2 December 1951

Bukit Tinggi

SpFK, Clinical Pharmaco

PB-IDI & FK UI, 1995

Professor
MD, FK USU, 1978
Head of Department
Pharmacology & Therap
PhD in Clinical PharmacologySchool of Medicine, USU
FUSA-Flinders Medical Centre
Jln. Tridharma 22
Australia, 1988
Kampus USU, Medan

Aznan Lelo
Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera
Utara
24 September 2011,
MS Pain, Lhokseumawe

Pain Market
PAIN
100%
ACUTE
34%

CHRONIC
66%
NOCICEPTIVE
80%

CANCER
4%

NEUROPHATIC
20%

NON-CANCER
96%
Nyoman Kertia, 2010

Common issues of NSAIDs

Different chemical families
Different pharmacokinetics and potency
Common mechanism of action (COX inhibition)
Different selectivity to COX-1 and COX-2

Common clinical indications

Analgesic (CNS and peripheral effect) may involve
non-PG related effects
Antipyretic (CNS effect)
Anti-inflammatory (mainly by PG inhibition)
Effective dose for analgesic anti-inflammatory
antipyretic

Common analgesic ceiling effect

Factors to consider when

choosing NSAID as pain killer

Drug issues
Efficacy
Tolerability
Safety
Dosage
Cost

BENEFITS
efficacy

RISKS
safety

Patient issues
Type, severity
Risk factors: GI,
platelet, renal and
cerebro-cardiovascular
system.
Co-prescription.
Co-morbidity.
Compliance.

Principles of Analgesic
Prescribing

WHO Analgesic Ladder

Strong opioid
NSAID
adjuvant analgesic
NSAID
adjuvant
analgesic
weak opioid
(codeine)
paracetamol
or NSAID
adjuvant analgesic
Pain threshold Pain tolerance

mild

moderat

severe

1
0

Critical approaches
in selecting medicines
Adverse
reaction
NNH

Therapeutic
NNT
effect
GREATEST
Minimal Maximal
SMALLEST
(> 100)

SMALLEST
(2-4)

Maximal
GREATEST
Minimal

Yes
?

?
No

There are two reasons to withdraw from the treatment e

no efficacy (NNT very high) or
serious adverse reactions (NNH very low).

discontinuation rate (%)

Withdrawal (%)

55%

23%

Henti terapi
karena
tidak
merasakan
efek terapi

19 %

9%
2.3 %

0.7 %

Henti terapi
karena
merasakan
efek samping

number needed to treat (NNT) for at least 50% pain relief

over 4-6 hours in patients with moderate to severe pain,
all oral analgesics except morphine, pethidine and ketorolac

NSAID

Dose

NNT

Ibuprofen

50 mg

4.7

100 mg

3.7

200 mg

2.7

400 mg

2.5

600/800 mg

1.7

25 mg

2.6

50 mg

2.7

100 mg

1.8

200 mg

4.5

400 mg

3.7

600/800 mg

3.0

Diclofenac

Percent Responders

NNT of NSAIDs at different doses

Placebo

Celecoxib Celecoxib Celecoxib

2 x 100 2 x 200 2 x 400

Incidence of Hypertension
as adverse effect of Rofecoxib

Etoricoxib:

efficacy-dose response at 6 weeks

Shibuya RB, 2009

Acute vs Chronic Pain

Drug
Duration of
pain

Component

Acute

Chronic

Rapid onset

Long duration

Short, self limiting, Persists after healing,

well-characterized
3 months

Nociceptive

Nociceptive
Neuropathic

Mild vs Severe Pain

Drug

Mild

Severe

Low dose

High dose
Potent agent

T-max and Onset of action of

NSAIDs
Onset
NSAID
T-max (hr)
Rapid Diclofenac
0.8
Nimesulide 1.2 2.7
Slow Celecoxib
24
Meloxicam
6

T-1/2 and Duration of action of

NSAIDs
Duration
short
moderate
long

NSAID
Diclofenac
Nimesulide
Celecoxib
Naproxen
Meloxicam
Etoricoxib

T-1/2 (hr)
1.1
1.8 4.7
11
14
20
22

NSAID use
Acute inflammatory pain or
Breakthrough pain
Short half-life NSAID
Ibuprofen, diclofenac, etc

Chronic inflammatory pain

Long half-life NSAID
Oxicam, COXIB

Etoricoxib, a long half-life (22 hours):

dosage and efficacy
Pain
Dose
Note
indications
(mg)
Chronic pain
OA
30 60 Curtis SP, et.al.
2005

Acute pain
Gouty arthritis
Dysmenorrhea

120

120

Maximum 8
days
Maximum 8

Acute Pain Severe Pain

How to change the onset of

action of the long half-life NSAID
Concentration

NSAID long half life

Acute

o
r
long duration e
g
By increasing thebut slow onset an
D
increaseddose ???:
?
earlier
theonset
dose becomes
!
c
i
but adverse effectsth
E
enhanced
Effective concentration
?
e
v
Sa
?
l
a
Time
n
o
i
t
Slowly

Chronic
a
R

DICLOFENA
C
and all
Acidic
BBB
BBB
NSAIDs

HYPERALGESIA
Prostaglandin

BBB

BBB BBB BBB BBB

INFLAMMATION

BBB

BBB

MACROPHAGES

TNF-
IL-6

IL-8

IL-1

SYMPATHETIC
NERVE

COX-2

PG

BK
POLYMORPHS

FIBROBLASTS

DICLOFENA
C
and
Ferreira, 1993
Nimesulide

NOCICEPTOR

ALGESIA

DICLOFENA
C
and all
Non-COXIB

Capone ML, et al. Int J Immunopathol Pharmacol.

16(2 Suppl):49-58,2003.

Clinical pharmacology of
selective COX-2 inhibitors
Acidic COX-2 inhibitors
have been hypothesized that this
peculiar chemical feature may lead to
an enhanced concentration in
inflammatory sites
that may translate into
an improved clinical efficacy

Tissue concentrations of total radiolabeled components

at 1, 4, 8 and 24 h after oral administration of
[14C] diclofenac sodium at a dose of 2 mg/kg to male rats
injected with carrageenan (T) or saline (C) into the left
front footpad and the left hind paw

Tissue
Injection
site nape
neck

Concentration of total radiolabeled

components (nmol/g)
1 hour
4 hours
8 hours
24 hours
T
C
T
C
T
C
T
C
0.79
1.20
0.18
0.12
0.30

tc

Untreated 0.16
0.15
0.20
0.20
footpads
0.04
0.10
Injection
site
footpads

1.00
1.30
0.12
0.23
0.5

nd

1.30
0.10

tc

0.20
0.04

nd

tc

nd

nd

nd

0.84
0.10

nd

tc

nd

Schweitzer A, N Hasler-Nguyen N, Zijlstra J. BMC, 2009

Mekanisme kerja AINS

Mekanis- Ibu- Diclome
profen fenac

Piroxicam

Celecoxib

Etoricoxib

COX-1

++

COX-2

++

++

+++

COX-3

+++

Anti-BK

K-opener

Tembus
BBB

platelet
aggregation

fewer
heart attack

COX-1
inhibitor
GI
bleeding

platelet
aggregation

GI
bleeding

more
heart attack COX-2

inhibitor

platelet
aggregation

GI
bleeding

The Implications of NSAID

Selectivity
Cardiovascular Risk

Gastrointestinal Risk

Thrombosis,
Myocardial Infarction

Bleeding Ulcer
Complications

Discontinuation

Discontinuation

Et
or
ic
Ro oxi
b
fe
co
xi
b
C
Di ele
cl c
of ox
en ib
ac
Ib
up
ro
fe
n
Na
pr
ox
en

Blood Pressure
Increase

COX-2

COX-1

Degree of Selectivity
Adapted from Antman EM, et al. Circulation. 2007;115:1634-

Adverse Effects of NSAIDs

Ototoxic

Bronchospam

Hepatotoxic

Bleeding

Allergy

Color blindness

CHF

UGIB
UGIB
Nephrotoxic

Tocolytic

Mechanism of = Mechanism of
therapeutic effects
adverse effects

phospholipids
arachidonic acid
COX-2

COX

COX-1

cyclic
endoperoxides
PGI2

stimulates platelet
aggregation,
vasoconstriction

hyperalgesia
PGD2
inhibits platelet
aggregation,
vasodilator

5-HPETE
TXA2

inhibits platelet
aggregation,
vasodilator,

PGE2
vasodilator,

LOX

PGF2alfa
bronchodilatation
myometrial contr.

hyperalgesia hyperalgesia

LTA4
LTB4
chemotaxis

LTC4
LTD4
LTE4

brochoconstriction
increase
vascular
permeability

RESPIRATORY TOXICITY
AA

LTs

NSAID

PGs

bronchoconstriction bronchodilatation

NSAID-induced asthma

Risk Factors of
Ulcer Complications from NSAIDs

Relative risk

incidence of ulcer (%)

Number of Risk Factors &

Incidence of Ulcer Complications
NNH 5

NNH 12
NNH 50
NNH 125

Silverstein FE. Ann Intern Med 1995;123:241-9

Lowest GI risk

NSAID GI
Toxicity
generally
varies
with halflife of the
agent

Shortest half-life

NSAID

Diclofenac

Naproxen

Piroxicam

Dose (mg/d)

100

750

20

Half-life (hr)

1.5

14

50

24 hr fecal blood
loss (mL)

0.53 +/- 0.21

2.76 +/- 2.22

1.16 +/- 0.62

Henry, et al. BMJ.312:1563,2000; Scharf, et al. Aust N Z J Med

Pain in risky population

PATIENT GROUP

PREDICTABLE
PROBLEMS

Babies & Infants

Elderly

Communication; drug handling

Coexisting illness; drug
handling

Respiratory
disease

Respiratory depression;
NSAIDs & asthma

Renal Failure
Drug handling; NSAIDs
Pregnant women Early closure of ductus
arteriosus

The pattern of NSAID plasma concentration

based on the dose and half-life of drug given

Drug accumulation
3x11x3
Efek terapeutik Efek samping obat
Choose the shortest half-life

Suggested dosages of some NSAIDs for

postoperative pain management
NSAID
Diclofenac
Ibuprofen
Flurbiprofen
Ketorolac
Ketoprofen
Naproxen
Nimesulide
Tenoxicam

Dose

Route

0.7 - 2 mg/kg Oral, Rectal, IM

5 - 10 mg/kg
oral
1 mg/kg
oral
0.3 0.5 mg/kg
IM, IV
1 2 mg/kg
IV
4 - 6 mg/kg
oral
1.5 mg/kg
oral
0.75 mg/kg
IM
Kokki H. Pediatr Drugs 5(2):103-23,2003

Nociceptive VS neuropathic pain

Nociceptive pain
Caused by activity in
neural pathway in
response to
potentially tissuedamaging stimuli

Mixed
pain
Caused by a
combination of both
primary injury or
secondary effects

ARTHRITIS

Postoperative
pain

NSAID
Sickle cell

Mechanical
LBP

Neuropathic pain

crisis

PHN

Initiated or caused by
primary lesion or
dysfunction in the
nervous system

CRPS

Adjuvant
Trigeminal
Neuropathic
neuralgia
LBP
ANALGESIC

Distal
Central post
Sport /
polyneuropat
stroke pain
exercise
hy (e.g.
injuries
International Association for the Study of diabetic)
Pain. IASP Pain Terminology.
Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed.

Adjuvant Analgesics
Defined as drugs with other indications
that may be analgesic in specific
circumstances
Numerous drugs in diverse classes
Sequential trials are often needed
Multipurpose analgesics

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
Antagonists

dextromethorphan, ketamine,
amantadine

Miscellaneous

baclofen, calcitonin

Topical

lidocaine, lidocaine/prilocaine,
capsaicin, NSAIDs

NNT and NNH adjuvant

analgesia for chronic noncancer pain
Drug
Phenytoin
TCAs
Carbamazepine
Pregabalin
Gabapentin
Mexiletine
Codeine

NNT
2.1
2.4
3.3
3.3
5.0
10
18

NNH
9.5
2.7
1.9
7.0
2.5
510
2

The role of neurotropic

vitamin in alleviating pain
Investigators

Year

Animal

Hanck & Weiser

Granados-Soto et al
Rocha-Gonzlez et al

1985
2004
2004

Rats
Rats
Rats

Medina-Santilln et al

2004

Rats

Wang et al
Caram-Salas et al

2005
2006

Rats
Rats

Song et al

2009

Rats

Vitamin Bs
B12
B12 + diclofenac
B1, B6, B12 +
diclofenac
B1, B6, B12 +
ketorolac
B1, B6, B12
B1, B6, B12 +
dexametasone
B1

The role of neurotropic

vitamin in alleviating pain
Investigators

Year

Subject

Mazzoni &Valenti
Hieber
Mder

1964
1974
1988

Vetter et al

1988

Patients
Patients
Cervicobrachialgia
Patients

Brggemann et al

1990

Patients

Abbas & Swai

Mauro et al
Peters et al
Mibielli et al

1997
2002
2006
2009

DM
LBP
Patients
Patients

Vitamin Bs
B1
B12
B1, B2, B9
B1, B6, B12 +
diclofenac
B1, B6, B12 +
diclofenac
B1, B6
B12
B1, B6, B12, B9
B1, B6, B12 +
diclofenac

Peters TJ, et al. Treatment of alcoholic

polyneuropathy with vitamin B complex: a
randomised controlled trial.
Alcohol Alcohol. 2006;41(6):636-42

McGill's
pain
questionnaire

New form. Old form.

B1, B2, B6, B1, B2, B6,
B12 + B9 B12 (-) B9
(N = 85)
(N = 83)

Total pain
score*,
VAS (mm)*,

8.6 (7.55) 7.5 (6.76) 3.8 (8.18)

35.0
(18.61)

34.9
(20.32)

P < 0.001: new formulation versus placebo (Wilcoxon-Rank Sum Test).

*P < 0.001: old formulation versus placebo (Wilcoxon-Rank
Sum Test).
*

Placebo
(N = 85)

9.5
(18.65)

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

A randomized, double blind controlled study in
parallel groups
Received twice-daily po.
Group DB (50 mg diclofenac, 50 mg B1, 50 mg
B6, 1 mg B12) vs Group D (50 mg diclofenac)
Sufficient pain reduction = VAS < 20 mm

The number of patients who meet the

confirmative primary study objective
at visit 2 (after 3 days of treatment)
Group DB
(n=187)

Group D
(n=185)

Treatment success

87

46.5

55

29.7

Treatment failure

10

5.3

10

5.4

Side effects (AEs)

1.6

Patients with continued

intervention

87

46.5

120

Study withdrawal reasons

64.9

Difference in treatment success. X2 = 12.06; p = 0.0005

% Patients

Patients response captured between visit 1

and visit 2 to the Visual Analogue Scale (VAS)

VAS mm

In children who received acetaminophen + B vitamins during the immedi

postoperative period, 58% had pain score 2 and
89% were discharged with pain score 1.
Acetaminophen + B vitamins showed a better pain score.

Percentage of patients
discharged with pain score
(VAS)

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

Efek Analgetik dan Neuroprotektif

Vitamin Neurotropik
(Zimmerman, 2006)

1. NMDA receptor antagonism

2. Block at Ca2+ channels
3. Blok of cytokine formation (eg: TNF-)
and receptor binding
Vitamin
B complex

TNF , growth factors,

IL 1, IL 8

Cerebral cortex
Hypothalamus

PAG

Enkephalin

NRM

ASCENDING
PATHWAY

Spinoreticulothalamic
Pain Projection

DESCENDING
PATHWAY

Spinoreticular
afferents

5-HT
Interneuron
-

NRPG

NE
Interneuron
-

C fibers

Neurotropic vitamins increase the production of

serotonin and noradrenalin, then inhibit the

 Optimal efficacy
Rapid onset
High potency
o Minimal value of ED-50 for analgesic effect

Multiple mechanism of action

o COX inhibition, Anti-cytokine, Anti-bradykinin
o K-channel opener

Optimal safety (minimal side effect)

Not only GI toxicity

Good pharmacokinetic profiles

Short half-life, Penetrate BBB
Has an acidic pKa

 For acute inflammatory pain

Short half-life NSAID (diclofenc)

Slow release short half-life NSAID

Long half-life NSAID (oxicam)

With inflammation NSAID + adjuvant

analgesic (DOLOFENAC)
Without inflammation paracetamol +
adjuvant analgesic (DOLONEUROBION)

For chronic inflammatory pain

For mixed pain

The best and safest adjuvant analgesic

is neurotropic vitamin

KEBANGGAAN
INDONESIA UNTUK
DUNIA