2 December 1951

Bukit Tinggi

MD, FK USU, 1978

PhD in Clinical Pharmacology

FUSA-Flinders Medical Centre
Australia, 1988

SpFK, Clinical Pharmacologist

PB-IDI & FK UI, 1995
Professor
Head of Department
Pharmacology & Therapeutic
School of Medicine, USU
Email: aznanlelo@yahoo.com Jln. Tridharma 22
Kampus USU, Medan
 Aznan Lelo
Dep. Farmakologi & Terapeutik,
Fakultas Kedokteran
Universitas Sumatera Utara
19 April 2014, PERDOSSI, Medan
 Kasus
• Wanita, 55 tahun, mengeluh nyeri wajah di
pipi kanan, kumat-kumatan, seperti
disayat pisau, terjadi pada saat
mengunyah, saat bicara, saat menguap,
atau dapat rangsangan dingin.
• Pada pemeriksaan neurologist lain dalam
batas normal.
• Riwayat sakit gigi (+) dan sudah dicabut.
Inflammaory nociceptive pain
Neuropathic pain
 Nociceptive VS neuropathic pain

Nociceptive pain Neuropathic pain

Caused by activity in neural Mixed pain Initiated or caused by
pathway in response to Caused by a combination primary lesion or
potentially tissue- of both primary injury or dysfunction in the nervous
damaging stimuli secondary effects system

CRPS
Postoperative ARTHRITIS PHN
pain
Adjuvant Trigeminal
Mechanical LBPNSAID
Sickle cell crisis Neuropathic LBP
neuralgia
ANALGESIC
Sport / exercise Distal Central post
injuries polyneuropathy stroke pain
(e.g. diabetic)
International Association for the Study of Pain. IASP Pain Terminology.
Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57
 Pharmacologic Agents
Affect Pain Differently
Inhibition of BRAIN
Ascending
Descending Modulation
Pain Pathways NSAIDs
Spinal Anticonvulsants
Opioids  CNS Cord Opioids
Tricyclic/SNRI Antidepressants

NSAIDs NT Dorsal Central Sensitization

PNS Horn Alpha-2 Delta agonists
Anticonvulsants
Antiarrhythmic Opioids
Peripheral Local Anesthetics
NMDA-Receptor Antagonists
Sensitization Topical Analgesics
Tricyclic/SNRI Antidepressants
Anticonvulsants
Tricyclic Antidepressants
Opioids
 Neuropathic Pain: Pharmacologic Therapies
DRUG DOSAGE / DAY COMMON SIDE EFFECTS
Antidepressants
Amitriptyline (TCA) 20–150 mg
Nortriptyline (TCA) 20–150 mg
Sedation, weight gain, anticholinergic
effects, sexual dysfunction, arrhythmia (side
Desipramine (TCA) 20–200 mg
effects most prominent with Amitriptyline)
Duloxetine (SNRI) 60–120 mg
Anticonvulsants
Gabapentin 600–3600 mg Sedation, dizziness, peripheral oedema,
Pregabalin 150–600 mg weight gain, Stevens-Johnson syndrome,
Lamotrigine 25–400 mg rash, dizziness, nausea,, ataxia, aplastic
Carbamazepine 200–1200 mg anaemia, liver enzyme elevation, fatigue,
Oxcarbazepine 600–2400 mg leukopenia
Topical anaesthetics
5% Lidocaine patch Every 12 hours Local oedema, burning, erythema
Capsaicin patch 3 or 4 times a day Burning
Opioids, opioid agonists
Tramadol 100–400 mg Sedation, dizziness, seizures, nausea,
Oxycodone 10–100 mg constipation, potential for addiction and abuse

Neurotropic Vitamin  B1, B6, B12 (+B9 Folic acid)

 Neuropathy
• Neuropathy is a general term that refers to
diseases or malfunctions of the nerves.
• Any nerves at any location in the body can
be damaged from injury, disease,
infections, or even vitamin deficiency
states.
• Regardless of the cause, neuropathy is
associated with characteristic symptoms,
but neuropathic pain is the most
frequent symptom.
 The goal of Treatment
• to manage the underlying condition
causing the neuropathy and
• repair damage, as well as
• provide symptom relief.

• neuropathic pain is the most

frequent symptom
 Pain Classification
Acute

Duration
Chronic
Nociceptive
Patho-
physiology Neuropathic
Mild

Severity
Severe
 Classification of Analgesics
Analgesic

Opioid Non-opioid

Anti- Anti-
Strong Weak pyretic inflammatory Adjuvant

Morphine Codeine Acetaminophen

Celecoxib Antidepressant

Metampyrone
Diclofenac Anticonvulsant
Fentanyl Tramadol Ibuprofen Local anesthetic

NSAID
 Targets for controlling
neuropathic pain
• activation of the inhibitory transmitter systems or
restore inhibitory neurotransmission
– GABA (gamma-amino butyric acid)
– Glycine
– Opioid
• block peripheral sensitization
– block sodium channels
– inhibition of both 5-HT and NE reuptake
• inhibition of excitatory neurotransmitter systems or
block central sensitization
– glutamate receptors
– NMDA receptors
• modulate Ca 2+ channels at the alpha-2-delta (α2δ)
subunit
Taylor BK. Curr Pain Headache Rep. 2001;5:151-161
 Neuropathic pain treatment
• Neuropathic pain is often difficult to control.
• In severe cases, a combination of medications
may be necessary.
• These oral medications have various
unacceptable adverse reactions.
• Consider safety and tolerability when initiating
treatment
• The number needed to harm (NNH) of those
adjuvant analgesics have a similar values with
their number needed to treat (NNT).
 Benefit-Risk Analysis of Agents Used to Treat Neuropathic Pain
Number of Patients Needed to Treat (NNT) for
Efficacy/Adverse Effects
Medication Painful/Diabetic Postherpetic Peripheral Trigeminal
Neuropathy Neuralgia Nerve Injury Neuralgia
Tricyclic antidepressants 2.4/4.9 2.3/6.0 —
2.5/ND
Amitriptyline 2.0/9.7 2.3/6.2 —
2.5/ND
Desipramine 3.4/20. 1.9/4.8 —
SSRIs 6.7/ND — — —
Paroxetine 2.9/ND — — —
Citalopram 7.7/ND — — —
Phenytoin 2.1/9.5 — — —
Carbamazepine 3.3/1.9 — — 2.6/3.4
Gabapentin 3.7/1.8 3.2/3.4 — —
Lamotrigine — — — 2.1/ND
Mexiletine 10.0/6.3 — — —
Baclofen — — — 1.4/ND
Tramadol 3.4/ND — — —
Oxycodone — 2.5/ND — —
Source: References 15,21,22,26,27,30-32,37
Diabetic Peripheral Neuropathy Pain

• Nerves that have been affected by neuropathy

can take time to recover, even when the
underlying cause is appropriately treated.
• In symptomatic diabetic peripheral neuropathy
(DPN) the level of vitamin Bs is much less
compared to normal healthy subjects.
• High dose of vitamin Bs improves clinical
symptoms of DPN, ie
– neuropathic pain (88.9%),
– numbness (82.5%) and
– parasthesia (89.7%).
 The role of B vitamins in
alleviating pain
Investigators Year Animal Vitamin Bs
Hanck & Weiser 1985 Rats B12
Wang et al 2005 Rats B1, B6, B12
Song et al 2009 Rats B1
Investigators Year Subject Vit. Bs
Mazzoni &Valenti 1964 Patients B1
Hieber 1974 Patients B12
Mäder 1988 Cervico- B1, B2, B9
brachialgia
Abbas & Swai 1997 DM B1, B6
Mauro et al 2002 LBP B12
Peters et al 2006 Patients B1, B6, B12,
B9
 Vitamin B-complex
Vitamin Chemical name Recommended intake
B1 Thiamine W = 1.1 mg/d; M = 1.2 mg/d
B2 Riboflavin W = 1.1 mg/d; M = 1.3 mg/d
B3 Nicotinamide (niacin), vit. P, vit PP W = 14 mg/d; M = 16 mg/d
B4 Adenine (no longer considered a
vitamin)
B5 Pantothenic acid W and M = 5 mg/d
B6 Pyridoxine W and M = 1.3 mg/d
B7 Biotin, vit. H W and M = 30 μg/d
B8 Inositol W and M = 400 μg/d
B9 Folacin (folic acid), vit. M, vit. B-c W and M = 5 mg/d
B10 p-aminobenzoic acid (PABA) / H1
B11 L-carnitine / b-OH-g-trimethyl-NH4 W = 425 mg/d;
butyrate (or choline) M = 550 mg/d
B12 Cyanocobalamin W and M = 2.4 μg/d
 The impact of thiamine treatment in the
diabetes mellitus.
Luong KV, Nguyen LT. J Clin Med Res. 2012;4(3):153-60.
• Thiamine levels and thiamine-dependent enzyme
activities have been reduced in DM.
• Thiamine and its derivatives prevent the activation of the
biochemical pathways in DM.
– increased flux through the polyol pathway,
– formation of advanced glycation end-products,
– activation of protein kinase C, and
– increased flux through the hexosamine biosynthesis pathway
• Thiamine definitively has a role in the diabetic
endothelial vascular diseases (micro and
macroangiopathy), lipidprofile, retinopathy, nephropathy,
cardiopathy, and neuropathy.
High dose thiamine therapy counters metabolic dysfunction

Glucose Polyol
pathway
ATP
Hexokinase
ADP

G-6-P
+ thiamine G-6-P
isomerase
Hexosamine
F-6-P pathway
ATP Phospho-
ADP fructokinase
High dose F-1,6-bis-P
thiamine + thiamine Aldolase
TPI
GA3P DHAP PKC activation
Transketolase
GA3PDH
Mitochondrial
G-3-P dysfunction
R-5-P MG
Reductive
PPP AGE
formation
NF-κB ↓ Pyruvate + NADH
Abbreviations: G-6-P, gluocse-6-phosphate; F-6-P, fructose-6-phosphate; F-1,6-bis-P,
+ fructose-1,6-bisphosphate; GA3P, glyceraldehyde-3-phosphate; DHAP,
L-Lactate + NAD dihydroxyacetonephosphate; G-3-P, glycerol-3-phosphate; MG, methylglyoxal; R-5-P,
ribose 5-phosphate.

Glycolysis (Thornalley, Curr Diabetes Revs 1, 287 – 298, 2005 )

 Cerebral cortex
Hypothalamus

PAG

DESCENDING
Spinoreticular

PATHWAY
afferents Enkephalin

NRM NRPG

Spinoreticulothalamic
Pain Projection 5-HT NE
Inter- Inter-
ASCENDING
PATHWAY

neuron neuron

- - C fibers

Neurotropic vitamins increase the production of serotonin and

noradrenalin, then inhibit the transmission of pain
 Excess Pyridoxine
• Vitamin B6 in excess of 500mg / day can cause
excessive membrane stabilization & neuropathy.
• Excessive vitamin B6 causes more conversion of
stimulatory glutamic acid to calming & stabilizing GABA
(gamma aminobutyric acid).
Bendich, A., et al. Vitamin B6 safety issues. Annals of the New York
Academy of Sciences, USA. 585:321-330, 1990.
Monograph: vitamin B6. Alternative Medicine Review. 6(1), 2001.
• Most reported cases of vitamin B6-induced neuropathy
have involved the intake of 500 mg or more per day for
at least two years.
• Non-excessive dosages (<200mg) of supplemental
vitamin B6 prevent & alleviate neuropathy.
 Jawa AA, et al. Nutrition-related vitamin B12 deficiency in
patients in Pakistan with type 2 diabetes mellitus not taking
metformin. Endocr Pract. 2010 Mar-Apr;16(2):205-8.

• Almost half of the subjects with type 2 diabetes

not taking metformin had biochemically proven
vitamin B12 deficiency.
• All subjects who enrolled in the intervention
phase had normalization of their vitamin B12
levels after 3 months of oral supplementation
with cobalamin (1,500 microg daily)
• This finding highlights the need for aggressive
and early diagnosis and treatment to avoid
complications of vitamin B12 deficiency.
Maladkar M, et al. Efficacy, safety, and tolerability
of Epalrestat compared to cobalamine in patients
with diabetic neuropathy.
Int J Diabetes Dev Ctries. 2009 Jan-Mar; 29(1): 28–34.
% of cases in pain with cobalamine
500 μg t.i.d for 12 weeks on
Diabetic Neuropathy
Mauro GL, Martorana U, Cataldo P, Brancato G, Letizia G. Vitamin B12
in low back pain: a randomised, double-blind, placebo-controlled study.
Eur Rev Med Pharmacol Sci. 2000 May-Jun;4(3):53-8.
effect of 14 daily 1000 μg vitamin B12 IM injection on chronic low back pain
 MoA of cobalamin
• B12 treatment normalized the nerve conduction velocity.
• Nerve PKC activity was normalized in treated animals.
– The decreased PKC activity in diabetic nerve was associated
with reduced expression of membrane PKCα and increased
membrane expression of PKCβII, and B12 treatment corrected
these changes.
– Diabetic nerve contained 8-hydroxydeoxyguanosine-positive
cells in the endoneurium, the latter of which was significantly
suppressed by B12 treatment.
– Elevated nerve polyol levels in diabetic nerve were partially
corrected by MC treatment.
• The correction of impaired neural signalling of PKC and
oxidative stress-induced damage may be a major
attribute to the beneficial effects of B12 on diabetic
nerve.
Mizukami H, et al. Methylcobalamin effects on diabetic neuropathy and nerve
protein kinase C in rats. Eur J Clin Invest. 2011 Apr;41(4):442-50
The Role of Neurotrophic Vitamin in Neuropathy

• Nerve energy supply

Thiamin
• Membrane nerve
(Vitamin B1) regeneration

• Synthesis of Amino Acid

Pyridoxine • Synthesis of neurotransmitter
(Vitamin B6) (5-HT, GABA, Dopamine, NE)
• Synthesis of Shingolipid

• Synthesis of nucleic acid

Cobalamin (myelin sheath)
(Vitamin B12) •  homocysteine
 Homocysteine & Neuropathy
• González R, et al. Plasma homocysteine levels are
independently associated with the severity of
peripheral polyneuropathy in type 2 diabetic
subjects. J Peripher Nerv Syst. 2012;17(2):191-6.
– For each increase of 1 µmol in plasma Hcy there was a 23% increase of
the risk of diabetic PN
• Li JB, et al. The relationship between plasma
homocysteine levels and diabetic peripheral
neuropathy. Zhonghua Nei Ke Za Zhi. 2011;50(1):14-7.
– Hyperhomocysteinemia was an independent risk factor for the
occurrence of diabetic peripheral neuropathy
• Ambrosch A, et al. Relation between
homocysteinaemia and diabetic neuropathy in
patients with Type 2 diabetes mellitus. Diabet Med.
2001;18(3):185-92.
 The role of B6 and B12 in
Homocysteine metabolism
cysteine
transmethylation Vit-B6
transsulphuration
methionine homocysteine cystathionine
Cystathionine β-Synthase
remethylation
Homosistein diisulfida

Homosistein sulfid
Vit-B12
Urinary excretion
5-methyl
Folic THF THF
acid
MTHFR

5,10-methyleneTHF Dietary intake

 Vitamin B12 Homocystein

Young

Old

Dresden, Germany, 12th June 2012

In a national survey of 21,500 People*, not a Single Person
consumed even the daily RDA amounts for the 10 most
important nutrients! Source: USDA 1994-96 CSFII
90
Percent of Adults Not Meeting RDA Males Females
80
70
60
50
40
30
20
10
0

“Low levels of antioxidant vitamins may increase the risk

of several chronic diseases.” JAMA, June 19, 2002
 Kasus
• Wanita, 55 tahun, mengeluh nyeri wajah di
pipi kanan, kumat-kumatan, seperti
disayat pisau, terjadi pada saat
mengunyah, saat bicara, saat menguap,
atau dapat rangsangan dingin.
• Pada pemeriksaan neurologist lain dalam
batas normal.
• Riwayat sakit gigi (+) dan sudah dicabut.
 Neuropathic Pain: Pharmacologic Therapies
DRUG DOSAGE / DAY COMMON SIDE EFFECTS
Antidepressants
Amitriptyline (TCA) 20–150 mg
Nortriptyline (TCA) 20–150 mg
Sedation, weight gain, anticholinergic
effects, sexual dysfunction, arrhythmia (side
Desipramine (TCA) 20–200 mg
effects most prominent with Amitriptyline)
Duloxetine (SNRI) 60–120 mg
Anticonvulsants
Gabapentin 600–3600 mg Sedation, dizziness, peripheral oedema,
Pregabalin 150–600 mg weight gain, Stevens-Johnson syndrome,
Lamotrigine 25–400 mg rash, dizziness, nausea,, ataxia, aplastic
Carbamazepine 200–1200 mg anaemia, liver enzyme elevation, fatigue,
Oxcarbazepine 600–2400 mg leukopenia
Topical anaesthetics
5% Lidocaine patch Every 12 hours Local oedema, burning, erythema
Capsaicin patch 3 or 4 times a day Burning
Opioids, opioid agonists
Tramadol 100–400 mg Sedation, dizziness, seizures, nausea,
Oxycodone 10–100 mg constipation, potential for addiction and abuse
 Benefit-Risk Analysis of Agents Used to
Treat Neuropathic Pain
NNT (NNH)
Medication Painful/Diabetic Postherpetic Trigeminal
Neuropathy Neuralgia Neuralgia
Tricyclic antidepressants
Amitriptyline 2.0/9.7 2.3/6.2 -
Desipramine 3.4/20. 1.9/4.8 -
SSRIs 6.7/ND - -
Phenytoin 2.1/9.5 - -
Carbamazepine 3.3/1.9 - 2.6/3.4
Gabapentin 3.7/1.8 3.2/3.4 -
Pregabalin 3.3/3.7 3.7/7.0 -
Lamotrigine - - 2.1/ND
Mexiletine 10.0/6.3 - -
Tramadol 3.4/ND - -
Oxycodone - 2.5/ND -
 The role of B vitamins + NSAID
in alleviating pain
Investigators Year Animal Vitamin Bs
Granados-Soto et al 2004 Rats B12 + diclofenac
Rocha-González et al 2004 Rats B1, B6, B12 +
diclofenac
Medina-Santillán et al 2004 Rats B1, B6, B12 +
ketorolac
Caram-Salas et al 2006 Rats B1, B6, B12 +
dexametasone
Investigators Year Subject Vit. Bs
Vetter et al 1988 Patients B1, B6, B12 +
diclofenac
Brüggemann et al 1990 Patients B1, B6, B12 +
diclofenac
Mibielli et al 2009 Patients B1, B6, B12 +
diclofenac
 Patients’ response captured between visit 1
and visit 2 to the Visual Analogue Scale (VAS)
60
DB
50
D
40
% Patients

30

20

10

0
< 0 mm 0 - 20 mm 21 - 40 mm 41 - 60 mm > 60 mm
VAS mm
Mibielli MA, et al. Diclofenac plus B vitamins versus diclofenac
monotherapy in lumbago: the DOLOR study. Curr Med Res Op 2009;25(11):2589-99
 Time course of the effect of diclofenac
alone or diclofenac plus B vitamins for
the treatment of pain

Ponce-Monter HA, dkk. Pain Res Treat. 2012;2012:104782.

The Influence of Vitamin B Group on
Diclofenac Metabolism.
Makhova AA , et al. BioNanoScience 2011,1(1-2):46-52

2500
Cmax Diclofenac ng/ml

2000

1500

1000

500

0
D D+B D + 2B
Interaction Diclofenac and B vitamin

Diclofenac

B vitamin
Cyp3A4

Metabolites of
Diclofenac
 Percentage of patients discharged
with pain score (VAS)
100
VAS < 2
VAS >3
80

60

40

20

0
Acetaminophen + B vitamins Acetaminophen

Galvan-Montano A, et al. Cir Cir 2010;78:400-9

• Neuropathic pain is the most frequent
symptom of neuropathy.
– NSAID has no benefit for neuropathic pain
– Adjuvant analgesics have good efficacy, but less
safety value.
• Vitamin Bs might contribute to the immediate
analgesia.
• The best and safest adjuvant analgesic is
neurotropic vitamin
• For mixed pain
• With inflammation  NSAID + neurotropic vitamin
• Without inflammation  paracetamol +
neurotropic vitamin
Menara Eifel juga ada di Gorontalo
KEBANGGAAN INDONESIA
UNTUK DUNIA
Adjuvant Analgesics for Neuropathic Pain
Class Examples
Antidepressants amitriptyline, desipramine, nortriptyline,
paroxetine, venlafaxine, citalopram, others
Anticonvulsants gabapentin, phenytoin, carbamazepine,
clonazepam, topiramate, oxcarbazepine, others
Alpha-2 adrenergic agonists tizanidine, clonidine
Local anesthetics mexiletine, tocainide
NMDA receptor dextromethorphan, ketamine, amantadine
Antagonists
Miscellaneous baclofen, calcitonin
Topical lidocaine, lidocaine/prilocaine, capsaicin,
NSAIDs
Steroids prednisone, dexamethasone
Neurotropic Vitamin B1, B6, B12 (+B9 Folic acid)
NNT and NNH adjuvant analgesia for
chronic non-cancer pain
Drug NNT NNH
Phenytoin 2.1 9.5
TCAs 2.4 2.7
Carbamazepine 3.3 1.9
Pregabalin 3.3 7.0
Gabapentin 5.0 2.5
Mexiletine 10 5–10
Codeine 18 2
• efek analgetik vitamin B ini adalah dikaitkan dengan
meningkatnya keberadaan dan atau efek noradrenalin
dan serotonin yang bertindak sebagai penghambat
transmisi sistem nosiseptif (Jurna, 1998).
• Huang dkk (2010) memberikan vitamin B6 dalam dosis
besar (100 mg/hari) pada pasien rheumatoid arthritis
dan menemukan sitokin pro-inflamasi (IL-6 dan TNF-a))
tertekan.
• Hurt dkk (2012) membuktikan bahwa prostatic acid
phosphatase (PAP) dapat memfosforilasi vitamin B1
seara in vitro, di syaraf dorsal root ganglia dan ujung
syaraf afferent di dorsal spinal cord. Kelompok peneliti
ini meyakini bahwa khasiat analgetik vitamin B1 semata-
mata bergantung pada keberadaan PAP di syaraf spinal.
• Seperti dikemukakan sebelumnya diatas, ada
berbagai mekanisme vitamin B sebagai
analetik, diantaranya menekan sitokin pro-
inflammatory (IL-6 dan TNF-a), menekan kanal
natrium diikuti dengan hambatan
hyperexcitability syaraf secara dose
dependent dan diperantarai melalui
pembebasan opioid endogen.
 Schema of the possible contribution of cGMP kinase I (cGKI) to cerebellar long-term
depression (LTD) induction.

Hofmann F et al. Physiol Rev 2006;86:1-23

©2006 by American Physiological Society