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The Pharmacological The Pharmacological Management of Diabetic Management of Diabetic Peripheral Neuropathy:Peripheral Neuropathy:
Disease Modifying vs. Disease Modifying vs. Symptomatic StrategiesSymptomatic Strategies
Presentation ObjectivesPresentation Objectives
Understand the economic and social impact of DPNUnderstand the economic and social impact of DPN
Distinguish between positive and negative symptoms Distinguish between positive and negative symptoms of diabetic peripheral neuropathyof diabetic peripheral neuropathy
Describe disease modifying vs. symptomatic strategies Describe disease modifying vs. symptomatic strategies in the management of DPNin the management of DPN
Understand the potential MOA of MetanxUnderstand the potential MOA of Metanx®® in the in the management of positive and negative DPN symptomsmanagement of positive and negative DPN symptoms
““I marvel that societyI marvel that societywould pay a surgeonwould pay a surgeona large sum of moneya large sum of moneyto remove a person’sto remove a person’sleg – but nothing toleg – but nothing tosave it.”save it.”
– – George Bernard ShawGeorge Bernard Shaw
Diabetic Peripheral Neuropathy: Diabetic Peripheral Neuropathy: What is it?What is it?
Nerve damage and dysfunction secondary to diabetes Nerve damage and dysfunction secondary to diabetes mellitus type 1 or 2mellitus type 1 or 2– Consensus definition: “the presence of symptoms Consensus definition: “the presence of symptoms
and/or signs of peripheral nerve dysfunctionand/or signs of peripheral nerve dysfunctionin people with diabetes after exclusion ofin people with diabetes after exclusion ofother causes”other causes”
A leading cause of neuropathic painA leading cause of neuropathic pain– A very common complication of diabetesA very common complication of diabetes
Tavakoli M, et al. Current Pain and Headache Reports. 2008;12:192-197.
DPN PrevalenceDPN Prevalence
Diabetic Neuropathy may occur inDiabetic Neuropathy may occur in50% to 90% of patients depending on50% to 90% of patients depending on
the criteria used for diagnosisthe criteria used for diagnosis
Impact of Diabetic NeuropathyImpact of Diabetic Neuropathy
60-70% of foot ulcers are 60-70% of foot ulcers are preceded by neuropathypreceded by neuropathy
85% of diabetes related85% of diabetes relatedlower limb amputations are lower limb amputations are preceded by a foot ulcerpreceded by a foot ulcer
3 out of 10 patients who 3 out of 10 patients who undergo lower limb undergo lower limb amputation will lose another amputation will lose another leg within 3 years and over leg within 3 years and over half of them will die within half of them will die within the first 5 years of thethe first 5 years of thefirst amputationfirst amputation
Gordois et al. Diabetes Care. 2003;26:1790-1795.Reiber G, et al. Diabetes in America. 1995; 2nd ed:409-428.
Impact of Diabetic NeuropathyImpact of Diabetic Neuropathy
Largest number of diabetesLargest number of diabetesrelated hospital bed-daysrelated hospital bed-days
Frykberg R, et al. Journ of Foot and Ankle Surgery 2006;45(5):S2-S8.
Most Common Proximate,Most Common Proximate,Nontraumatic Cause of AmputationsNontraumatic Cause of Amputations
Reiber GE, Vilekyte L, Bokyo EJ et al. Diabetes Care.1999;22.Pecoraro RE, Reiber GE, Burgess EM. Diabetes Care. 1990;13.
Clinical Unmet Needs in DPNClinical Unmet Needs in DPN
There are a wide range ofThere are a wide range oftreatments available fortreatments available forneuropathic painneuropathic pain
This prescribing pattern This prescribing pattern suggests that there is no one suggests that there is no one treatment that addressestreatment that addressesall the factorsall the factors
Despite a spectrum of drugsDespite a spectrum of drugsavailable with different modes available with different modes of action, many patients of action, many patients remain inadequately treated in remain inadequately treated in several aspects of the diseaseseveral aspects of the disease
Datamonitor Research 2008.
IncreasingIncreasinglevel oflevel ofimportanceimportance
ImprovedImprovedefficacyefficacy
Improved sideImproved sideeffect profileeffect profile
Reduced time toReduced time toonset of actiononset of action
Fewer drug-drugFewer drug-druginteractionsinteractions
Reduced pillReduced pillburdenburden
Diabetic Neuropathy: Diabetic Neuropathy: The Forgotten ComplicationThe Forgotten Complication
Only one in four survey respondents who experience symptoms Only one in four survey respondents who experience symptoms of diabetic neuropathy have been diagnosed with the condition.of diabetic neuropathy have been diagnosed with the condition.
The majority of respondents who experience symptoms (56%) The majority of respondents who experience symptoms (56%) remain unaware of the term diabetic neuropathy.remain unaware of the term diabetic neuropathy.
62% believe that their symptoms are associated with their 62% believe that their symptoms are associated with their diabetes, but only 42% have been told by their physician that diabetes, but only 42% have been told by their physician that diabetes is the cause.diabetes is the cause.
Approximately one in seven people who said they talked to their Approximately one in seven people who said they talked to their doctor about their symptoms and pain reported that no cause doctor about their symptoms and pain reported that no cause was mentioned.was mentioned.
Results of the 2005 ADA National Survey
May 10, 2005 /PR Newswire via COMTEX.
Boulton AJ, et al. Diabetes Care. 2005 April; 28(4):956-62.
Signs and Symptoms ofSigns and Symptoms ofDiabetic Peripheral NeuropathyDiabetic Peripheral Neuropathy
SignsSigns Diminished vibratory Diminished vibratory
perceptionperception Decreased knee and ankle Decreased knee and ankle
reflexesreflexes Reduced protective Reduced protective
sensation, such as pressure, sensation, such as pressure, hot and cold, painhot and cold, pain
Diminished ability to sense Diminished ability to sense position of toes and feetposition of toes and feet
SymptomsSymptoms Numbness, loss of feeling, Numbness, loss of feeling,
prickling, tinglingprickling, tingling Aching painAching pain Burning painBurning pain Lancinating painLancinating pain Unusual sensitivity or Unusual sensitivity or
tenderness when feet are tenderness when feet are touched (allodynia)touched (allodynia)
Distal symmetrical sensorimotor polyneuropathy is the mostcommon form of DPN. Signs and symptoms may progress from
distal to proximal over time.
DPN Produces Positive andDPN Produces Positive andNegative SymptomsNegative Symptoms
Positive SymptomsPositive Symptoms Spontaneous PainSpontaneous Pain
DysesthesiasDysesthesias– C-FibersC-Fibers– UnpleasantUnpleasant
ParesthesiasParesthesias– A-FibersA-Fibers– Not UnpleasantNot Unpleasant
Negative SymptomsNegative Symptoms Loss/impairment ofLoss/impairment of
sensory qualitysensory quality
NumbnessNumbness
Dry skinDry skin
Erectile dysfunctionErectile dysfunction
IncontinenceIncontinence
Gait instability and fall riskGait instability and fall risk
Baron R. Clin J Pain. 2000;16(2 suppl):S12-S20.Argoff CE, et al. Mayo Clin Proc. 2006;81(4 Suppl):S3-S11.Boulton AJ, et al. Diabetes Care. 2005;28(4):956-962.
Neuropathic Symptoms and Neuropathic Symptoms and Quality of LifeQuality of Life
Positive and negative symptoms have an impact on functioning, activities of Positive and negative symptoms have an impact on functioning, activities of daily living (ADL) and QOLdaily living (ADL) and QOL
QOL is a unique, individual experience – how persons perceive and react to QOL is a unique, individual experience – how persons perceive and react to their health statustheir health status
Psychosocial MorbidityPsychosocial Morbidity– DepressionDepression– AnxietyAnxiety– AngerAnger– Loss of Self-EsteemLoss of Self-Esteem
Societal ConsequencesSocietal Consequences– Social isolation Social isolation – Strained relationships with family and friendsStrained relationships with family and friends– Effects upon intimacy/sexual activityEffects upon intimacy/sexual activity
Argoff CE, et al. Mayo Clin Proc. 2006;81(4 Suppl):S3-S11.
Diabetic Neuropathy: SymptomsDiabetic Neuropathy: Symptoms
Majority of symptomaticMajority of symptomaticDPN patients are insensateDPN patients are insensate
Argoff CE, et al. Mayo Clin Proc. 2006;81:(S4).Boulton AJM, et al. Diabetes Care. 2004;27.
Pain
Asymptomatic
SensoryLoss
Clinical Impact of Positive and Negative Clinical Impact of Positive and Negative DPN Symptoms DPN Symptoms
DPNDPN
Boulton A. NCVH. Oral Presentations. 2007.
MortalityMortality
CostCost
ImpairmentImpairmentDisabilityDisabilityHandicapHandicap
InfectionInfection(skin, bone)(skin, bone)
Charcot Charcot FootFoot
FootFootUlcersUlcers
Painful Painful NeuropathyNeuropathy
Quality ofQuality ofLifeLife
SensorySensoryLossLoss
Surgery, Surgery, AmputationAmputation
ADA Consensus StatementADA Consensus Statement
““The effort to optimize foot care for patients with The effort to optimize foot care for patients with diabetes led to the American Diabetes Association diabetes led to the American Diabetes Association
consensus statement on foot care, which consensus statement on foot care, which recommended that the recommended that the cutaneous pressure cutaneous pressure thresholdthreshold be measured at least once a year” be measured at least once a year”
““The goal of this recommendation is to reduceThe goal of this recommendation is to reducethe risk of ulceration, infection and amputationthe risk of ulceration, infection and amputation
due to due to sensory losssensory loss that can occur through that can occur through progressive neuropathy”progressive neuropathy”
Barber MA. Journ of APMA. 2001;91(10):508-514.
Vinik A. The Amer Journal of Med. August 1999.
DIABETESDIABETES
HyperglycemiaHyperglycemia
DAGDAGPKCPKC
Impaired n-6 fattyImpaired n-6 fattyacid metabolismacid metabolism
PolyolPolyolpathwaypathway
Sugar Sugar autoxidationautoxidation
Advanced Advanced glycationglycation
OXIDATIVE STRESSOXIDATIVE STRESS
ENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTION
capillary blood flow capillary blood flow endoneurial hypoxiaendoneurial hypoxia
NERVE DYSFUNCTIONNERVE DYSFUNCTIONNCV, NCV, Regeneration, Structural damageRegeneration, Structural damage
TriglyceridesTriglyceridesLDLLDL
Etiology of Diabetic NeuropathyEtiology of Diabetic Neuropathy
Endothelial Dysfunction inEndothelial Dysfunction inDiabetic NeuropathyDiabetic Neuropathy
EndotheliumEndothelium: a biologically active organ: a biologically active organ
Deranged nitric oxide pathwaysDeranged nitric oxide pathways
MultifactorialMultifactorial– HyperglycemiaHyperglycemia– Insulin resistanceInsulin resistance– FFA production / metabolismFFA production / metabolism
Minami M, et al. Journ of Cardiovas Pharmacol. 1998;31(Suppl 1):S467-S469.Wu G and Meininger CJ. Biofactors. 2009;35(1):21-27.Veves A, et al. Diabetes. 1998;47:457-463.
ADA Statement Diabetic Neuropathies ADA Statement Diabetic Neuropathies Classification of NeuropathiesClassification of Neuropathies
Generalized symmetric polyneuropathiesGeneralized symmetric polyneuropathies– Acute sensorimotorAcute sensorimotor– Chronic sensorimotorChronic sensorimotor– AutonomicAutonomic
Focal and multifocal neuropathiesFocal and multifocal neuropathies– CranialCranial– TruncalTruncal– Focal limbFocal limb– Proximal (Amyotrophy)Proximal (Amyotrophy)– Co-existing CIDPCo-existing CIDP
Boulton AJ, et al. Diabetes Care. 2005;28(4):956-962.
Sensorimotor NeuropathySensorimotor Neuropathy
Most common type of diabetic neuropathyMost common type of diabetic neuropathy
Affects 30-50% of all diabetic populationAffects 30-50% of all diabetic population
Most commonly involved in diabetic foot problemsMost commonly involved in diabetic foot problems
Diabetic Neuropathies: A Statement by the ADA. Diabetes Care. 2005;28(4):956-962.
Sensorimotor NeuropathySensorimotor Neuropathy
Development progressive, initially involving more Development progressive, initially involving more distal partsdistal parts
Main symptoms are numbness of the legs andMain symptoms are numbness of the legs andfeet, muscular cramps, pins and needles, shooting, feet, muscular cramps, pins and needles, shooting, deep aching and burning pain. Nocturnaldeep aching and burning pain. Nocturnalexacerbation characteristicexacerbation characteristic
Symptoms may be absent or present either in theSymptoms may be absent or present either in theearly or late stagesearly or late stages
Symptoms
Diabetic Neuropathies: A Statement by the ADA. Diabetes Care. 2005;28(4):956-962.
Acute Sensory and ChronicAcute Sensory and ChronicSensory NeuropathiesSensory Neuropathies
Acute SensoryAcute Sensory Chronic SensorimotorChronic Sensorimotor
Mode of onsetMode of onset Relatively rapidRelatively rapid Gradual, insidiousGradual, insidious
SymptomsSymptoms Severe burning pain, aching: Severe burning pain, aching: weight loss usualweight loss usual
Burning pain, paresthesia, Burning pain, paresthesia, numbness: weight loss usualnumbness: weight loss usual
Symptom severitySymptom severity ++++++ 0 to ++0 to ++
SignsSigns Mild sensory in some:Mild sensory in some:motor unusualmotor unusual
Stocking and glove sensory Stocking and glove sensory loss: absent ankle reflexesloss: absent ankle reflexes
Other diabetic Other diabetic complicationscomplications UnusualUnusual Increased prevalenceIncreased prevalence
Electrophysiological Electrophysiological investigationsinvestigations
May be normal or minor May be normal or minor abnormalitiesabnormalities
Abnormalities unusual in Abnormalities unusual in motor and sensory nervesmotor and sensory nerves
Natural historyNatural history Complete recovery withinComplete recovery within12 months12 months
Symptoms may persist Symptoms may persist intermittently for years: at risk intermittently for years: at risk of foot ulcerationof foot ulceration
Diabetic Neuropathies: A Statement by the ADA. Diabetes Care. 2005;28(4):956-962.
Autonomic NeuropathyAutonomic Neuropathy
Heart rate abnormalitiesHeart rate abnormalities
Postural hypotensionPostural hypotension
Abnormal sweatingAbnormal sweating
GastroparesisGastroparesis
Neuropathic diarrheaNeuropathic diarrhea
ImpotenceImpotence
Retrograde ejaculationRetrograde ejaculation
Diabetic Neuropathies: A Statement by the ADA. Diabetes Care. 2005;28(4):956-962.
Predictors of Foot UlcerationPredictors of Foot Ulceration
Rich J, Veves A. Wounds. 2000;12(4):82-87.
VariableVariable No Ulcer (127)No Ulcer (127) Ulcer (53)Ulcer (53) P-valueP-value
NSSNSS 2.1 + 2.42.1 + 2.4 2.7 + 2.82.7 + 2.8 0.2970.297
NDSNDS 13 + 813 + 8 18 + 518 + 5 0.00010.0001
VPT (volts)VPT (volts) 38 + 1538 + 15 46 + 646 + 6 0.00010.0001
SWFSWF 5.90 + 1.205.90 + 1.20 6.63 + 0.746.63 + 0.74 0.00010.0001
NP Pedal PulseNP Pedal Pulse 28 (22%)28 (22%) 20 (38%)20 (38%) 0.0350.035
STJ mobilitySTJ mobility 22 + 722 + 7 22 + 1122 + 11 0.7840.784
1st MTP mobility1st MTP mobility 71 + 1871 + 18 61 + 2061 + 20 0.0020.002
Forefoot PPForefoot PP 6.6 + 2.86.6 + 2.8 8.2 + 4.38.2 + 4.3 0.0050.005
Rearfoot PPRearfoot PP 3.1 + 1.53.1 + 1.5 3.4 + 1.83.4 + 1.8 0.370.37
Other Diagnostic Tools forOther Diagnostic Tools forDetection of DPNDetection of DPN
5.07 Semmes-Weinstein Monofilament 5.07 Semmes-Weinstein Monofilament BiosthesiometerBiosthesiometer®®
Calibrated Tuning ForkCalibrated Tuning Fork Diskcriminator for 2 Point SpacingDiskcriminator for 2 Point Spacing Neurometer CPTNeurometer CPT®® (A-beta,A-delta,C fibers) (A-beta,A-delta,C fibers) PSSDPSSD®® (Earliest detection of pathology of A-beta skin surface/touch fibers (Earliest detection of pathology of A-beta skin surface/touch fibers Neuropad (correlates with IENFD, p=0.04)Neuropad (correlates with IENFD, p=0.04)
Quatrini C, Boulton A, et al. Diabetologia. 2008;51(6):1046-1050.Boulton AJ, et al. Diabetes Care. 2004;27(6):1458-1486.Boulton AJ, et al. Prev and Treatment of Diab and its Compli. 1998;82(4):909-919.Barber MA, et al. J Am Podiatr Med Assoc. 2001;91(10):508-514.Kiso T, et al. Journ of Pharmaco and Experi Therap. 2001;297(1):352-356.
Diagnostic Tests for DPNPDiagnostic Tests for DPNP
Nerve Conduction Studies/ElectromyogramNerve Conduction Studies/Electromyogram– Measures the speed and amplitude of sensory and motor conductionMeasures the speed and amplitude of sensory and motor conduction– Objective, parametric, non-invasiveObjective, parametric, non-invasive– Insensitive in acute and small-fiber neuropathyInsensitive in acute and small-fiber neuropathy– > 50% False Negative for Tarsal Tunnel Syndrome> 50% False Negative for Tarsal Tunnel Syndrome
Quantitative Sensory TestQuantitative Sensory Test– Detects sensory thresholds for vibration, heat and painDetects sensory thresholds for vibration, heat and pain– Useful in tracking the progression of neuropathy in large cohorts and the efficacy Useful in tracking the progression of neuropathy in large cohorts and the efficacy
of treatment end points in multicenter clinical trialsof treatment end points in multicenter clinical trials
Skin Biopsy (IENFD)Skin Biopsy (IENFD)– Measures density of intraepidermal nerve fibers at various sites in the legMeasures density of intraepidermal nerve fibers at various sites in the leg– Loss of nerve fibers is associated with increased neuropathic painLoss of nerve fibers is associated with increased neuropathic pain– Although the test is invasive, it requires a 3mm skin biopsy specimen and enables Although the test is invasive, it requires a 3mm skin biopsy specimen and enables
a direct study of small nerve fibersa direct study of small nerve fibers
Pathways: Perspectives in Modern Neurology and Pain Management. Vol 3. July 2007; Page 6.
Diagnosing Small Fiber Neuropathy with Diagnosing Small Fiber Neuropathy with Skin Punch BiopsySkin Punch Biopsy
Small Fiber Neuropathy (SFN) is a major cause of painful Small Fiber Neuropathy (SFN) is a major cause of painful burning, numbness and tingling in feet/handsburning, numbness and tingling in feet/hands
SFN often precedes diagnosis of diabetes a.k.a. “impaired SFN often precedes diagnosis of diabetes a.k.a. “impaired glucose tolerance neuropathy”glucose tolerance neuropathy”
Diagnostic efficiency of skin punch biopsy is ≈ 88% Diagnostic efficiency of skin punch biopsy is ≈ 88%
Findings on routine nerve conduction studies and Findings on routine nerve conduction studies and electromyography are typically normal (large fiber only)electromyography are typically normal (large fiber only)
Management of SFN should involve controllingManagement of SFN should involve controllingthe symptoms and aggressively treating thethe symptoms and aggressively treating theunderlying causeunderlying cause
Tavee et al. Cleveland Clinic Journal of Medicine. May 2009.
Skin BiopsySkin Biopsy
Normal nerve fiber density. Arrow pointsNormal nerve fiber density. Arrow pointsto the small nerve fiber in the epidermalto the small nerve fiber in the epidermallayer of skin, arrowhead points to thelayer of skin, arrowhead points to thebasement membrane that separates thebasement membrane that separates thedermis from the epidermis. dermis from the epidermis.
Low normal nerve fibers, consistent withLow normal nerve fibers, consistent withsmall fiber neuropathy. The arrow pointssmall fiber neuropathy. The arrow pointsto the basement membrane of the epidermis. to the basement membrane of the epidermis.
Images Courtesy of Therapath, LLC.
Diabetic Neuropathy: Diabetic Neuropathy: Current TreatmentsCurrent Treatments
25% NO TREATMENT25% NO TREATMENT
53.9% OPIOIDS53.9% OPIOIDS
39.7% NSAIDS39.7% NSAIDS
21.1% SSRIs21.1% SSRIs
11.3% TCAs11.3% TCAs
11.1% ANTICONVULSANTS11.1% ANTICONVULSANTS
Berger A, Dukes EM, Oster G. J Pain. 2004;5.
Only Target PositiveOnly Target Positive(Painful) Symptoms(Painful) Symptoms
Treatment Options for DPNP: Treatment Options for DPNP: Palliative AgentsPalliative Agents
ClassClass TherapyTherapy Dose (mg/day)Dose (mg/day)
Aldose reductase inhibitorsAldose reductase inhibitors EpalrestatEpalrestat Only licensed in JapanOnly licensed in Japan
Angiotensin-convertingAngiotensin-convertingenzyme inhibitorsenzyme inhibitors
TrandaloprilTrandalopril More studies neededMore studies needed
Tricyclic antidepressantsTricyclic antidepressants AmitriptylineAmitriptylineImipramineImipramine
20-15020-15025-15025-150
SNRIsSNRIs Duloxetine*Duloxetine* 60-12060-120
AnticonvulsantsAnticonvulsants GabapentinGabapentinLamotrigineLamotrigineCarbamazepineCarbamazepinePregabalin*Pregabalin*
900-3600900-3600200-400200-400200-600200-600300-600300-600
AntiarrhythmicsAntiarrhythmics MexiliteneMexilitene Up to 900Up to 900
OpioidsOpioids TramadolTramadol 50-40050-400
*FDA Approved.Adapted from Tavakoli M and Malik R. Expert Opin Pharmacother. 2008.
Current Palliative TreatmentsCurrent Palliative Treatments
Chen H, Lamer TH, Rho RH, et al. Mayo Clin Proceed. 2004;79.
Distal NeuropathyDistal Neuropathy
C-fibers (dysesthesias,C-fibers (dysesthesias,allodynia, burning)allodynia, burning)
A-fibers (paresthesias,A-fibers (paresthesias,radiating, night cramps)radiating, night cramps)
Capsaicin creamCapsaicin creamClonidineClonidineLidocaineLidocaine
Insulin InfusionInsulin InfusionCarbamazepineCarbamazepine
LidocaineLidocaineMuscle relaxantMuscle relaxant
NSAIDsNSAIDs
TramadolTramadolTCATCA
GabapentinGabapentinPregabalinPregabalinDuloxetineDuloxetine
Treatment Options for DPN: Treatment Options for DPN: Disease Modifying AgentsDisease Modifying Agents
ClassClass TherapyTherapy Dose (mg/day)Dose (mg/day)
Glucose ControlGlucose Control –– ––
Pancreas transplantationPancreas transplantation –– ––
AntioxidantAntioxidant Alpha Lipoic AcidAlpha Lipoic Acid600 mg intravenously600 mg intravenously1200-1800 mg orally1200-1800 mg orally
Neurotrophic SupportNeurotrophic Support L-methylfolate, P5P, Me-CblL-methylfolate, P5P, Me-Cbl 2.8 mg, 25 mg, 2 mg, BID2.8 mg, 25 mg, 2 mg, BID
Adapted from Tavakoli M and Malik R. Expert Opin Pharmacother. 2008.
L-MethylfolateL-Methylfolate 2.8 mg2.8 mgMethylcobalaminMethylcobalamin 2 mg 2 mgPyridoxal 5’ –phosphate 25 mgPyridoxal 5’ –phosphate 25 mgMETANXMETANX®®
Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabeticperipheral neuropathy.Verhaar, et al. Circulation. 1998.Yaqub, et al. Clin Neurol and Neuros. 1992.Beck W. New Eng Journ Med. 1988.Goh S and Cooper M. Clin Endocrin & Metabol. 2008.Wantanabe, et al. Journ of Neurolog Scien. 1994.
L-methylfolateL-methylfolate Active form of folate necessary for neural functionActive form of folate necessary for neural function Works with Methyl BWorks with Methyl B1212 to activate protein, DNA / RNA synthesis to activate protein, DNA / RNA synthesis Increase nitric oxide synthesisIncrease nitric oxide synthesis
MethylcobalaminMethylcobalamin Neurologically active form of BNeurologically active form of B1212
Methyl donor in DNA metabolism, Up-regulate gene transcription for Methyl donor in DNA metabolism, Up-regulate gene transcription for peripheral nerve repair & regenerationperipheral nerve repair & regeneration
Enhance protein metabolism in Schwann CellsEnhance protein metabolism in Schwann Cells
Pyridoxal 5’-phosphatePyridoxal 5’-phosphate Active form of BActive form of B66, Necessary for neural function, Necessary for neural function May inhibit effects of advanced glycation end productsMay inhibit effects of advanced glycation end products
MetanxMetanx®®: A Medical Food: A Medical Food
1988 via amendments to the Federal Food, Drug and Cosmetic Act:1988 via amendments to the Federal Food, Drug and Cosmetic Act: Active ingredient: present in / derived from a food (e.g. folate)Active ingredient: present in / derived from a food (e.g. folate)
Oral dosage formOral dosage form
Addresses distinct nutritional requirements of patients with Addresses distinct nutritional requirements of patients with specific diagnosed diseases or conditions (e.g. low plasma / specific diagnosed diseases or conditions (e.g. low plasma / RBC folate, hyperhomocysteinemia, endothelial dysfunction)RBC folate, hyperhomocysteinemia, endothelial dysfunction)
Efficacy/dosing must be proven in peer-reviewedEfficacy/dosing must be proven in peer-reviewedscientific literature scientific literature
Only under care of health care provider (Available by Only under care of health care provider (Available by prescription)prescription)
Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabeticperipheral neuropathy.
Medical FoodsMedical Foods
PharmaceuticalPharmaceutical Medical FoodMedical FoodDietary SupplementDietary Supplement(Neutraceutical)(Neutraceutical)
Intended UseIntended Use To treat, prevent, or mitigate a To treat, prevent, or mitigate a disease or conditiondisease or condition
Nutritional or dietary management Nutritional or dietary management of a specific diseaseof a specific disease
To maintain the well-being of a To maintain the well-being of a particular function in the body particular function in the body (e.g. maintain healthy joints(e.g. maintain healthy joints
ConsumerConsumer Person suffering from a disease or Person suffering from a disease or abnormal conditionabnormal condition
Person suffering from a disease or Person suffering from a disease or abnormal conditionabnormal condition
Normal, relatively healthy personNormal, relatively healthy person
Evidence RequirementsEvidence Requirements Must have 2+ placebo controlled Must have 2+ placebo controlled trials (and a maintenance trial for trials (and a maintenance trial for certain disease states). Usually certain disease states). Usually involves animal testing: Phase 1, involves animal testing: Phase 1, 2, & 3 clinical trials2, & 3 clinical trials
The distinct nutritional The distinct nutritional requirement of the specific requirement of the specific disease and product performance disease and product performance must be supported by peer must be supported by peer reviewed literature, reviewed literature, clinical/scientific study, and clinical/scientific study, and medical determinationmedical determination
No specific requirements forNo specific requirements forpre-market testingpre-market testing
SafetySafety Pharmacology and toxicology Pharmacology and toxicology testing required. Must be deemed testing required. Must be deemed ‘safe & efficacious’ by the FDAs ‘safe & efficacious’ by the FDAs review of adverse events, drug review of adverse events, drug interactions, dosing and toxicityinteractions, dosing and toxicity
Ingredients must attain FDA GRAS Ingredients must attain FDA GRAS (Generally Regarded as Safe) (Generally Regarded as Safe) status. GRAS denotes broad scale, status. GRAS denotes broad scale, up-front safetyup-front safety
Ingredients have some Ingredients have some ‘expectations’ of safety as ‘expectations’ of safety as evidenced by having been sold in evidenced by having been sold in the U.S. market prior to October the U.S. market prior to October 19941994
Medical CareMedical Care Must be prescribed by a physician Must be prescribed by a physician or licensed NP/PAor licensed NP/PA
Must be used under a physician’s Must be used under a physician’s supervision (or licensed) by supervision (or licensed) by prescriptionprescription
None. Supplements are typically None. Supplements are typically self-administered by the consumer self-administered by the consumer and are sold over the counterand are sold over the counter
Regulatory Review Body of the Regulatory Review Body of the FDAFDA
Center for Drug Evaluation and Center for Drug Evaluation and Research (CDER)Research (CDER)
Center for Food Safety and Center for Food Safety and Applied Nutrition (CFSAN) Applied Nutrition (CFSAN)
DSHEA – Dietary Supplement DSHEA – Dietary Supplement Health Education Act (1994) under Health Education Act (1994) under the same center (CFSAN) as the same center (CFSAN) as medical foods.medical foods.
MetanxMetanx®® Indication and Dosage Indication and Dosage
The distinct nutritional requirements of patients withThe distinct nutritional requirements of patients withendothelial dysfunction:endothelial dysfunction: Who present with loss of protective sensation and neuropathic Who present with loss of protective sensation and neuropathic
pain associated with diabetic peripheral neuropathypain associated with diabetic peripheral neuropathy
and/or hyperhomocysteinemia who present with lower extremity and/or hyperhomocysteinemia who present with lower extremity ulceration(s)ulceration(s)
Identification StatementIdentification Statement MetanxMetanx®® is an orally administered prescription medical food for is an orally administered prescription medical food for
the dietary management of endothelial dysfunction in patients the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathywith diabetic peripheral neuropathy
DosageDosage 1 tablet twice daily1 tablet twice daily
Metanx Package Insert 2009.
MetanxMetanx®® Safety Profile Safety Profile
Adverse Reactions: Adverse Reactions: While allergic sensitization has been reported following While allergic sensitization has been reported following
both oral and parenteral administration of folic acid, both oral and parenteral administration of folic acid, allergic sensitization has not been reported with the allergic sensitization has not been reported with the use of L-methylfolate. use of L-methylfolate.
Paresthesia, somnolence, nausea and headaches have Paresthesia, somnolence, nausea and headaches have been reported with P-5-P. Mild transient diarrhea, been reported with P-5-P. Mild transient diarrhea, polycythemia vera, itching, transitory exanthema and polycythemia vera, itching, transitory exanthema and the feeling of swelling of the entire body has been the feeling of swelling of the entire body has been associated with cobalamin.associated with cobalamin.
Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.Metanx Package Insert 2009.
MetanxMetanx®® Safety Profile Safety Profile
MetanxMetanx®® is well tolerated in short-term and chronic use: is well tolerated in short-term and chronic use: Side effects and/or discontinuation rates similar to placeboSide effects and/or discontinuation rates similar to placebo The Ingredients in MetanxThe Ingredients in Metanx®® are generally recognized as safe are generally recognized as safe
(GRAS) as designated by the FDA or independent review(GRAS) as designated by the FDA or independent review
Precautions:Precautions: Pyridoxal 5’-phosphate (P-5-P) should not be given in patients Pyridoxal 5’-phosphate (P-5-P) should not be given in patients
receiving levodopa, because the action of levodopa is receiving levodopa, because the action of levodopa is antagonized by P-5-P. However, P-5-P may be used concurrently antagonized by P-5-P. However, P-5-P may be used concurrently in patients receiving carbidopa/levodopain patients receiving carbidopa/levodopa
While the concurrent use of phenytoin and folic acid may result While the concurrent use of phenytoin and folic acid may result in decreased phenytoin effectiveness, no such decreased in decreased phenytoin effectiveness, no such decreased effectiveness has been reported with the use of L-methylfolateeffectiveness has been reported with the use of L-methylfolate
Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabeticperipheral neuropathy.Metanx Package Insert 2009.Abstracts of the 7th Annual Conference on Arteriosclerosis, Thrombosis, and Vascular Biology. Oral Presentations. Arterioscler Thromb Vasc Biol.2003;26:e43-e52.
Vitamin B for Peripheral Neuropathy: Vitamin B for Peripheral Neuropathy: Cochrane DatabaseCochrane Database
13 Studies / 741 Patients13 Studies / 741 Patients
2 Studies No Short-Term Pain Reduction2 Studies No Short-Term Pain Reduction
1 Study Vibration Detection Improved1 Study Vibration Detection Improved(Thiamine derivative)(Thiamine derivative)
Higher Doses Improved Short-Term Paresthesias, Pain, Higher Doses Improved Short-Term Paresthesias, Pain, Temperature, Vibration, NumbnessTemperature, Vibration, Numbness
Still Limited Data Still Limited Data
Ang, CD, Alviar, MJM, Dans, AL, Bautista-Velez, GGP, et al. Cochrane Database of Systemic Reviews. Issue 3, Article #CD004573, 2008.
(Metanx(Metanx®®)L-methylfolate, Me-Cbl, P-5-P:)L-methylfolate, Me-Cbl, P-5-P:Correlative DataCorrelative Data
Subjective VAS Study as isolated therapySubjective VAS Study as isolated therapy
Subjective VAS study combined with palliative agentSubjective VAS study combined with palliative agent
Quantitative Sensory Testing Quantitative Sensory Testing
Intraepidermal Nerve Fiber Density Testing Intraepidermal Nerve Fiber Density Testing
Jacobs, AM. Abstracts of the New Cardiovascular Horizons Meeting. Orally Administered L-methylfolate, Me-Cbl, P-5-P Reduces theSymptoms of Diabetic Peripheral Neuropathy. Oral Presentations 2008.Jacobs, AM. Abstracts of the New Cardiovascular Horizons Meeting. L-methylfolate, Me-Cbl, P-5-P supplementation to pregabalin partialresponders for the treatment of painful diabetic neuropathy. Oral Presentations 2008.
Orally Administered L-methylfolate,Orally Administered L-methylfolate,Me-Cbl, and P-5-P Reduces DPNPMe-Cbl, and P-5-P Reduces DPNP
Results from a 20 week, randomized, Results from a 20 week, randomized, controlled study of 97 patients to evaluatecontrolled study of 97 patients to evaluateMetanxMetanx®® in patients with DPNP. in patients with DPNP.
After nutritional management with MetanxAfter nutritional management with Metanx®®:: The average absolute pain reduction after The average absolute pain reduction after
20 weeks in the study group was 1.73 20 weeks in the study group was 1.73 compared to .44 in the active group compared to .44 in the active group ((PP<0.008)<0.008)
Compared to baseline, after 10 weeks the Compared to baseline, after 10 weeks the study group demonstrated a reduction in study group demonstrated a reduction in VAS of 32.92% compared to the active VAS of 32.92% compared to the active control group of 11.57% reduction in VAS control group of 11.57% reduction in VAS ((PP<0.01)<0.01)
Compared to baseline, after 20 weeks the Compared to baseline, after 20 weeks the study group demonstrated a reduction in study group demonstrated a reduction in VAS of 35.28% compared to the active VAS of 35.28% compared to the active control group of 11.73% reduction in VAS control group of 11.73% reduction in VAS ((PP<0.01)<0.01)*L-methylfolate, Me-Cbl, P-5-P vs. Acetaminophen at 10 weeks.
†L-methylfolate, Me-Cbl, P-5-P vs. Acetaminophen at 20 weeks.Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.Jacobs AM. NCVH Oral Presentations 2008.
0
-0.2
-0.4
-0.6
-0.8
-1
-1.2
-1.4
-1.6
-1.8
-20 10 20
Weeks
Pain
Red
uctio
n
*P<0.01 †P=0.008
Acetaminophen
L-methylfolate,Me-CBl, P-5-P
Mean Pain Reduction From Baseline
L-Methylfolate, Me-Cbl, and P-5-P Administration to L-Methylfolate, Me-Cbl, and P-5-P Administration to Pregabalin Partial-Responders for Management of DPNPPregabalin Partial-Responders for Management of DPNP
Results from a 20 week, open trial of 24 Results from a 20 week, open trial of 24 patients to evaluate Metanx with patients to evaluate Metanx with ≤≤ 50% 50% response to pregabalin (VAS score).response to pregabalin (VAS score).
After nutritional management with Metanx:After nutritional management with Metanx: The average absolute pain reduction The average absolute pain reduction
after 20 weeks in the study group was after 20 weeks in the study group was 3.0 compared to .25 in the active3.0 compared to .25 in the activecontrol group (control group (PP<0.001)<0.001)
After 20 weeks, the study group After 20 weeks, the study group experienced greater pain relief experienced greater pain relief compared to the active control group, compared to the active control group, 87.5% vs. 25.0% reduction in NPS 87.5% vs. 25.0% reduction in NPS respectively (respectively (PP=0.005)=0.005)
Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.Jacobs AM. NCVH Oral Presentations 2008.
0
-0.5
-1
-1.5
-2
-2.5
-3
-3.50 20
Weeks
Pain
Red
uctio
n
P<0.001
Pregabalin
L-methylfolate,Me-CBl, P-S-P/Pregabalin
Mean Pain Reduction From Baseline
Restoration of Cutaneous Sensorum Restoration of Cutaneous Sensorum
16 consecutive DPN patients with established sensory 16 consecutive DPN patients with established sensory loss were quantified utilizing the PSSDloss were quantified utilizing the PSSD
Study outcomes were measured at Study outcomes were measured at baseline, 6 months baseline, 6 months and 1 yearand 1 year after L-methylfolate, Me-Cbl, P-5-P for all after L-methylfolate, Me-Cbl, P-5-P for all8 measurements8 measurements
FootFoot Medial HeelMedial Heel Great Toe PulpGreat Toe Pulp
Left / RightLeft / Right 1 & 2 point static touch1 & 2 point static touch 1 & 2 point static touch1 & 2 point static touch
Walker MJ, et al. Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
Eight Outcome MeasurementsEight Outcome Measurements
Restoration of Cutaneous Sensorum Restoration of Cutaneous Sensorum
Improved sensory perception at theImproved sensory perception at themedial heel and great toemedial heel and great toe
Walker MJ, et al. Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
Baseline, 6 month, & 1 year follow up
60
50
40
30
20
10
0
gm/m
m2
Baseline 6 months 1 year
P=0.006†
P<0.001‡
Normal*
2 Point Static Great ToeLeft/Right Combined
*<25.7 gm/mm2 represents normal pressure thresholds for Pressure Specified SensoryDevice™ (PSSD) 99% Confidence level.†Baseline vs. 6 month. ‡Baseline vs. 1 year. n = 16
60
50
40
30
20
10
0gm
/mm
2Baseline 6 months 1 year
P<0.001†
P<0.001‡
Normal*
2 Point Static Medial HeelLeft/Right Combined
*<30.0 gm/mm2 represents normal pressure thresholds for Pressure Specified SensoryDevice™ (PSSD) 99% Confidence level.†Baseline vs. 6 month. ‡Baseline vs. 1 year. n = 16
The Pharmacological Management of Diabetic Small Fiber The Pharmacological Management of Diabetic Small Fiber Neuropathy Utilizing MetanxNeuropathy Utilizing Metanx®® as a Neurotrophic Agent as a Neurotrophic Agent
11 patients symptomatic DPN 11 patients symptomatic DPN patients patients
Baseline / 6 month skin Baseline / 6 month skin biopsies (n=22)biopsies (n=22)
MetanxMetanx®® B.I.D. for 6 months B.I.D. for 6 months demonstrated 97% ↑ ENFDdemonstrated 97% ↑ ENFD
Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
P=0.004
Epidermal Nerve Fiber Density
1.56
3.07
0
0.5
1
1.5
2
2.5
3
3.5
4
Baseline 6 months
ENFD
/mm
Clinical Case Outcome IClinical Case Outcome I
BaselineBaseline 6 months6 months
Patient received baseline skin punch biopsy and given L-methylfolate, Me-Cbl, P-5-P (Metanx ®) twice daily and followed for six months. Left image represents baseline skin punch biopsy at right calf. Right image represents six month follow up skin punch biopsy at right calf. Patient average increase of 3.02 nerve fibers per mm. Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC
Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
Clinical Case Outcome IIClinical Case Outcome II
Patient received baseline skin punch biopsy and given L-methylfolate, Me-Cbl , P-5-P (Metanx ®) twice daily and followed for six months. Left image represents baseline skin punch biopsy at right calf. Right image represents six month follow up skin punch biopsy at right calf. Patient averaged an increase of .76 nerve fibers per mm. Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC.
BaselineBaseline 6 months6 months
Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
The Pharmacological Management of Diabetic Small Fiber The Pharmacological Management of Diabetic Small Fiber Neuropathy Utilizing L-Methylfolate, Me-Cbl, P-5-P as a Neuropathy Utilizing L-Methylfolate, Me-Cbl, P-5-P as a Neurotrophic AgentNeurotrophic Agent
This preliminary study suggests that the administration ofThis preliminary study suggests that the administration of2.8 mg L-Methylfolate, 2 mg Me-Cbl, 25 mg P-5-P appears to be 2.8 mg L-Methylfolate, 2 mg Me-Cbl, 25 mg P-5-P appears to be associated with increased ENFD in patients with DPN. associated with increased ENFD in patients with DPN.
The increased epidermal nerve fiber density may beThe increased epidermal nerve fiber density may beassociated with diminished symptoms of anesthesia, associated with diminished symptoms of anesthesia, paresthesia, or dysesthesia. paresthesia, or dysesthesia.
Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
SummarySummary
Distal symmetrical sensorimotor polyneuropathy is the Distal symmetrical sensorimotor polyneuropathy is the most common form of DPN most common form of DPN
Etiology of DPN may primarily be microvascular Etiology of DPN may primarily be microvascular insufficiency insufficiency
Treatment should be based upon individualTreatment should be based upon individualpatient factors patient factors
Focus on disease modifying agents to manipulate Focus on disease modifying agents to manipulate underlying pathophysiology of DPN underlying pathophysiology of DPN