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Treatment of Painful Diabetic Neuropathy

(Practical Guidelines with "Dalang" and Formula 3-3-3-3)
2005
(28)
1
Diabetes and Nutrition Centre - Dr. Soetomo Teaching Hospital
Airlangga University School of Medicine, Surabaya
Askandar Tjokroprawiro
Indonesian Neuroscience Summit 2005
Batam (Planet Holiday Hotel), 13-14 August 2005
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2
(Tjokroprawiro, 1993, Revised : 1998, 2002)
Chronic Diabetic Complications and Provided Information
Retinopathy : "The Window of Microangiopathy" CHD : "The Window of Macroangiopathy"
Microalbuminuria (30-299 mg/day or 20-199 mg/min) : is referred to as having Incipient Nephropathy
Microangiopathy : Retinopathy, Nephropathy, Neuropathy Macroangiopathy : CHD, Stroke, PVD
Inability to achieve or maintain an erection sufficient
for satisfactory sexual performance
Erectile Dysfunction = ED (NIH-Consensus 1993)
IIEF 1997 : Score < 21
:
*) + 5% of this Prevalence : PDN
%
67.0
51.4
50.9
27.2
25.5
16.3
12.8
12.1
10.0
5.7
4.2
3.8
3.0
Retinopathy
Joint Manifestation
Cataract
Pulmonary Tbc
Hypertension (WHO,1983)
CHD
Clinical Nephropathy
Stroke
Cellulitis - Gangrene
Symptomatic Gall Stone
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0
Dyslipidemia
Hypertension in Europe : 30 %
(Williams, 1991)
Commulative Prevalence of CVD : 63.0%
(in line with Dyslipidemia)
30 million in USA
(FELDMAN, et al 1994)
Erectile Dysfunction
Symptomatic Neuropathy*)
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Schiff Base
(Hours)

Amadori Products
(Days)

AGEs
(Week-Months)
PHASE-1


PHASE-2


PHASE-3


AGE-Protein
(Brownlee, 1995)

Nucleic Acid Histones

Mutation

Gene Expression
Cancer
3
Pancreatic Ca Liver Ca
Microvascular Damage
DIABETIC NEUROPATHY
Aminoguanidine*
)

(Kowluru et al 1999)
Excellent
Glycemic Control
Macrophage
RAGE (SR1, SR2)

TNF, IL-1, IGF-1
Production

Proliferation of
Cells and Matrix
2


Endothelial Cell
RAGE (R1, R2, R3)
Oxidative Stress
Endothelin-1
Tissue Factor Production
Vasoconstriction
Focal Thrombosis
1
Adhesion Mol.
Expression
(Lopes-Virella et al 1999)
3
Clinical Staging of Hyperglycemia
Microvascular and Diabetic Neuropathy
(Summarized : Tjokroprawiro 1994, 1995, 1996, 1997, 1999, 2001, 2002, 2003, 2004)
*) AGE and Oxidative Stress
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Pathologic Effects of AGE
S
: "BIME"
(Summarized : Tjokroprawiro 1999, 2000, 2001, 2002, 2003)

Macromolecular
Endocytosis
I ntracellular
I
l

l

l
NO Quenching
Cell-Cell
Matrix-Matrix
Matrix-Cell
INTERACTIONS
M atrix Molecular
M
Adhesion of Monocyte
to
Endothelium
E xtracellular
E
Microvascular Damage DIABETIC NEUROPATHY
B inding Proteins
B
RAGE: Oxidative Stress

p60 (AGE-R1)
p90 (AGE-R2)
Galectin-3 (AGE-R3)
SR1
SR2
1
2
3
4
5
6 NF-kB
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(Tjokroprawiro 1997, 2002, 2003, 2005)
"Syndrome-HDL27" or "Syndrome-999"
ENDOTHELIAL CELL DYSFUNCTION ERECTILE DYSFUNCTION
5

DIABETES MELLITUS
(Tjokroprawiro 1996,1997,1998,1999,2000)
9
Diaclyglycerol
(DAG)
9 HYPERTENSION
1 Activated Platelet
2 Activated Monocytes
3 Cell Ahesin Molecules :
E. Selectin, ICAM-1, VCAM-1
4 Blood Viscoscity
5 Endothelial Permeability
6 Endothelial Production
7 Generation of AII
8 Matrix Expression
9 Responsiveness of SMC to GFs
9 LIPIDS
1 Induction of VCAM
2 MCP-1 expression
3 NO (NOS Inhibits)
4 LDL-Oxidation
5 Cholesterol Accumulation
in Macrophage
6 SMC Proliferation
7 SMC Migration
8
Anti Inflammatory
9
Plaque Instability
-II
Protein Kinase C
Specifically PKC-
Cell Proliferation
Neovascularization
4
Na
+
/H
+
Antiport
Intracellular pH
3
Expression of
Adhesion Mol
( VCAM, ICAM)
2
Vascular
Permeability
1
Vasoconstrictor
Prostanoids
6
Vasoactive
Hormones
7
Altered Gene Expression
(Transcription or Translation Levels)
9
ET-1 8
5
Collagen
BM Synthesis

- Type IV-Collagen
- Fibronectin
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Four Major Biochemical Pathways of
Hyperglycemia-Induced Vascular Damage
(Brownlee 2000, Modified : Tjokroprawiro 2002, 2003, 2004)
Hyperglycemia
MITOCHONDRIUM
AR 1 PKC 2 AGEs 3 NFkB 4
Microvascular Damage
Diabetic Neuropathy
Glucose
ROS : Oxidative Stress
"APAN"
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Oxidative Stress and Diabetes
Multiple Organs
Potential Areas of Impact of Oxidative Stress
(Evans et al 2000, Provided : Tjokroprawiro 2004)
-Cell
Apoptosis
1
Diabetic Complications
Neuropathy, Retinopathy,
Nephropathy, Cataract
4
Insulin
Resistance
2
Endothelial
Dysfunction
3
CAD
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Hyperglycemia (DIR-C-GOS) and Diabetic Neuropathy
Giugliano et al 1996; Ceriello 1998; Jennings 1998, Tomkinson 2003
(Tjokroprawiro 1999, 2003, 2004)
Free Radicals Formation Oxidative Stress

Increased O
2

and Decreased NO
8
DIABETIC NEUROPATHY

DIABETIC VASCULAR COMPLICATIONS
Endothelial Dysfunction and Microvascular Damage
VCAM-1 , ICAM-1 , MCP-1 , Ox-LDL , Ca
2+
, SMC Proliferation ,
Coagulation , Heparan Sulphate , Hypoxia , NCV , Endoneural Blood Flow
(AGE-Formation)
G
G lycation G lycation
(Glucose Autooxidation)

O
O xidants
S
(Poliol Pathway)
S orbitol
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Pathogenesis of Diabetic Neuropathy
(Ward et al 1997; Modified 1999, 2003)
Diffuse Diabetic Polyneuropathy
BM Thickening
Endothelial- Diabetes
Swelling
Blood Coagulability
Diabetes Platelet Reactivity
Rigid Red Blood Cells
Vasoconstriction

Occlusion of
Endoneurial
Capillaries
Nerve Hypoxia
Microvascular Damage
Nerve Conduction Velocity Structural Damage Axonal Loss (Irreversible Neuropathy)
AGE Formation Polyol Pathway Activity
(G) (S)
Diabetes
Nerve Glucose


Free Radical Formation
(O)

NO Quenching NO Generation
Uncontrolled
Diabetes
GLA
Uncontrolled
Diabetes
Endothelin
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(Nitric Oxide Synthase)
NOS
(Summarized : Tjokroprawiro 1997,1998,1999,2002)
+
NO
US-TRIO WINS PRICE-1998 (US $ 1.6 Million)
Furchgott (82), Murad (62), Ignarro (57)
ADMA = Asymetric Di Methyl Arginine
Co-Factors : NADPH, Calmodulin + Ca
++
,
Tetrahydrobiopterin
Plants (Source of Arginine) :
Peanut, Red Bean, Soy-Bean, Small Green Pea
Animals (Arginine) :
Fishes (Sunu, Japuh, Selar, Eel), Fish Egg, Lamb, Chicken
ADMA, L-NMMA, L-NAME

(Ho et al 1999)
L-ARGININE

in
Endothelial Cell
Oxidation
L-CITRULLINE
STATINS,TESTOTERON
10
Hypercholesterolemia
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A : Lebih dari 2000 mg

Kedelai Hitam 2098
Kedelai Putih 2355

Kacang Merah 2681
Kacang Tanah 2719
C : 400 - 1000 mg

Beras Giling 472
Emping 578
Jagung 590
Telor Ayam Ras 684
Telor Ayam Lokal 756
Telor Ikan Mujaer 834
Ikan Mas 848
Kandungan ARGININ per 100 gram
(Asam Amino Ateroprotektif)
Pusat Diabetes dan Nutrisi*)- Instalasi Gizi**)
RSUD Dr. Soetomo - FK Unair, Surabaya
(Tjokroprawiro dkk* 1999, Hariwitarti**, Frieda**, Eko**)
B : 1000 - 2000 mg
Daging Sapi 1100
Telur Ikan 1188
Daging Ayam 1189
Daging Kambing 1222
Kacang Hijau 1516

Kecipir 1557
Lamtoro 1652

Ikan Sunu Asin 1835
Belut 1048
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Diet-KV : Stroke, CAD, POAD, MS

Diet-B plus 5 Specifications
Diet-G : G angrene
Diet-B
1
plus 6 Specifications
Able to Reduce
Homocysteinemia

Diet-B (% Cal) : 68% Cbh, 20% F, 12% P
(Chol. < 300 mg/day)


1 Arginin Content
2 Fiber 25-35 g/day
3 Folate
4 Vit B
6


5 Vit B
12

Able to Reduce
Homocysteinemia

Diet-B
1
(% Cal) : 60% Cbh, 20% F, 20% P

1 Arginin Content
2 Fiber 25-35 g/day
3 Cholesterol < 300 mg/day

4 Folate
5 Vit B
6


6 Vit B
12

Arginin : Atheroprotective
Homocysteine : Atherogenic
(Tjokroprawiro et al, 1999, 2001; Hariwitarti et al, 1999)

DIET-G and DIET-KV
SPECIFICATIONS : 2 of 21 Diabetic Diets in Dr. Soetomo Hospital
12
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In
Out
+
Intracellular
Na
Na
+
Inositol
polyphosphates
Na --K -- TPase
Ca mobilization
2+
Diacylglycerol
+ +

Protein kinase C
Phosphatidylinositol
13
4-Possible Mechanisms of Intracellular Myoinositol Depletion
(Ida Giargino, et al, 1997, Modified : 2003)
Myoinositol
Myoinositol

Glucose
Glucose

Sorbitol
1
2
3
4
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Diabetic Neuropathy
Ward et al 1997, Hewitt 2000,
Provided : Tjokroprawiro 1999,2000,2001,2003,2004)
Oxidative Stress
Microvascular Neural Cell Damage
14
Nerve Na
Conduction Velocity
Na -K ATPase
+ +
+
NO
Quenching
NO
Production
Citrulline
AGE
formation
NADP
NADPH
L-Arginine
Aldose
Reductase
HYPERGLYCAEMIA
Sorbitol

Nerve
Glucose
MYOINOSITOL
Nerve
Myoinositol

Protein
Kinase C
NOS' Inactivactors : ADMA, L-NMMA, L-NAME
NOS' Co-Factors : NADPH, Calmodulin + Ca ,
Tetrahydrobiopterin
++
NO
Synthase
3
4
2
5
1
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GLA
Gamma Linolenic Acid
Evening Primrose Oil : EPO
Linoleic Acid 75%, GLA 8-10%
15
The Roles of EFA-GLA in Diabetic Neuropathy
(Summarized : Tjokroprawiro 1999, 2003, 2004)
Linoleic Acid
Essential Fatty Acid
(EFA)
-6 Desaturase
DIABETIC NEUROPATHY GLA Deficiency Reduced Nerve Blood Flow
Reverses
Biochemical and Functional
Diabetic Nerve Defects
Precursor of
Prostanoids (PGI
2
)
Uncontrolled Diabetes and Insulin Deficiency
Insulin
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CLINICAL STAGING OF HYPERGLYCEMIA
(Summarized : Tjokroprawiro 1997)
FF1,
1
AFGP,
2
Pyrroline,
4
Crossline
6
Glucose Schiff
+
NH2 - R Base
PHASE-1
K
1

Hours
Glucose & Schiff Base
Amadori
Products
PHASE-2
K
2

Days
Amadori Products
AGE
s

PHASE-3
K
n

Weeks -Months
AGE
Carboxy Methyl Lysine and Pentosidine
Both are
Most Toxic
AGE
s
: 6 Subproducts
(Advanced Glycosylated End products)
CML,
3
Pentosidine,
5
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Various Information About Diabetic Neuropathy
Ward et al 1997, Watkins et al 1997, Tomkinson 2003, Young 1997, 2003
(Summarized : 2004)
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Many Classifications of Diabetic Neuropathy :
II "Insulin Neuritis" :
- Acute Diffuse Neuropathy, often painful
- Developes Fall in Nerve Blood Flow Stimulates Abnormal New Vessel
Formation "Steals" Blood Flow from the Nerve Core
I Diabetic Nerve Damage :
Hyperglycemic Neuropathy (Acute and Reversible)
Symmetrical Polyneuropathies (Chronic, "Glove and Stocking" Distribution)
Focal and Multifocal Lesions
Compressive Neuropathies
1
2
3
4
III Painful Diabetic Neuropathy = PDN :
Diabetic Neuropathy Nerve Injury with 3 Consequences, through 3 pathways.
These 3 mechanisms result in the Activation of C and A Fibers that may cause
EAA-Release. The EAAs activate NMDA-Receptors, and the latter may stimulate
Hyperexcitability of Spinal Cord and Dorsal Horn Neurons, PDN may pursue
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Excessive Stimulation

Destruction of
Inhibitory Interneurons
Intracellular Ca
++


Activated PKC
ACTIVATION OF NMDA RECEPTORS
HYPEREXCITABILITY OF SPINAL CORD
DORSAL HORN NEURONS

PAINFUL DIABETIC NEUROPATHY
Fixation of EAA
on Receptors
Activation
of NOS
Fixation of SP
on NK1 Receptors
Three Molecular Mechanisms-Activation of C and A Fibers
(Attal and Bouhassira, 1999, Summarized : Tjokroprawiro 2001, 2003)
PAINFUL DIABETIC NEUROPATHY : PDN
Ectopic Discharges Fiber interactions
Diabetic Neuropathy
NERVE INJURY

Nociceptor Sensitization

Tonic Activation of C and A Fibers

Release of EAA
1 2 3
GABAPENTIN
Excellent Glycemic Control Excellent Glycemic Control
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Relating Symptoms to Mechanisms of Neuropathic Pain
(Summarized : Tjokroprawiro 2004)
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Possible Mechanisms
1 Ectopic Impulses
2 Loss of Inhibitory Control,
Peripheral Nociceptor Sensitization,
Ectopic Discharges in C Fibers
3 Ectopic Discharges
4 Loss of Inhibitory Controls,
Central Sensitization of A Fibers,
Central Reorganization of A Fibers,
Peripheral Nociceptor Sensitization
5 Peripheral Sensitization
Symptoms or Signs
1 Paraesthesias/Dysesthesias
2 Burning Pain (C-Fibers)
3 Shooting or Lancinating Pain
4 Allodynia (A Fibers)
5 Hyperalgesia (Sharp Pain)
Hyperalgesia : An increased response to a stimulus that is normally painful
Allodynia : Pain due to a stimulus that is not normally painful
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Five-Underlying Mechanisms of Neuropathic Pain
(Summarized : Tjokroprawiro 2004)
5 Loss of Inhibitory Controls of C and A Fibers
(Allodynia, Burning)
1 Peripheral Nociceptor Sensitization
(Allodynia, Burning, Hyperalgesia)

2 Ectopic Discharges in C Fibers
(Burning)

3 Central Sensitization of A Fibers
(Allodynia)

4 Central Reorganization of A Fibers
(Allodynia)

20
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ICNeP (1999)
The International Coalition for Neuropathic Pain
(Karisten 1997, de Wit et al 1999, Summarized : Tjokroprawiro 2004)
1 Paresthesias/Dysesthesias
2 Burning Pain
(Ectopic Discharges in C-Fibres)
3 Shooting Pain or Lancinating
4 Allodynia : Dull Pain
(not normally painful, A Fibers)
5 Hyperalgesia (normally
painful) : Sharp Pain
Signs and Symptoms
1 Injury : Trauma, Surgical,
Procedures, Pressure

2 Metabolics : PDN, etc

3 Infections : PHN, etc

4 Cancer

5 Exposure to :
Toxins, Drugs, Alcohol

6 Vascular Diseases

7 Nutritional Deficiencies
Causes
Quality, Intensity, Location, Pattern
1 MPQ = McGill Pain
Questionnaire
2 VAS : Visual Analog Scales
3 Patient Diary
4 NPS = Neuropathic Pain Scale
Scales in Pain
Nociceptive Pain : An Appropriate Physiologic Response to Painful Stimuli
Neuropathic Pain : An Appropriate Response caused by Primary Lession or Dysfunction
in the Nervous System
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Excellent Continuous Glycemic Control
Optimize Blood Pressure and Lipid Profile
Attention (!!) : Phase I, Phase II, and Phase III of Hyperglycemic Stages
22
(Summarized : Tjokroprawiro 1999, 2003, 2004)
Management of Diabetic Neuropathy
Diabetic Neuropathy Painful Diabetic Neuropathy
1 Neuropathic Pain Syndromes
2 Burning Pain-Aching Sensation
3 Lancinating Pain-Shooting Pain
4 Allodynia (Contact Sensitivity)
5 Restless Legs
6 Painful Cramps
7 Dull-Pain / Throbbing Pain
8 Hyperalgesia
9 Phantom Limb Pain
10 SUNCT Syndrome ?
"DALANG"

1 D iabetes

2 A nti Platelet

3 L ipids

4 A mitriptyline

5 N eurotropic

6 G abapentin
1 GLA Supplementation (EPO)
2 Various Vasodilators : ACE-Is, Etc
3 Pimagedine = Aminoguanidine (AGE-Inhibitor)
4 rhNGF (recombinant human Nerve Growth Factor)
5 Anti Oxidants
6 Anti Platelet Agents
7 Alpha-Lipoic Acid (ALA)
Possible Drugs ARI
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General Measures
Excelent Glycemic Control is Mandatory; Possible Modifying Drugs
Exclude or Treat Other Contributory F actors : Alcohol Excess Vitamin B12 Deficiency Uraemia
23
(Clinical Experiences : 2001, 2003, 2004)
Management of Painful Diabetic Neuropathy
Choose Drugs according to the Patients's Dominant Symptoms
"DALANG" : D iabetes, A nti Platelet, L ipids, A mitriptyline, N eurotropic, G abapentin
1 Anticonvulsants :
Carbamazepine 400-800 mg/day
Oxcarbazepine 1200-2400 mg/day
Gabapentin 300-1200 mg/day
Phenytoin 100 mg tid
2 Tricyclic Agents
3 Capsaicin 0.075% qid
1 Tricyclic Drugs :
Imipramine 25 mg tid
Amitryptiline 25-100 mg at night
Fluphenazine 1 mg tid
2 Capsaicin 0.075% qid
1 Contact Discomfort (Allodynia)
Plastic Film (Opsite) on legs

2 Restless legs :
Clonazepam

3 Painful Cramps :
Quinine Sulphate 300 mg at night
Shooting Pain Other Symptoms Burning Pain
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Neuropathic Pain Syndromes
(Clinical Experiences : Tjokroprawiro, 2000, 2003, 2004)
Hyperexcitability of Spinal Cord Dorsal Horn Neurons
Painful Diabetic Neuropathy
Diabetic Neuropathy
Nerve Injury
Activated C and A-Fibers
EAA-Release
Activated NMDA Receptors
(N-Methyl-D-Aspartate)
Intracelluar Ca
++


Activated PKC
GABAPENTIN
Dose : 300-1200 mg/day
Excellent
Glycemic Control
Excellent
Glycemic Control
GABAPENTIN
Dose : 300-1200 mg/day
"DALANG" "DALANG"
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GABAPENTIN (R/NEURONTIN)
A New Tool in the Treatment of Neuropathic Pain
(Harden, 1999; Summarized : Tjokroprawiro 1999, 2003, 2004)
III
GABAPENTIN (GBPT) may be effective in :
1 Painful Diabetic Neuropathy 6 Allodynic Pain
2 Pain in PHN 7 Intractable Chronic Pain
3 Trigeminal Neuralgia 8 Complex Regional Pain Syndrome
4 Neuropathic Cancer Pain 9 AIDS-related Neuropathy
5 SUNCT Syndromes 10 Phantom Limb Pain
IV
GBPT is well tolerated, with minor sides effects : Somnolence, Dizziness
V
Dose (Clinical Experiences) : 300-1200 mg/daily are often effective
VI
GBPT can be considered as the First Line Drug in "DALANG"
I I-Aminomethyl Cyclohexaneacetic Acid :
Non-Opioid Agent (GABA-Analogue)
Lipophilic Penetrates Blood Brain Barrier; USA: as Anti Convulsant in 1994
turning down Allodynic Pain
or "Wind Up"
II GABA (in DORSAL HORN) :


Release of EAA

Activated NMDA-Receptor Intra. Ca
++


Intracellular Ca
++



PKC

PDN
works at Calcium Channels : to access neurotransmission at many levels
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"DALANG" and FORMULA 3-3-3-3
Practical Guidelines for the Treatment of PDN
(Clinical Experiences : Tjokroprawiro 2002, 2004, 2005)
D Diabetes : 1 FPG 90-130; Peak PP < 180; A1C < 6-7%
2 < 130/80; ISH (>180) Gradually Lowered in Stages
A Anti Platelet Agents : ASA, Cilostazol, Naftidrofuryl, Clopidogrel, Etc
L Lipids : Tot.C < 200 LDL-C < 100; HDL-C > 40 ( ), >50 ( ); TG<150
(mg/dl)
A Amitriptyline : 25-100 mg/day at Night, Escalating Doses
N Neurotropic Agents : Vit B
12
, B
6
, B
1
, Etc
G Gabapentin : GABA-Analog, 300-1200 mg/day : Formula 3-3-3-3
(Titrated Doses)
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Treatment of Painful Diabetic Neuropathy with GABAPENTIN
by
Dalang and Formula 3-3-3-3
(Clinical Experiences : Tjokroprawiro 2000, 2004, 2005)
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Excellent
"HDL"
A Continuous Tight Glycemic Control ("D") is an Obligatory :
Optimized Blood Pressure ("H") and Lipid Profile ("L")
B One Tablet of GABAPENTIN : 300 mg
1 Starting Dose : 1 Tablet/Evenings for 3 Days 0-0-0-1 300 mg/day
2 Titrated up to 600 mg after 3 Days 0-0-1-1 600 mg/day
3 Titrated up to 900 mg after 3 Days 0-1-1-1 900 mg/day
4 Last Titrated Dose 1200 mg after last 3 Days 1-1-1-1 1200 mg/day
C If no adequate response with GBPT 1200 mg/day Use Amitriptyline
with Starting Dose : 25 mg at night, titrated up to 100 mg given before sleep
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Kuta Beach
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Copacabana Beach - Rio de Janeiro
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