes mellitus type 1 or 2Consensus definition: “the presence of symptoms and/or signs ofperipheral nerve dysfunction in people with diabetes afterexclusion of other causes”A leading cause of neuropathic painA very common complication of diabetesDiabetic 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
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; 2004Boulton AJM, Mailik RA, ArezzoJC, Sosenko JM. Diab.Care 27, 2004Wendling Patrice. 45% of Diabetic Patients Not Reaching HbA1C Target. Internal Medicine News. July ;40(No.14):1, 20.
7Impact of Diabetic Neuropathy 15% of diabetics will developan ulcer.One in six of those with ulcerswill have an amputation.Half of those will have an ulceron the opposite foot withinthree 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
8Impact of Diabetic Neuropathy LARGEST NUMBER OF DIABETES RELATED HOSPITAL BED-DAYSMost Common Proximate, Nontraumatic Cause of AmputationsOf 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, 1999Pecoraro RE, Reiber GE, Burgess EM. Diabetes Care 13, 1990Reiber GE. Diab. Med 13 (SUPPL 1) 1996
9Improved side effect profile Clinical Unmet Needs in DPNIncreasing level of importanceImproved efficacyImproved side effect profileReduced time to onset of actionFewer drug-drug interactionsReduced pill burdenThere are a wide range oftreatments available forneuropathic painThis prescribing pattern suggeststhat there is no one treatment thataddresses all the factors.Despite a spectrum of drugsavailable with different modes ofaction, may patients remaininadequately treated in severalaspects of the disease.There are a wide range of treatments available neuropathic painThis prescribing pattern suggests that there is no one treatment that addresses all the factors.Some treatments have specific indications and some are off-labelDatamonitor Research 2008
10Diabetic Neuropathy: The Forgotten Complication Results of the 2005 ADA National SurveyOnly one in four survey respondents who experience symptoms of diabeticneuropathy have been diagnosed with the condition.The majority of respondents who experience symptoms (56%) remainunaware of the term diabetic neuropathy.62% believe that their symptoms are associated with their diabetes, butonly 42% have been told by their physician that diabetes is the cause.Approximately one in seven people who said they talked to their doctorabout 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 damageThe majority of individuals experiencing symptoms are not acutely aware of the term DPN diabetic neuropathyOnly 42% of respondents have been told that diabetes is the cause of their symptomsClearly we have to do a better job at communicating with our patients regarding the various complications associated with diabetes, including peripheral neuropathyMay 10, 2005 /PR Newswire via COMTEX
11Signs and Symptoms of Diabetic Peripheral Neuropathy Distal symmetrical sensorimotor polyneuropathyis the most common form of DPN. Signs and symptomsmay progress from distal to proximal over time.SIGNSDiminished vibratory perceptionDecreased knee and ankle reflexesReduced protective sensation, such aspressure, hot and cold, painDiminished ability to sense position oftoes and feetBoulton AJ, et al. Diabetes Care. 2005;28(4):SYMPTOMSNumbness, loss of feeling, prickling,tinglingAching painBurning painLancinating painUnusual sensitivity or tendernesswhen feet are touched (allodynia)
12DPN Produces Positive and Negative Symptoms Positive SymptomsSpontaneous PainDysesthesiasC-FibersUnpleasantParasthesiasA-FibersNot UnpleasantNegative SymptomsLoss/impairment of sensory qualityNumbnessDry skinErectile dysfunctionIncontinenceGait 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.
13Neuropathic Symptoms and Quality of LifePositive and negative symptoms have an impact on functioning, activities of daily living (ADL) and QOLQOL is an unique, individual experience – how persons perceive and react to their health statusPsychosocial MorbidityDepressionAnxietyAngerLoss of Self-EsteemSocietal ConsequencesSocial isolationStrained relationships with family and friendsEffects upon intimacy/sexual activityNeuropathic 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
14Diabetic Neuropathy: Symptoms Majority of symptomatic DPN patients are insensateAlmost 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, 2004M. Clin. Diab. 23, 2005
15Clinical Impact of Positive and Negative DPN SymptomsMortalityCostDPNPainfulNeuropathyImpairmentDisabilityHandicapSensory LossQuality ofLifeFoot UlcersInfection(skin, bone)CharcotFootSurgery,AmputationBoulton A. NCVH. Oral Presentations 2007.
16ADA 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 visitHow 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
17Diagnostic Tests for DPNP NCS/EMGMeasures the speed and amplitude of sensory and motor conductionObjective, parametric, non-invasiveInsensitive in acute and small-fiber neuropathy> 50% False Negative for Tarsal Tunnel SyndromeQSTDetects sensory thresholds for vibration, heat and painUseful in tracking the progression of neuropathy in large cohorts and the efficacy of treatment end points in multicenter clinical trialsSkin Biopsy (IENFD)Measures density of intraepidermal nerve fiber at various sites in the legLoss of nerve fibers is associated with increased neuropathic painAlthough the test is invasive, it requires a 3mm skin biopsy specimen and enables a direct study of small nerve fibersPathways: Perspectives in Modern Neurology and Pain Management. Vol 3. July 2007; Page 6
18Skin BiopsySensitivity 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.
19Skin BiopsyThis 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.
20Other Diagnostic Tools for Detection of DPN 5.07 Semmes-Weinstein MonofilamentBiosthesiometer®Calibrated Tuning ForkDiskcriminator for 2 Point SpacingNeurometer CPT® (A-beta,A-delta,C fibers)PSSD® (Earliest detection of pathology of A-beta skin surface/touch fibersNeuropad (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 DIABETESHyperglycemia DAGPKCImpairedn-6 fatty acidmetabolismPolyolpathwaySugarautoxidationAdvancedglycationOXIDATIVE STRESSENDOTHELIAL DYSFUNCTIONcapillary blood flow endoneurial hypoxiaNERVE DYSFUNCTION NCV, Regeneration, Structural damage TriglyceridesLDLIt 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.
22Etiology of Diabetic Neuropathy HyperglycemiaMicrovascular DiseaseOxidative StressFree radicals produced from an advanced glycation lead to damaged neuronsRelieved by improving blood flowSorbitol ConcentrationExcess sorbitol within the nerve causes it to retain water and nerve edema/compressionMyoinositol DepletionMyoinositol helps nerves conduct electricityK+, Na+, and Ca+ are regulated by MyoinositolNeurotrophic FactorsDiabetic nerves are folate, B6, and B12 deficientOther 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 problematicMyoinositol 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 neuropathyNeurotrophic 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 nervesVinik A. The Amer. Journal of Med. August 1999.
23Pathophysiology HYPERGLYCEMIA Microvascular Ischemia Polyol Pathway Oxidative StressLoss of Neurotrophic SupportImmune MechanismsAltered Protein SynthesisThis 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.
24Endothelial Dysfunction Diabetes andEndothelial DysfunctionEndothelium: a biologically active organDeranged nitric oxide pathwaysMultifactorialHyperglycemiaInsulin resistanceFFA production / metabolismEndothelial 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.
25ADA Statement Diabetic Neuropathies Classification of Neuropathies Generalized symmetric polyneuropathiesAcute sensorimotorChronic sensorimotorAutonomicFocal and multifocal neuropathiesCranialTruncalFocal limbProximal (Amyotrophy)Co-existing CIDPThe 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
26Predictors of Foot Ulceration Variable No Ulcer(127) Ulcer(53) p-valueNSSNDSVPT (volts)SWMFNP Pedal Pulse 28 (22%) (38%)STJ mobility1st MTP mobilityForefoot PPRearfoot PPThis 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
27Proximal 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:
28Autonomic Neuropathy Heart rate abnormalities Postural hypotension Abnormal sweatingGastroparesisNeuropathic diarrheaImpotenceRetrograde ejaculationAutonomic 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.
29Sensorimotor Neuropathy Most common type of diabetic neuropathyAffects 30-50% of all diabetic populationMost commonly involved in diabetic foot problemsSensorimotor neuropathy is most common and affects about 40% of people with diabetes.
30Sensorimotor Neuropathy SymptomsDevelopment progressive, initially involving more distal partsMain symptoms are numbness of the legs and feet, muscularcramps, pins and needles, shooting, deep aching and burning pain.Nocturnal exacerbation characteristic.Symptoms may be absent or present either in the early or latestagesThe 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.
31Sensorimotor Neuropathy Clinical SignsReduced or absent sensation to pain, touch, cold, hotand vibration in a stocking-glove distribution mostcommon signs of sensory neuropathy.Reduced or absent ankle reflexes, muscle weakness,small muscle atrophy and prominence of themetatarsal 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.
32Sensorimotor Neuropathy DiagnosisShould be based on:clinical symptomsclinical signsquantitative sensory testingelectrophysiologysural nerve biopsiesNot all methods necessary on a daily clinical baseSimple tests can identify the at risk patientThe 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
33Pharmacologic Therapies Neuropathic Pain:Pharmacologic TherapiesGabapentin, carbamazepine, lamotrigine,and newerAEDsAntidepressantsOpiod analgesicsLidocaine (transdermal, intravenous [IV]), mexiletineAlpha-2 adrenergic agonistsSo 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.
34Adjuvant 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 / atypicalantidepressants (e.g., paroxetine, venlafaxine*,maprotiline, bupropion, others) and these are bettertolerated yet.Duloxetine SSRI /SNRI now FDA approvedThe 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
35Only Target Positive (Painful) Symptoms Diabetic Neuropathy:Current Treatments25% NO TREATMENT53.9% OPIOIDS39.7% NSAIDS21.1% SSRI’s11.3% TCA’s11.1% ANTICONVULSANTSOnly Target Positive (Painful) SymptomsThere 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 onlyBerger A, Dukes EM, Oster G; J. Pain 5; 2004
36Current Palliative Treatments Distal NeuropathyC-fibers (dysesthesias,allodynia, burning)A-fibers (paresthesias,radiating, night cramps)Capsaicin creamClonidineLidocaineInsulin InfusionCarbamazepineLidocaineMuscle relaxantNSAID’sTreatment 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.TramadolTCAGabapentinPregabalinDuloxetineChen H, Lamer TH, Rho RH et al. Mayo Clin Proceed. 79; 2004
37Symptomatic Palliative DPNP Therapies FDA Approved Drugs for the Treatment of DPNPPregabalin (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.
38Pregabalin INDICATIONS DOSAGE SIDE EFFECTS DRUG INTERACTIONS DPNP FibromyalgiaPost herpetic neuralgiaAdjunctive seizure medicationDOSAGEStart at 50mg tid and may increase to 100mg tid within one week150mg tidPost-herpetic neuralgia200mg tidSIDE EFFECTSDizziness, drowsiness, dry mouth, edemaDRUG INTERACTIONSAlcohol and drugs that cause sedation may increase the sedative effects of those agents.No pharmacokinetic interactions have been demonstrated in vivo.
39Subunit 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 channelsModulates calcium influx in hyperexcited neuronsReduces neurotransmitter releasePharmacologic effect requires binding at this siteThe clinical significance of these observations in humans is currently unknownTaylor. CNS Drug Rev. 2004;10:
40Pregabalin 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:
41Pregabalin: 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:
42Duloxetine InsideCymbalta.com INDICATIONS Depression Generalized anxiety disorderDPNPFibromyalgiaDOSAGETreatment 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 EFFECTSDuloxetine 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 INTERACTIONSDiet drugs like Redux, Adipex, Meridia, fenfluramineMAOIs like Carbex/Eldepryl, Marplan, Nardil, and ParnateThe chemotherapy drug, Matulane (procarbazine)SSRIs like Celexa, Lexapro, Prozac, Luvox, Paxil, ZoloftSt. John's WortThioridazineTryptophanEffexor XR
44Duloxetine Phase 2This is duloxetine phase 2 trial, improving pain by as many as 3 points on the scale.
45Duloxetine Phase 2This 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
46Anticonvulsant Drugs Carbamazepine 600mg/day Phenytoin 300mg/day Valporate mg/kg/dayGabapentin mg/dayTopiramate mg/dayLamotrigine mg/dayFelbamate mg/dayAnticonvulsant 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???).
47New Therapeutic Approaches to Diabetic NeuropathyAldose reductase inhibitors IneffectiveAnti-oxidants (a-lipoic acid) EffectiveNerve growth factors IneffectiveGamma linolenic acid IneffectiveAldose 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.
49MEDICAL FOOD1988 via amendments to the Federal Food, Drug and Cosmetic Act:Active ingredient: present in / derived from a food (e.g. folate)Oral dosage formAddresses 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 literatureOnly under care of M.D. (Rx Only)
50Vitamin B for Peripheral Neuropathy: Cochrane Database 13 Studies / 741 Patients2 Studies No Short-Term Pain Reduction1 Study Vibration Detection ImprovedHigher Doses Improved Paresthesias, Pain, Temperature, Vibration, NumbnessStill Limited DataANG, C.D., ALVIAR, M.J.M., DANS, A.L., BAUTISTA-VELEZ, G.G.P., ET ALCOCHRANE DATABASE OF SYSTEMATIC REVIEWS ISSUE 3, ARTICLE #CD004573, 2008
51METANX® L-methylfolate Methylcobalamin Pyridoxal 5’-phosphate L-Methylfolate 2.8mgMethylcobalamin mgPyridoxal 5’ –phosphate mgMETANX®L-methylfolateActive form of folate necessary for neural functionWorks with MethylB12 to activate protein, DNA / RNA synthesisIncrease nitric oxide synthesisMethylcobalaminNeurologically active form of B12Methyl donor in DNA metabolism, Up-regulate gene transcription for peripheral nerve repair & regenerationEnhance protein metabolism in Schwann CellsPyridoxal 5’-phosphateActive form of B6, Necessary for neural functionMay inhibit effects of advanced glycation endproductsB12 as a methyldonor in DNA metabolism, up-regulate gene transcription which may in turn increase protein synthesis for nerve regeneration
52L-methylfolate, Me-Cbl, P-5-P: Correlative DataSubjective VAS Study as isolated therapySubjective VAS study combined with palliative agentQuantitative Sensory TestingIntraepidermal Nerve Fiber Density Testing
53Orally Administered L-methylfolate, Me-Cbl, and P-5-P Reduces DPNP Results from a 20 week, randomized,controlled study of 97 patients to evaluateMetanx in patients with DPNP.The average absolute pain reduction after20 weeks in the study group was 1.73compared to .44 in the active group(p<0.008)Compared to baseline, after 10 weeks thestudy group demonstrated a reduction inVAS of 32.92% compared to the activecontrol group of 11.57% reduction in VAS(P<0.01)Compared to baseline, after 20 weeks theVAS of 35.28% compared to the activecontrol group of 11.73% reduction in VASJacobs AM. NCVH Oral Presentations 2008.
54L-Methylfolate, Me-Cbl, and P-5-P Supplementation to Pregabalin Partial-Responders for Management of DPNPResults from a 20 week, opentrial of 24 patients to evaluateMetanx.The average absolute painreduction after 20 weeks in thestudy group was 3.0 comparedto .25 in the active controlgroup (p<0.001)After 20 weeks, the study groupexperienced greater pain reliefcompared to the active controlgroup, 87.5% vs. 25.0%reduction in NPS respectively (p=0.005)ObjectiveDetermine 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.Methodology24 consecutive patients who received pregabalin > 4 monthswith partial (<50% NPS reduction) resolution of paresthesiaswere enrolled.Study group (n=16) continued the pretrial pregabalin dose towhich 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 20weeks.Jacobs AM. NCVH Oral Presentations 2008.
55RESTORATION 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 PulpLeft / Right1 & 2 point static touchAbstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
56Restoration of Cutaneous Sensorum Baseline, 6 month, & 1 year follow up Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
57The Pharmacological Management of Diabetic Small Fiber Neuropathy Utilizing Metanx as a Neurotrophic AgentEpidermal Nerve Fiber DensityENFD/mm11 patients symptomatic DPN patientsBaseline / 6 month skin biopsies (n=22)Metanx B.I.D. for 6 months demonstrated 97% ↑ ENFDP=0.00482% of study participants experienced reduced frequency and intensity of paresthesias and dysesthesias with MetanxAbstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
58Clinical Case Outcome I Baseline6 monthsSkin Punch Biopsy Analysis and Images Performed by Therapath, LLC
59Clinical Case Outcome II Baseline6 MonthsSkin Punch Biopsy Analysis and Images Performed by Therapath, LLC
60New Therapeutic Approaches to Diabetic Neuropathy Treatments to Improve Nerve HypoxiaACE inhibitors EffectiveVEGF gene Under StudyVEGF zinc finger protein Under StudyRuboxistaurin Under StudyBenfotiamine Under StudyPyridoxamine Under StudyACE 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…)
61Metanx Indication and Dosage Identification StatementMetanx is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathyThe distinct nutritional requirements of patients with endothelial dysfunction:who present with loss of protective sensation and neuropathic pain associated with diabetic peripheral neuropathy. Dosage1 tablet twice daily
62Ongoing Clinical Trial Effects of L-methylfolate, Me-Cbl, P5P in Subjects with DPNRandomized, Double-Blind, Placebo-controlled trial studying 216 patients with definite sensorimotor DPNPrimary End PointTo determine if Metanx improves VPT in DPN patientsPrinciple InvestigatorsVivian Fonseca, MD - Tulane MedicalJulio Rosenstock, MD – Dallas Diabetes and Endocrine CenterLawrence Lavery, DPM –Texas A&M University Health Sciences CenterCyrus Desouza, MD – Omaha VA Medical CenterDouglas Denham, MD – DgD Research, Inc.Fernando Ovalle, MD – University of Alabama School of MedicineExpected Completion Date: February 2010
63SUMMARY Most Patients with DPN experience Loss of Protective Sensation Etiology of DPN may primarily be microvascular insufficiencyTreatment should be based upon individual patient factorsNeed to focus on disease modifying agents to manipulate underlying pathophysiology of DPNMost 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.