Silence of the Limbs
Bruce Trippe, M.D., F.A.C.E.
Montgomery, AL
“I marvel that society
would pay a surgeon a
large sum of money to
remove a person’s legbut nothing to save it.”
- George Bernard Shaw
Presentation Objectives
 Understand the economic and social impact of diabetic
peripheral neuropathy
Distinguish between positive and negative symptoms of
diabetic peripheral neuropathy
Describe remittive vs. palliative therapy in the management
of diabetic peripheral neuropathy
Understand the potential mechanism of action of diabetic
peripheral neuropathy prescribed therapies
Diabetic Peripheral Neuropathy:
What is it?
• Nerve damage and dysfunction secondary to
diabetes mellitus type 1 or 2
 Consensus definition: “the presence of symptoms and/or signs of
peripheral nerve dysfunction in people with diabetes after
exclusion of other causes”
• A leading cause of neuropathic pain
• A very common complication of diabetes
Pathogenesis of Diabetic Neuropathy
~ 66% Diabetic
Neuropathy
Chen H, Lamer TH, Rho RH et al. Mayo Clin Proceed. 79; 2004
Boulton AJM, Mailik RA, ArezzoJC, Sosenko JM. Diab.Care 27, 2004
Wendling Patrice. 45% of Diabetic Patients Not Reaching HbA1C Target. Internal Medicine News. July 15 2007;40(No.14):1, 20.
Impact of Diabetic Neuropathy
• 15% of diabetics will develop
an ulcer.
• One in six of those with ulcers
will have an amputation.
• Half of those will have an ulcer
on the opposite foot within
three years.
Gordois et al. Diabetes Care 26:1790-1795, 2003
Impact of Diabetic Neuropathy
LARGEST
Most NUMBER
Common Proximate,
OF DIABETES
Nontraumatic
Cause of Amputations
RELATED HOSPITAL
BED-DAYS
Reiber GE, Vilekyte
L, Bokyo
EJ etMed
al. Diabetes
Care
22, 1999
Reiber
GE. Diab.
13 (SUPPL
1) 1996
Pecoraro RE, Reiber GE, Burgess EM. Diabetes Care 13, 1990
Clinical Unmet Needs in DPN
Improved efficacy
• There are a wide range of
treatments available for
neuropathic pain
Improved side effect profile
Reduced time to onset of action
Fewer drug-drug interactions
Reduced pill burden
Increasing
level of
importance
• This prescribing pattern suggests
that there is no one treatment that
addresses all the factors.
• Despite a spectrum of drugs
available with different modes of
action, may patients remain
inadequately treated in several
aspects of the disease.
Datamonitor Research 2008
Diabetic Neuropathy:
The Forgotten Complication
Results of the 2005 ADA National Survey
• Only one in four survey respondents who experience symptoms of diabetic
neuropathy have been diagnosed with the condition.
• The majority of respondents who experience symptoms (56%) remain
unaware of the term diabetic neuropathy.
• 62% believe that their symptoms are associated with their diabetes, but
only 42% have been told by their physician that diabetes is the cause.
• Approximately one in seven people who said they talked to their doctor
about their symptoms and pain reported that no cause was mentioned.
May 10, 2005 /PR Newswire via COMTEX
Signs and Symptoms of Diabetic
Peripheral Neuropathy
Distal symmetrical sensorimotor polyneuropathy
is the most common form of DPN. Signs and symptoms
may progress from distal to proximal over time.
SIGNS
•Diminished vibratory perception
•Decreased knee and ankle reflexes
•Reduced protective sensation, such as
pressure, hot and cold, pain
•Diminished ability to sense position of
toes and feet
Boulton AJ, et al. Diabetes Care. 2005;28(4):956-962.
SYMPTOMS
• Numbness, loss of feeling, prickling,
tingling
• Aching pain
• Burning pain
• Lancinating pain
• Unusual sensitivity or tenderness
when feet are touched (allodynia)
DPN Produces Positive and Negative
Symptoms
• Positive Symptoms
– Spontaneous Pain
– Dysesthesias
• C-Fibers
• Unpleasant
– Parasthesias
• A-Fibers
• Not Unpleasant
• Negative Symptoms
– Loss/impairment of
sensory quality
– Numbness
– Dry skin
– Erectile dysfunction
– Incontinence
– Gait instability and fall
risk
Baron R. Clin J Pain. 2000;16(2 suppl):S12-S20.
Neuropathic Symptoms and
Quality of Life
•
Positive and negative symptoms have an impact on functioning, activities of daily
living (ADL) and QOL
•
QOL is an unique, individual experience – how persons perceive and react to their
health status
•
Psychosocial Morbidity
–
–
–
–
•
Depression
Anxiety
Anger
Loss of Self-Esteem
Societal Consequences
– Social isolation
– Strained relationships with family and friends
– Effects upon intimacy/sexual activity
The National Initiative on Pain Control, 2002
Vileikyte et al, Diabetes Care 2005
Diabetic Neuropathy: Symptoms
Majority of symptomatic DPN
patients are insensate
Argoff et al. Mayo Clin. Proc. 2006:81 (S4)
Boulton AJM et al. Diab. Care 27, 2004
M. Clin. Diab. 23, 2005
Clinical Impact of Positive and Negative
DPN Symptoms
DPN
Painful
Neuropathy
Impairment
Disability
Handicap
Sensory Loss
Mortality
Foot Ulcers
Quality of
Life
Charcot
Foot
Infection
(skin, bone)
Surgery,
Amputation
Boulton A. NCVH. Oral Presentations 2007.
Cost
ADA Consensus Statement
“The effort to optimize foot care for patients with
diabetes led to the American Diabetes
Association consensus statement on foot care,
which recommended that the cutaneous
pressure threshold be measured at least once a
year”
“The goal of this recommendation is to reduce the
risk of ulceration, infection and amputation due
to sensory loss that can occur through
progressive neuropathy”
American Diabetes Association: Foot care guidelines. Diabetes Care 2355;2000
Diagnostic Tests for DPNP
• NCS/EMG
– Measures the speed and amplitude of sensory and motor
conduction
– Objective, parametric, non-invasive
– Insensitive in acute and small-fiber neuropathy
– > 50% False Negative for Tarsal Tunnel Syndrome
• QST
– Detects sensory thresholds for vibration, heat and pain
– Useful in tracking the progression of neuropathy in large cohorts
and the efficacy of treatment end points in multicenter clinical trials
• Skin Biopsy (IENFD)
– Measures density of intraepidermal nerve fiber at various sites in
the leg
– Loss of nerve fibers is associated with increased neuropathic pain
– Although the test is invasive, it requires a 3mm skin biopsy specimen
and enables a direct study of small nerve fibers
Pathways: Perspectives in Modern Neurology and Pain Management. Vol 3. July 2007; Page 6
Skin Biopsy
• Sensitivity of skin biopsy in diagnosing small fiber neuropathy is
88.4%, with a specificity of 95% to 97%.
• Skin specimens are routinely obtained by punch biopsy at the foot,
calf, and/or thigh, under local anesthesia.
• The ENFD at the calf-foot/ankle is routinely compared to that at the
thigh, to help differentiate between distal neuropathy and
neuronopathy or multifocal neuropathy.
• Skin biopsy specimens are routinely obtained for analysis, using a 3
mm punch biopsy.
• Patients with small fiber neuropathy exhibit a reduction is the
epidermal nerve fiber density, or structural abnormalities that are
indicative of neuropathy.
Skin Biopsy
This image demonstrates skin with
normal nerve fiber density
(Epidermal Nerve Fiber Density).
Arrow points to the small nerve
fiber in the epidermal layer of skin,
arrowhead points to the basement
membrane that separates the
dermis from the epidermis.
Skin with low normal nerve fibers,
consistent with small fiber
neuropathy. The arrow points to the
basement membrane of the
epidermis.
Other Diagnostic Tools for
Detection of DPN
•
•
•
•
•
•
5.07 Semmes-Weinstein Monofilament
®
Biosthesiometer
Calibrated Tuning Fork
Diskcriminator for 2 Point Spacing
®
Neurometer CPT (A-beta,A-delta,C fibers)
PSSD® (Earliest detection of pathology of A-beta skin
surface/touch fibers
• Neuropad (correlates with IENFD, p=0.04)*
* The Neuropad test: a visual indicator test for human diabetic neuropathy.
Quatrini C, Boulton A, et al. 22 Feb 2008. Diabetologia.
DIABETES
Hyperglycemia
 DAG
PKC
 Triglycerides
LDL
Impaired
n-6 fatty acid
metabolism
Polyol
pathway
Sugar
autoxidation
Advanced
glycation
OXIDATIVE STRESS
ENDOTHELIAL DYSFUNCTION
capillary blood flow endoneurial hypoxia
NERVE DYSFUNCTION
 NCV, Regeneration, Structural
damage
Etiology of Diabetic Neuropathy
•
•
•
Hyperglycemia
Microvascular Disease
Oxidative Stress
–
–
•
•
•
Free radicals produced from an advanced
glycation lead to damaged neurons
Relieved by improving blood flow
Sorbitol Concentration
–
Excess sorbitol within the nerve causes it to
retain water and nerve edema/compression
Myoinositol Depletion
–
–
Myoinositol helps nerves conduct electricity
K+, Na+, and Ca+ are regulated by Myoinositol
Neurotrophic Factors
–
Diabetic nerves are folate, B6, and B12 deficient
Vinik A. The Amer. Journal of Med. August 1999.
Pathophysiology
HYPERGLYCEMIA
Microvascular
Ischemia
Polyol
Pathway
Oxidative
Stress
Loss of
Immune
Neurotrophic Mechanisms
Support
Altered
Protein
Synthesis
Diabetes and
Endothelial Dysfunction
• Endothelium: a biologically active organ
•Deranged nitric oxide pathways
•Multifactorial
 Hyperglycemia
 Insulin resistance
 FFA production / metabolism
ADA Statement Diabetic Neuropathies
Classification of Neuropathies
• Generalized symmetric polyneuropathies
 Acute sensorimotor
Chronic sensorimotor
 Autonomic
• Focal and multifocal neuropathies
 Cranial
Truncal
 Focal limb
 Proximal (Amyotrophy)
 Co-existing CIDP
Boulton, et al. Diabetes Care; April 2005
Predictors of Foot Ulceration
Variable
No Ulcer(127)
Ulcer(53)
p-value
NSS
2.1 + 2.4
2.7 + 2.8
0.297
NDS
VPT (volts)
SWMF
NP Pedal Pulse
STJ mobility
1st MTP mobility
Forefoot PP
Rearfoot PP
13 + 8
38 + 15
5.90+1.20
28 (22%)
22 + 7
71 +18
6.6 + 2.8
3.1 + 1.5
18 + 5
46 + 6
6.63+0.74
20 (38%)
22 + 11
61 + 20
8.2 + 4.3
3.4 + 1.8
0.0001
0.0001
0.0001
0.035
0.784
0.002
0.005
0.37
Rich, Veves,Wounds,2000;12:82-87
Proximal Neuropathies
Pascoe et al, Mayo Clin Proc,1997;72:1123-1132
Autonomic Neuropathy
• Heart rate abnormalities
• Postural hypotension
• Abnormal sweating
• Gastroparesis
• Neuropathic diarrhea
• Impotence
• Retrograde ejaculation
Sensorimotor Neuropathy
• Most common type of diabetic neuropathy
•Affects 30-50% of all diabetic population
•Most commonly involved in diabetic foot problems
Sensorimotor Neuropathy
Symptoms
• Development progressive, initially involving more distal parts
•Main symptoms are numbness of the legs and feet, muscular
cramps, pins and needles, shooting, deep aching and burning pain.
Nocturnal exacerbation characteristic.
•Symptoms may be absent or present either in the early or late
stages
Sensorimotor Neuropathy
Clinical Signs
• Reduced or absent sensation to pain, touch, cold, hot
and vibration in a stocking-glove distribution most
common signs of sensory neuropathy.
• Reduced or absent ankle reflexes, muscle weakness,
small muscle atrophy and prominence of the
metatarsal heads main signs of motor neuropathy.
Sensorimotor Neuropathy
Diagnosis
• Should be based on:
 clinical symptoms
 clinical signs
 quantitative sensory testing
 electrophysiology
 sural nerve biopsies
• Not all methods necessary on a daily clinical base
•Simple tests can identify the at risk patient
Neuropathic Pain:
Pharmacologic Therapies
• Gabapentin, carbamazepine, lamotrigine,
and newerAEDs
•Antidepressants
•Opiod analgesics
•Lidocaine (transdermal, intravenous [IV]), mexiletine
•Alpha-2 adrenergic agonists
Adjuvant Analgesics:
Antidepressants
• Best evidence: 30 amine TCAs (e.g., amitriptyline)
•20 amine TCAs (desipramine, nortiptyline)
better tolerated and also analgesic.
•Some evidence for SSRI / SSNRIs / atypical
antidepressants (e.g., paroxetine, venlafaxine*,
maprotiline, bupropion, others) and these are better
tolerated yet.
• Duloxetine SSRI /SNRI now FDA approved
*Kunz NR et al ADA, San Antonio, 2000
Diabetic Neuropathy:
Current Treatments
• 25% NO TREATMENT
• 53.9% OPIOIDS
• 39.7% NSAIDS
Only Target Positive (Painful)
• 21.1% SSRI’s
Symptoms
• 11.3% TCA’s
• 11.1% ANTICONVULSANTS
Berger A, Dukes EM, Oster G; J. Pain 5; 2004
Current Palliative Treatments
Distal Neuropathy
C-fibers (dysesthesias,
A-fibers (paresthesias,
allodynia, burning)
Capsaicin cream
Clonidine
Lidocaine
radiating, night cramps)
Tramadol
TCA
Gabapentin
Pregabalin
Insulin Infusion
Carbamazepine
Lidocaine
Muscle relaxant
NSAID’s
Duloxetine
Chen H, Lamer TH, Rho RH et al. Mayo Clin Proceed. 79; 2004
Symptomatic Palliative DPNP
Therapies
FDA Approved Drugs for the Treatment of DPNP
 Pregabalin (Lyrica®)
Duloxetine (Cymbalta®)
Pregabalin
• INDICATIONS
–
–
–
–
DPNP
Fibromyalgia
Post herpetic neuralgia
Adjunctive seizure medication
• DOSAGE
– DPNP
• Start at 50mg tid and may increase to 100mg tid within one week
– Fibromyalgia
• 150mg tid
– Post-herpetic neuralgia
• 200mg tid
• SIDE EFFECTS
– Dizziness, drowsiness, dry mouth, edema
• DRUG INTERACTIONS
– Alcohol and drugs that cause sedation may increase the sedative effects
of those agents.
– No pharmacokinetic interactions have been demonstrated in vivo.
Subunit of Voltage-Gated Ca2+
Channels in the Central Nervous System
• Pregabalin selectively binds to α2-δ subunit of calcium channels
• Modulates calcium influx in hyperexcited neurons
• Reduces neurotransmitter release
•Pharmacologic effect requires binding at this site
•The clinical significance of these observations in humans is currently unknown
Taylor. CNS Drug Rev. 2004;10:183-188.
Pregabalin Effect on Mean Weekly
pain Scores in Painful DPN
Rosenstock et al. Pain 2004; 110:628-638.
Pregabalin: Percentage of Patients with >
50% Reduction in Pain in Painful DPN*
Rosenstock et al. Pain 2004; 110:628-638.
Duloxetine
•
InsideCymbalta.com
•
INDICATIONS
– Depression
– Generalized anxiety disorder
– DPNP
– Fibromyalgia
•
DOSAGE
– Treatment should begin at 30 mg once daily for 1 week, to allow patients to adjust to the medication before
increasing to 60 mg once daily.
– Some patients may respond to the starting dose.
– There is no evidence that doses greater than 60 mg/day confer additional benefit, even in patients who do not
respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions.
•
SIDE EFFECTS
– Duloxetine can cause hepatotoxicity in the form of transaminase elevations.
– It may also be a factor in causing more severe liver injury, but there are no cases in the NDA database that
clearly demonstrate this.
– Use of duloxetine in the presence of ethanol may potentiate the deleterious effect of ethanol on the liver.
•
DRUG INTERACTIONS
– Diet drugs like Redux, Adipex, Meridia, fenfluramine
– MAOIs like Carbex/Eldepryl, Marplan, Nardil, and Parnate
– The chemotherapy drug, Matulane (procarbazine)
– SSRIs like Celexa, Lexapro, Prozac, Luvox, Paxil, Zoloft
– St. John's Wort
– Thioridazine
– Tryptophan
– Effexor XR
Duloxetine Proposed MOA
Duloxetine Phase 2
Duloxetine Phase 2
Goldstein et al. PAIN 2005
Anticonvulsant Drugs
• Carbamazepine
• Phenytoin
• Valporate
600mg/day
300mg/day
15-60mg/kg/day
• Gabapentin
• Topiramate
• Lamotrigine
• Felbamate
900-1800mg/day
50-400mg/day
300-500mg/day
1200-3600mg/day
New Therapeutic Approaches to
Diabetic Neuropathy
• Aldose reductase inhibitors
Ineffective
•Anti-oxidants (a-lipoic acid)
Effective
• Nerve growth factors
Ineffective
•Gamma linolenic acid
Ineffective
Potential Disease State Modifying Therapies
• Control Diabetes (blood sugar)
•Alpha Lipoic Acid
•L-Methylfolate, Me-Cbl, P-5-P (Metanx®)
MEDICAL FOOD
 1988 via amendments to the Federal Food, Drug and
Cosmetic Act:
• Active ingredient: present in / derived from a food (e.g. folate)
 Oral dosage form
 Addresses distinct nutritional requirements of patients with specific
diagnosed diseases or conditions (e.g. low plasma / RBC folate,
hyperhomocysteinemia, endothelial dysfunction)
 Efficacy/dosing must be proven in peer-reviewed scientific literature
 Only under care of M.D. (Rx Only)
Vitamin B for Peripheral Neuropathy:
Cochrane Database
•
•
•
•
13 Studies / 741 Patients
2 Studies No Short-Term Pain Reduction
1 Study Vibration Detection Improved
Higher Doses Improved Paresthesias, Pain, Temperature,
Vibration, Numbness
• Still Limited Data
ANG, C.D., ALVIAR, M.J.M., DANS, A.L., BAUTISTA-VELEZ, G.G.P., ET AL
COCHRANE DATABASE OF SYSTEMATIC REVIEWS ISSUE 3, ARTICLE #CD004573, 2008
METANX®
L-Methylfolate
Methylcobalamin
Pyridoxal 5’ –phosphate
2.8mg
2mg
25mg
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
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
Orally Administered L-methylfolate, MeCbl, and P-5-P Reduces DPNP
• Results from a 20 week, randomized,
Mean Pain Reduction From Baseline
controlled study of 97 patients to evaluate
Metanx in patients with DPNP.
0
Acetaminophen
-0.2
L-methylfolate, MeCbl, P-5-P
-0.4
Pain Reduction
-0.6
-0.8
-1
-1.2
* p <0.01
** p = 0.008
-1.4
•The average absolute pain reduction after
20 weeks in the study group was 1.73
compared to .44 in the active group
(p<0.008)
•Compared to baseline, after 10 weeks the
study group demonstrated a reduction in
VAS of 32.92% compared to the active
control group of 11.57% reduction in VAS
(P<0.01)
•Compared to baseline, after 20 weeks the
study group demonstrated a reduction in
VAS of 35.28% compared to the active
control group of 11.73% reduction in VAS
(P<0.01)
-1.6
-1.8
-2
0
10
20
Weeks
* L-methylfolate,Me-Cbl, P-5-P vs. Acetaminophen at 10
weeks
** L-methylfolate, Me-Cbl, P-5-P vs. Acetaminophen at 20
weeks
Jacobs AM. NCVH Oral Presentations 2008.
L-Methylfolate, Me-Cbl, and P-5-P Supplementation to
Pregabalin Partial-Responders for Management of
DPNP
Mean Pain Reduction from Baseline
•Results from a 20 week, open
trial of 24 patients to evaluate
Metanx.
0
-0.5
Pregabalin
Pain Reduction
-1
L-methylfolate, MeCbl, P-5-P/Pregabalin
-1.5
P<0.001
-2
•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)
-2.5
-3
-3.5
0
20
Weeks
• After 20 weeks, the study group
experienced greater pain relief
compared to the active control
group, 87.5% vs. 25.0%
reduction in NPS respectively
(p=0.005)
Jacobs AM. NCVH Oral Presentations 2008.
RESTORATION OF CUTANEOUS
SENSORUM
• 16 consecutive DPN patients with established sensory loss were
quantified utilizing the PSSD.
• Study outcomes were measured at baseline, 6 months and 1 year
after L-methylfolate, Me-Cbl, P-5-P for all 8 measurements.
Eight Outcome Measurements:
Foot
Left / Right
Medial Heel
1 & 2 point static touch
Great Toe Pulp
1 & 2 point static touch
Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
Restoration of Cutaneous Sensorum
Baseline, 6 month, & 1 year follow up
Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
The Pharmacological Management of Diabetic Small Fiber
Neuropathy Utilizing Metanx as a Neurotrophic Agent
Epidermal Nerve Fiber Density
• 11 patients symptomatic DPN patients
P=0.004
ENFD/mm
• Baseline / 6 month skin biopsies (n=22)
• Metanx B.I.D. for 6 months
demonstrated 97% ↑ ENFD
Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.
Clinical Case Outcome I
Baseline
6 months
Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC
Clinical Case Outcome II
Baseline
6 Months
Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC
New Therapeutic Approaches to
Diabetic Neuropathy
Treatments to Improve Nerve Hypoxia
• ACE inhibitors
• VEGF gene
• VEGF zinc finger protein
• Ruboxistaurin
• Benfotiamine
• Pyridoxamine
Effective
Under Study
Under Study
Under Study
Under Study
Under Study
Metanx Indication and Dosage
Identification Statement
• Metanx is an orally administered prescription medical food for the
dietary management of endothelial dysfunction in patients with
diabetic peripheral neuropathy
The distinct nutritional requirements of patients with
endothelial dysfunction:
• who present with loss of protective sensation and neuropathic
pain associated with diabetic peripheral neuropathy.
Dosage
1 tablet twice daily
Ongoing Clinical Trial
Effects of L-methylfolate, Me-Cbl, P5P in Subjects with DPN
• Randomized, Double-Blind, Placebo-controlled trial studying 216
patients with definite sensorimotor DPN
• Primary End Point
» To determine if Metanx improves VPT in DPN patients
• Principle Investigators
»
»
»
»
»
»
Vivian Fonseca, MD - Tulane Medical
Julio Rosenstock, MD – Dallas Diabetes and Endocrine Center
Lawrence Lavery, DPM –Texas A&M University Health Sciences Center
Cyrus Desouza, MD – Omaha VA Medical Center
Douglas Denham, MD – DgD Research, Inc.
Fernando Ovalle, MD – University of Alabama School of Medicine
• Expected Completion Date: February 2010
SUMMARY
• Most Patients with DPN experience Loss of Protective
Sensation
• Etiology of DPN may primarily be microvascular insufficiency
• Treatment should be based upon individual patient factors
• Need to focus on disease modifying agents to manipulate
underlying pathophysiology of DPN