Treatment of Painful Diabetic Neuropathy

(Practical Guidelines with "Dalang" and Formula 3-3-3-3)

2005
(28)
Askandar Tjokroprawiro
Diabetes and Nutrition Centre - Dr. Soetomo Teaching Hospital
Airlangga University School of Medicine, Surabaya

Indonesian Neuroscience Summit 2005

Batam (Planet Holiday Hotel), 13-14 August 2005
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Chronic Diabetic Complications and Provided Information
(Tjokroprawiro, 1993, Revised : 1998, 2002)

Dyslipidemia 67.0
Symptomatic Neuropathy*) 51.4
Erectile Dysfunction 50.9
Retinopathy 27.2
30 million in USA
Joint Manifestation 25.5 (FELDMAN, et al 1994)
Cataract 16.3
Pulmonary Tbc 12.8
Hypertension in Europe : 30 %
Hypertension (WHO,1983) 12.1
CHD 10.0
(Williams, 1991)
Clinical Nephropathy 5.7
Stroke 4.2 Commulative Prevalence of CVD : 63.0%
Cellulitis - Gangrene 3.8 (in line with Dyslipidemia)
Symptomatic Gall Stone 3.0
*) + 5% of this Prevalence : PDN 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 %

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

Erectile Dysfunction = ED (NIH-Consensus 1993) Inability to achieve or maintain an erection sufficient

:
IIEF 1997 : Score < 21 for satisfactory sexual performance
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 Clinical Staging of Hyperglycemia 3
Microvascular and Diabetic Neuropathy
(Summarized : Tjokroprawiro 1994, 1995, 1996, 1997, 1999, 2001, 2002, 2003, 2004)

Schiff Base PHASE-1

Excellent (Hours)
Glycemic Control
Amadori Products PHASE-2
(Days) Adhesion Mol.
Aminoguanidine*) Expression
(Kowluru et al 1999) AGEs PHASE-3 (Lopes-Virella et al 1999)
(Week-Months)
*)  AGE and  Oxidative Stress
AGE-Protein
(Brownlee, 1995)
2 1
Macrophage Nucleic Acid Histones Endothelial Cell
RAGE (SR1, SR2) Mutation RAGE (R1, R2, R3)
Oxidative Stress
Gene Expression
TNF, IL-1, IGF-1
Endothelin-1
Production 3
Tissue Factor Production
Pancreatic Ca Cancer Liver Ca

Proliferation of Microvascular Damage Vasoconstriction

Cells and Matrix DIABETIC NEUROPATHY Focal Thrombosis
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Pathologic Effects of AGES : "BIME"

(Summarized : Tjokroprawiro 1999, 2000, 2001, 2002, 2003)

B I M E
Binding Proteins Intracellular Matrix Molecular Extracellular

RAGE: Oxidative Stress Macromolecular NO Quenching Adhesion of Monocyte

Endocytosis l Cell-Cell to
1 p60 (AGE-R1)
2 p90 (AGE-R2) l Matrix-Matrix Endothelium
3 Galectin-3 (AGE-R3) l Matrix-Cell
4 SR1 INTERACTIONS
5 SR2
6 NF-kB

Microvascular Damage DIABETIC NEUROPATHY

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 "Syndrome-HDL•27" or "Syndrome-9•9•9" 5
(Tjokroprawiro 1997, 2002, 2003, 2005)

ENDOTHELIAL CELL DYSFUNCTION – ERECTILE DYSFUNCTION

HYPERTENSION 9 DIABETES MELLITUS 9 LIPIDS 9

(Tjokroprawiro 1996,1997,1998,1999,2000)
1 Activated Platelet 1 Induction of VCAM
2 Activated Monocytes 2 MCP-1 expression
3 Cell Ahesin Molecules : 3 NO (NOS Inhibits)
E. Selectin, ICAM-1, VCAM-1 4 LDL-Oxidation
4 Blood Viscoscity 5 Cholesterol Accumulation
5 Endothelial Permeability Diaclyglycerol in Macrophage
6 Endothelial Production (DAG) 6 SMC Proliferation
7 Generation of AII 7 SMC Migration
8 Matrix Expression 8 Anti Inflammatory
9 Responsiveness of SMC to GFs 9 Plaque Instability

ET-1 8 Protein Kinase C Vasoactive

7
 -II  Hormones
Altered Gene Expression Specifically PKC-
9
(Transcription or Translation Levels) 6 Vasoconstrictor
Prostanoids
5
1 2 3 4 Collagen
Vascular Expression of BM Synthesis
Permeability Adhesion Mol Na+/H+ Antiport Cell Proliferation
- Type IV-Collagen
Intracellular pH Neovascularization
( VCAM, ICAM) - Fibronectin
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Four Major Biochemical Pathways of
Hyperglycemia-Induced Vascular Damage
(Brownlee 2000, Modified : Tjokroprawiro 2002, 2003, 2004)

Hyperglycemia

 Glucose

 ROS : Oxidative Stress

"APAN"

1  AR 2  PKC 3 AGEs 4 NFkB

Microvascular Damage
Diabetic Neuropathy

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Oxidative Stress and Diabetes
Multiple Organs

1
-Cell 2
Apoptosis Insulin 3
Resistance CAD
Endothelial 4
Dysfunction Diabetic Complications
Neuropathy, Retinopathy,
Nephropathy, Cataract

Potential Areas of Impact of Oxidative Stress

(Evans et al 2000, Provided : Tjokroprawiro 2004)
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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)

G O S
G lycation O xidants S orbitol
(AGE-Formation) (Glucose Autooxidation) (Poliol Pathway)

Free Radicals Formation Oxidative Stress

Increased O2– and Decreased NO

Endothelial Dysfunction and Microvascular Damage

VCAM-1 , ICAM-1 , MCP-1 , Ox-LDL , Ca2+ , SMC Proliferation ,
Coagulation , Heparan Sulphate , Hypoxia , NCV , Endoneural Blood Flow 
DIABETIC VASCULAR COMPLICATIONS

DIABETIC NEUROPATHY
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Pathogenesis of Diabetic Neuropathy
(Ward et al 1997; Modified 1999, 2003)
Diabetes

Nerve Glucose

AGE Formation Free Radical Formation Polyol Pathway Activity

(G) (O) (S)

NO Quenching NO Generation
Uncontrolled Uncontrolled
Endothelin Vasoconstriction GLA
Diabetes Diabetes

Blood Coagulability Occlusion of BM Thickening

Diabetes Platelet Reactivity Endoneurial Endothelial- Diabetes
Rigid Red Blood Cells Capillaries Swelling

Nerve Hypoxia
Microvascular Damage

Structural Damage Axonal Loss (Irreversible Neuropathy) Nerve Conduction Velocity

Diffuse Diabetic Polyneuropathy

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Plants (Source of Arginine) :
Peanut, Red Bean, Soy-Bean, Small Green Pea
Animals (Arginine) :
Fishes (Sunu, Japuh, Selar, Eel), Fish Egg, Lamb, Chicken

Oxidation
L-ARGININE L-CITRULLINE + NO
in
Endothelial Cell US-TRIO WINS PRICE-1998 (US $ 1.6 Million)
Furchgott (82), Murad (62), Ignarro (57)
Hypercholesterolemia
Co-Factors : NADPH, Calmodulin + Ca++,
Tetrahydrobiopterin

ADMA, L-NMMA, L-NAME NOS STATINS,TESTOTERON

(Ho et al 1999)
(Nitric Oxide Synthase)
ADMA = Asymetric Di Methyl Arginine
(Summarized : Tjokroprawiro 1997,1998,1999,2002)
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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**)

A : Lebih dari 2000 mg B : 1000 - 2000 mg C : 400 - 1000 mg

Kedelai Hitam 2098 Belut 1048 Beras Giling 472
Kedelai Putih 2355 Daging Sapi 1100 Emping 578
Telur Ikan 1188 Jagung 590
Kacang Merah 2681 Daging Ayam 1189 Telor Ayam Ras 684
Kacang Tanah 2719 Daging Kambing 1222 Telor Ayam Lokal 756
Kacang Hijau 1516 Telor Ikan Mujaer 834
Ikan Mas 848
Kecipir 1557
Lamtoro 1652
Ikan Sunu Asin 1835

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SPECIFICATIONS : 2 of 21 Diabetic Diets in Dr. Soetomo Hospital
DIET-G and DIET-KV
(Tjokroprawiro et al, 1999, 2001; Hariwitarti et al, 1999)

Diet-G : Gangrene Diet-KV : Stroke, CAD, POAD, MS

Diet-B1 plus 6 Specifications Diet-B plus 5 Specifications

Diet-B1 (% Cal) : 60% Cbh, 20% F, 20% P Diet-B (% Cal) : 68% Cbh, 20% F, 12% P
(Chol. < 300 mg/day)
1 Arginin Content 
2 Fiber 25-35 g/day 1 Arginin Content 
3 Cholesterol < 300 mg/day 2 Fiber 25-35 g/day
4 Folate 3 Folate
Able to Reduce 4 Vit B6 Able to Reduce
5 Vit B6
Homocysteinemia 5 Vit B12 Homocysteinemia
6 Vit B12

Arginin : Atheroprotective
Homocysteine : Atherogenic
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 Myoinositol 13
Glucose 1

Glucose 2
Myoinositol

Sorbitol 3 4
Phosphatidylinositol
Intracellular
Inositol Na+
polyphosphates

Ca2+ mobilization Diacylglycerol

Protein kinase C Na+

In
Na+ --K+ -- TPase
Out

4-Possible Mechanisms of Intracellular Myoinositol Depletion

(Ida Giargino, et al, 1997, Modified : 2003)
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HYPERGLYCAEMIA
MYOINOSITOL
1

NOS' Inactiv actors : ADMA, L-NMMA, L-NAME

NOS' Co-Factors : NADPH, Calmodulin +Ca++ ,
Nerve Na+ 5
Tetrahy drobiopterin

Na+ -K+ ATPase Nerve

Nerve 2
Glucose L-Arginine
Myoinositol
NADPH
Aldose NO
Protein Synthase
Kinase C Reductase AGE
formation
NADP
3 Sorbitol Citrulline
NO NO
Conduction Velocity Production Quenching

4
Diabetic Neuropathy Oxidative Stress
Ward et al 1997, Hewitt 2000, Microvascular Neural Cell Damage
Provided : Tjokroprawiro 1999,2000,2001,2003,2004)

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The Roles of EFA-GLA in Diabetic Neuropathy
(Summarized : Tjokroprawiro 1999, 2003, 2004)

Evening Primrose Oil : EPO

Linoleic Acid 75%, GLA 8-10%

Linoleic Acid GLA Precursor of

Essential Fatty Acid
Gamma Linolenic Acid Prostanoids (PGI2)
(EFA)

Reverses
Insulin -6 Desaturase Biochemical and Functional
Diabetic Nerve Defects

Uncontrolled Diabetes and Insulin Deficiency

GLA Deficiency Reduced Nerve Blood Flow DIABETIC NEUROPATHY

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CLINICAL STAGING OF HYPERGLYCEMIA
(Summarized : Tjokroprawiro 1997)

PHASE-1 PHASE-2 PHASE-3

Hours Days Weeks -Months
Glucose & Schiff Base Amadori Products AGE
K1 K2 Kn
Glucose Schiff Amadori AGEs
+ Products
NH2 - R Base

AGEs : 6 Subproducts
(Advanced Glycosylated End products)

FF1, AFGP, CML, Pyrroline, Pentosidine, Crossline

1 2 3 4 5 6

Both are
Carboxy Methyl Lysine and Pentosidine Most Toxic
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Various Information About Diabetic Neuropathy
Ward et al 1997, Watkins et al 1997, Tomkinson 2003, Young 1997, 2003
(Summarized : 2004)

Many Classifications of Diabetic Neuropathy :

I Diabetic Nerve Damage :
1 Hyperglycemic Neuropathy (Acute and Reversible)
2 Symmetrical Polyneuropathies (Chronic, "Glove and Stocking" Distribution)
3 Focal and Multifocal Lesions
4 Compressive Neuropathies
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
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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 PAINFUL DIABETIC NEUROPATHY : PDN 18
Three Molecular Mechanisms-Activation of C and A Fibers
(Attal and Bouhassira, 1999, Summarized : Tjokroprawiro 2001, 2003)
Excellent Glycemic Control Diabetic Neuropathy Excellent Glycemic Control

NERVE INJURY
1 2 3
Ectopic Discharges Nociceptor Sensitization Fiber interactions

Fixation of SP
Tonic Activation of C and A Fibers
on NK1 Receptors
Release of EAA GABAPENTIN
Fixation of EAA
on Receptors ACTIVATION OF NMDA RECEPTORS
Intracellular Ca++ Excessive Stimulation

Destruction of
Activation Activated PKC Inhibitory Interneurons
of NOS
HYPEREXCITABILITY OF SPINAL CORD
DORSAL HORN NEURONS

PAINFUL DIABETIC NEUROPATHY

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Relating Symptoms to Mechanisms of Neuropathic Pain
(Summarized : Tjokroprawiro 2004)

Symptoms or Signs Possible Mechanisms

1 Paraesthesias/Dysesthesias 1 Ectopic Impulses
2 Burning Pain (C-Fibers) 2  Loss of Inhibitory Control,
 Peripheral Nociceptor Sensitization,
 Ectopic Discharges in C Fibers
3 Shooting or Lancinating Pain 3 Ectopic Discharges
4 Allodynia (A Fibers) 4  Loss of Inhibitory Controls,
 Central Sensitization of A Fibers,
 Central Reorganization of A Fibers,
 Peripheral Nociceptor Sensitization
5 Hyperalgesia (Sharp Pain) 5 Peripheral Sensitization

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)

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)
5 Loss of Inhibitory Controls of C and A Fibers
(Allodynia, Burning)
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ICNeP (1999)
The International Coalition for Neuropathic Pain
(Karisten 1997, de Wit et al 1999, Summarized : Tjokroprawiro 2004)

Causes Scales in Pain Signs and Symptoms

1 Injury : Trauma, Surgical, Quality, Intensity, Location, Pattern 1 Paresthesias/Dysesthesias
Procedures, Pressure
1 MPQ = McGill Pain 2 Burning Pain
2 Metabolics : PDN, etc (Ectopic Discharges in C-Fibres)
Questionnaire
3 Infections : PHN, etc
2 VAS : Visual Analog Scales 3 Shooting Pain or Lancinating
4 Cancer
3 Patient Diary 4 Allodynia : Dull Pain
5 Exposure to :
Toxins, Drugs, Alcohol 4 NPS = Neuropathic Pain Scale (not normally painful, A Fibers)
6 Vascular Diseases 5 Hyperalgesia (normally
7 Nutritional Deficiencies painful) : Sharp 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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Management of Diabetic Neuropathy

(Summarized : Tjokroprawiro 1999, 2003, 2004)

Excellent Continuous Glycemic Control

Optimize Blood Pressure and Lipid Profile
Attention (!!) : Phase I, Phase II, and Phase III of Hyperglycemic Stages

Diabetic Neuropathy Painful Diabetic Neuropathy

1 Neuropathic Pain Syndromes "DALANG"

Possible Drugs ARI 2 Burning Pain-Aching Sensation
3 Lancinating Pain-Shooting Pain 1 Diabetes
4 Allodynia (Contact Sensitivity) 2 Anti Platelet
1 GLA Supplementation (EPO)
2 Various Vasodilators : ACE-Is, Etc 5 Restless Legs 3 Lipids
3 Pimagedine = Aminoguanidine (AGE-Inhibitor) 6 Painful Cramps
7 Dull-Pain / Throbbing Pain 4 Amitriptyline
4 rhNGF (recombinant human Nerve Growth Factor)
5 Anti Oxidants 8 Hyperalgesia 5 Neurotropic
6 Anti Platelet Agents 9 Phantom Limb Pain
6 Gabapentin
7 Alpha-Lipoic Acid (ALA) 10 SUNCT Syndrome ?

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Management of Painful Diabetic Neuropathy
(Clinical Experiences : 2001, 2003, 2004)

General Measures
Excelent Glycemic Control is Mandatory;Possible Modifying Drugs
Exclude or Treat Other Contributory Factors : • Alcohol Excess • Vitamin B12 Deficiency • Uraemia

Choose Drugs according to the Patients's Dominant Symptoms

Burning Pain Shooting Pain Other Symptoms

1 Tricyclic Drugs :
• Imipramine 25 mg tid
• Amitryptiline 25-100 mg at night
• Fluphenazine 1 mg tid
2 Capsaicin 0.075% qid
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 Contact Discomfort (Allodynia)
• Plastic Film (Opsite) on legs
2 Restless legs :
• Clonazepam
3 Painful Cramps :
• Quinine Sulphate 300 mg at night

"DALANG" : Diabetes, Anti Platelet, Lipids, Amitriptyline, Neurotropic, Gabapentin

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Neuropathic Pain Syndromes
(Clinical Experiences : Tjokroprawiro, 2000, 2003, 2004)

Excellent Diabetic Neuropathy Excellent

Glycemic Control Glycemic Control
Nerve Injury

Activated C and A-Fibers

GABAPENTIN GABAPENTIN
EAA-Release
Dose : 300-1200 mg/day Dose : 300-1200 mg/day
Activated NMDA Receptors
(N-Methyl-D-Aspartate)

"DALANG" Intracelluar Ca++ "DALANG"

Activated PKC

Hyperexcitability of Spinal Cord Dorsal Horn Neurons

Painful Diabetic Neuropathy
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GABAPENTIN (R/NEURONTIN)
A New Tool in the Treatment of Neuropathic Pain
(Harden, 1999; Summarized : Tjokroprawiro 1999, 2003, 2004)

I I-Aminomethyl Cyclohexaneacetic Acid :

• Non-Opioid Agent (GABA-Analogue)
• Lipophilic Penetrates Blood Brain Barrier; USA: as Anti Convulsant in 1994
II GABA (in DORSAL HORN) :
 Release of EAA turning down Allodynic Pain
 Activated NMDA-Receptor  Intra. Ca++
or "Wind Up"
 Intracellular Ca++  PKC  PDN
works at Calcium Channels : to access neurotransmission at many levels
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"
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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 B12, B6, B1, 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)

A Continuous Tight Glycemic Control ("D") is an Obligatory : Excellent

Optimized Blood Pressure ("H") and Lipid Profile ("L") "HDL"
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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