Update in Nociceptive

Pain Treatment
A. Husni Tanra

Dept. of Anesthesiology, Intensive Care and

Pain Management
Faculty of Medicine, Hasanuddin University Makassar

After Tissue Injured

Peripheral sensitization

INFLAMMATION

Prostaglandins are one of a number of mediators of

the inflammatory process
Source
Tissue damage, degeneration (cell membranes)
Inflammatory cells (WBC, macrophages)
Effects
Vasodilatation (redness)
Increased permeability (swelling)
Pain
Localised heat or fever

5/7/16

Prostaglandin VS Cortisone or
Thyroxin

PG are synthesized in broad range of tissue types and

serve as:
Autocrine
Paracrine
PG performing as a hausekeeping to regulate normal cell
activity.
Cox
2
AA PGs

PGs

Paracrine

Cox1

AA
PGs

Autocrine

Epithelial cell

Autocrine PGs

Neighboring
cell

Cortisone & Thyroxin are released from a single site but

have broad systemic effect, it is called as:
endocrine

What is prostaglandine?

Is an eicosanoid (local hormone) which plays a big role in

normal physiologic as well as in patophysiologic condition

Normal physiology
Blood clotting
Ovulation
Initiation of labor
Bone metabolism
Nerve growth & development
Wound healing
Kidney function
Blood vessel tone
Immune response, etcl

Pathol. condition
Inflammation process
Pain
Swelling

Disebut prostaglandin,karena pertama ditemukan dalam

cairan prostat.
Prostaglandin diproduksi lokal untuk kebutuhan lokal
diberbagai organ tubuh

Prostaglandin Sythesis
The key enzym required for conversion
arachidonic acid prostaglandin is
Cyclooxigenase (Cox)
Arachidonic Acid

Cyclooxygenase
(Cox)
1997: Aspirin,
NSAID

Prostaglandin

1990, 2 isoform of cyclooxygenase was

identified
Cox1 = enzym produce constitutively in GI,
kidney & platelate

Tissue Trauma
Cell Membrane
Phospholipids
Phospholipase

Arachidonic
Acid
C
O
X

Cyclooxygenase

Endoperoxides
Thromboxane
Prostaglandin
s

Toxic Oxygen Radicals

Prostacyclin

Mechanism of Prostanoids
Arachidonic acid

Cyclooxygenase

X
Prostanoids
Support
Support renal
renal and
and
platelet
platelet function
function

Protect
gastroduodenal
gastroduodenal
mucosa
mucosa

Anti-inflammatory
Anti-inflammatory
Analgesic
Analgesic
Antipyretic
Antipyretic
Gastrointestinal toxicity
Renal
Renal toxicity
toxicity

Mediate
inflammation,
inflammation, pain,
pain,
and fever

Arachidonic Acid
Cyclooxygenase-1
Cyclooxygenase-2

NSAIDS

PGG2
PGH2

PGF2..

PGD2

PGE2

PGI2

TXA2

Arachidonic Acid Cascade

Membrane phospholipids

Arachidonic acid

Phospholipase
A2

COX-2

COX-1
Prostaglandin G2
Prostaglandin H2

Tissue-specific isomerases
Prostacycli
THX = n
thromboxane.

THX A2

PGD2

PGE2

PGF2

Adapted from FitzGerald GA et al. N Engl J Med.

COX-1 vs COX-2 Inhibitors

Cyclooxygenase-1 (COX-1) was first
characterized in 1970s and is widely
distributed in all tissues
Selective COX-2, an inducible form, was
identified in early 1990s and found mainly in
brain and kidney, but appear widely in
inflammation area.

NSAID ? History

1893, Felix Hoffman (ahli kimia Jerman,

bapaknya
menderita
RA)
menemukan
asetilsalisilat (aspirin)
Tahun yang sama ditemukan Parasetamol
Keduanya dikenal sbg analgesik biasa

analgesic)

(usual

1971,
Vene
dkk
menemukan
enzim
Cyclooxygenase (COX) yang dpt diblok oleh
NSAID atau AINS = anticyclooxygenase
1990, ditemukan Cox2 yang merupakan
isoform Cox1 yg muncul setelah terjadi
inflamasi dsb Coxib
2002, Dr. Simmons menemukan enzim lain
yang dapat diblok oleh hanya paracetamol

COX-1 vs COX-2
COX-1

COX-2

Constitutive
Inducible (in most
tissues)
Present in most tissues
Induced mainly at sites
Synthesizes
of inflammation by
prostaglandins (PGs)
that regulate physiologic cytokines
Synthesizes PGs that
processes
mediate inflammation,
Especially important in
pain, and fever
gastric mucosa
kidneys
Constitutive expression
platelets
primarily in
vascular endothelium
brain
kidneys
Needleman P et al. J Rheumatol. 1997;24(suppl 49):6-8.
ovaries
DuBois RN et al. FASEB J. 1998;12:1063-73.

NSAID
Contraindications
Dehydration
Hypovolemia
Nephrotoxic agents
Anticoagulants

Vimolluck Sanansilp, Siriraj

NSAIDs and Asthma

Study of stable asthmatics given
diclofenac orally (Short et al. 2000)
Measured PEFR and FEV 1 pre- and post
administration
56% had drop in values but max 15%
None had to increase their medication
Suggest - acceptable in stable asthmatics

Vimolluck Sanansilp, Siriraj

Schematic diagram of the arachidonic acid

pathway
Arachidonic Acid

Leukotrienes
Anaphylaxis
Bronchoconstriction
Chemotaxis
Inflammatory
response
Vascular
permeability
Prostaglandin
D2
( PGD2 )
Vasodilatation
( weak )
( Mast cell
mediator /

Prostaglandin
E2
( PGE2 )

Prostaglandins G2
( PGG2 )
Prostaglandins H2
( PGH2 )
Prostaglandin
F2
( PGF2 )

Prostaglandin
I2
( PGI2 )

Thromboxane
A2
( TXA2 )

Vasodilatation,diur Vasodilatation,diur Vasodilatation,diur Vasoconstriction

esis and
esis and
esis and
platelet
natriuresis
natriuresis
natriuresis
aggregation
Renin
release
Inhibits

Inflammation

Prostaglandins are one of a number of

mediators of the inflammatory process
Source
Tissue damage, degeneration (cell membranes)
Inflammatory cells (WBC, macrophages)

Effects

5/7/16

Vasodilatation (redness)
Increased permeability (swelling)
Pain
Localised heat or fever

Role of COX-2 in
Inflammatory Pain

Peripheral
induction
at site of injury
local

prostaglandin
synthesis pain,
inflammation

Central induction
via PNS
independent of

PNS transmission
occurs even
following complete
sensory nerve
block
blood-borne
humorally
mediated
(IL-1,
IL-6)
Samad TA et al. Nature. 2001;410:471-5.

The Pain Response

Tissue Damage

Transmission of the Pain

Signal to the Brain

Activation of the
Peripheral Nervous
System

Activation of the Central

Nervous System
at the Spinal Cord Level

Pain
Samad TA et al. Nature. 2001;410:471-5.

Arachidonic
Arachidonic
Acid
Acid
Cyclo-oxygenase
Cyclo-oxygenase
(1or
or2)
2)
(1

PGH2
PGH2

TXA2
TXA2

PGI2
PGI2

PGE2
PGE2
PGF2
PGF2
PGD2
PGD2

Kam PCA Anesthesia 2000; 55: 442-229

Cyclo-oxygenase Enzymes
COX-1
Constitutive
Potential 5x
Expressed:
GI mucosa
Kidneys
Platelets
Vascular

endothelium

COX-2
Inducible
Potential 80x
Expressed:
Site of injury
CNS

The Arachidonic Acid Cascade and

COX-1
and COX-2 Inhibition
Arachidonic Acid

COX-1

COX-2

(Constitutive)

(Inducible)
()

Stomach
Intestine
Kidney
Platelet

()

NSAIDs
Inflammatory Site
Macrophages
Synoviocytes

Adapted from Needleman P et al. J Rheumatol. 1997;24(Suppl 49):7.

Glucocorticoids
Block mRNA expression

TARGET FOR A
COX-2 SPECIFIC
INHIBITOR

Acetominophen (COX
3)

Has been used as analgesic since >

100 years
2002, Danniel Simmons found a
variety of COX called COX 3 which is
sensitive to acetaminophen
It has analgesic & antipyretic but has
no anti-inflammatory effect.
Work centrally, decrease pain &
fever
Basic component of multimodal

Acetominophen
Acetominophen should be the first
line analgetic agent in pain relief than
antiinflammatory drugs due to its
favorable side effect and safety profile.
This consensus is recomendede by :
1. American College of Rheumatology
2. American Pain Society
3. European League Against Rheumatism
(Schmitzer, T.J. Update on guidelines for the treatment of chronic musculoskeletal
pain. Clin Rheumatol 25: S22-S29, 2006)

Role of Prostaglandins in Pain

A Working Hypothesis

Peripheral

Central (CNS)

Trauma/noxious stimulus
Release of arachidonic acid
COX-2
Prostaglandins

Pathophysiologic conditions
(eg, ischemia, hypoxia) or
inflammatory stimuli

IL-6?
PGES?

Expression of COX-2
IL-1b

Sensitivity of peripheral

Prostaglandins

nociceptors

Central sensitization

Activation of CNS at spinal

cord level (reducing pain

Abnormal pain sensitivity

threshold)
Pain

Acute Inflammation-Based Pain: Hargreaves

Model
Hyperalge
sia

Carrageenan
injection

COX-2 induction
Swelling
Thermal
sensitivity
(Maximal by 3
hours)

Swelling &
Hyperalgesia

COX-2 Induction
in Spinal Cord

COX-2 Induction
in Inflamed Paw

oral

Role of COX-2 in Inflammatory

Pain Summary

Peripheral
induction
at site of injury
local
prostaglandin
synthesis pain,
inflammation

Central induction
via PNS
independent of PNS
transmission
occurs even
following complete
sensory nerve block
blood-borne
humorally mediated
(IL-1, IL-6)
long lasting

Samad TA et al. Nature. 2001;410:471-5.

COX-2 Induction Hypothesis

and COX-2 Specific Inhibitors

COX-2 specific inhibitor therapy may

work at both peripheral and central sites
must readily cross blood-brain barrier
for CNS effects1
prevent COX-2 up-regulation in the CNS
with early use2
inhibition of central sensitization
caused by COX-2 induction (
prostaglandin synthesis,
neurotransmitter release, neuronal
excitability)
1. Samad TA et al. Trends Mol Med.

2002;8:390-6.
2. Samad TA et al. Nature. 2001;410:471-5.

Currently Available Pain

Medications
Mechanism of
Action
Nonspecific
NSAIDs
Inhibition

of COX-1
and COX-2
isoenzymes
inhibits prostaglandin
synthesis

Benefits

Anti-inflammatory,

analgesic, antipyretic
Long clinical history
of efficacy in
managing pain

Adverse Effects

GI,

hypertension,
edema, renal adverse
effects, antiplatelet
effects

COX-2 specific
inhibitors
Selective

for COX-2
isoenzyme inhibition

Anti-inflammatory,

GI,

hypertension,
edema, renal adverse
effects

analgesic, antipyretic
Fewer GI adverse
effects with selective
inhibition
Needleman P et al. J Rheumatol. 1997;24(suppl 49):6-8.
Brooks P. Am J Med. 1998;104(suppl 3A):9S-13S.

Currently Available Pain

Medications
Mechanism of
Action
Acetaminophen*

Inhibit prostaglandin
synthesis in the CNS?

Benefits
Antipyretic

and
analgesic activity
Well tolerated
Few adverse effects

Adverse Effects
Little

or no antiinflammatory activity
Hepatic necrosis with
overdose, alcohol use

Tramadol

Mixed actions
opioid agonist plus
norepinephrine/
serotonin reuptake
inhibitor

*Paracetamol in some countries.

Useful in patients
with contraindication
to COX-2 specific
inhibitor or
nonspecific NSAID
therapy

Nausea, constipation,
drowsiness
May induce psychic
and physical
dependence
Lowers seizure
threshold

Lipsky PE. Harrisons Principles of Internal Medicine. 1998:1880-8.

Insel PA. Goodman and Gilmans The Pharmacological Basis of Therapeutics. 1996:617-57.
ACR Subcommittee on OA Guidelines. Arthritis Rheum. 2000;43:1905-15.
Ultram [prescribing information]. Raritan, NJ: Ortho-McNeil; 2001.

Currently Available Pain

Medications
Mechanism of
Action

Benefits

Adverse Effects

Opioids

Bind to opioid
receptors, producing
agonist action that
inhibits pain impulses

Effective

in severe

pain
Do not cause GI
bleeding
Low risk of addiction
when used properly

Respiratory

depression
Drowsiness, nausea,
constipation
Limited control of
pain on motion
Abuse potential if
used improperly

Fields HL et al. Harrisons Principles of Internal Medicine. 1998:53-8.

Murphy GP et al. Informed Decisions. 1997.

Pain Mechanisms: Peripherally and Centrally Induced COX-2 1,2

Peripheral

Central

Trauma / inflammation
PLA2

IL-1

IL-6?

Release of arachidonic acid

induction of COX-2

Induction of COX-2
Prostaglandins

Prostaglandins
Central sensitization
Sensitivity of
peripheral nociceptors

Abnormal pain sensitivity

Pain
1
2

Samad TA et al. Nature. 2001;410:471-475.

Smith CJ, Zhang Y, Koboldt CM, et al. Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc Natl Acad Sci USA. 1998; 95:13313-13318.

Role of COX-2 in
Inflammatory Pain
Peripheral induction

At site of injury
Local prostaglandin
synthesis leads to pain and
inflammation

Samad TA et al. Nature. 2001;410:471-475.

Central induction1
Via peripheral nervous system
(PNS)
or
Independent of PNS
transmission
Occurs at a reduced rate even
following complete sensory
nerve block

COX-1 vs COX-2
COX-1

1
2
3

Constitutive in many
tissues
Present in most tissues
Synthesizes PGs
that regulate physiologic
processes
Especially important in
Gastric mucosa
Kidneys
Platelets
Vascular endothelium

1-3

COX-2

Inducible (in most tissues)

Induced mainly at sites of
inflammation by cytokines
Synthesizes PGs that
mediate inflammation,
pain, and fever
Constitutive expression
primarily in
CNS
Kidneys

Needleman P et al. J Rheumatol. 1997;24(suppl 49):6-8.

DuBois RN et al. FASEB J. 1998;12:1063-1073.
Samad TA, Moore KA, Saperstein A, et al. Interleukin-1-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature.
2001;410:471-475.

Benefits of COX-2
Inhibition
Sparing COX-1 reduces the risk of upper GI adverse effects

No

effect on bleeding time2

COX-2 inhibition results in anti-inflammatory and analgesic
effects1
Selectivity for the COX-2 enzyme offers
Comparable efficacy to nonselective NSAIDs studied3-6
No effect on platelets or bleeding time2,7

Stoltz RR et al. Am J Gastroenterol. 2002;97:65-71.

Noveck RJ et al. Clin Drug Invest. 2001;21:465-476.
3
Pavelka K et al. Rheumatology. 2003;42:1207-1215.
4
Bensen W et al. Rheumatology. 2002;41:1008-1016.
5
Daniels SE et al. Clin Ther. 2001;23:1018-1031.
6
Data on file. Integrated Summary of Efficacy. August 29, 2000. Pfizer Inc., New York, NY.
7
Data on file. Integrated Summary of Safety Information. August 26, 2000. Pfizer Inc., New York, NY.
1
2

History of non opioid

analgesia
1897 Aspirin
1950 Paracetamol
1963 NSAIDs
1971 Mechanism of
Cox-1
1990 Discovery of
COX-2
2002 Discovery of
COX-3, a variant of
COX, sensitive to

Dr Felix
HoffmanSir

Sir John
Vane

PARACETAMOL
(is aniline analgesic class.)

Chemical name:
Para - acetylaminophenol Paracetamol
Para -acetylaminophenol Acetamoniphen
N-acetyl-para - aminophenol APAP
Daniel Simmon (2002) COX-3 inhibitor
Trade name:
Panadol in UK, Australia, Indonesia
Tyleno in US
Other name - Tempera - Efferalgan
- Datrin - Crocin (India)
- Anocin - Napa (Bangladesh)

PARACETAMOL (Clinical)
Commonly used for relief of

fever, head aches and minor

pain.
Major ingredient in numerous
cold and flu remedies.
Is a non prescription drug (free
marketing)
The most consume drug after
amoxicillin in Indonesia.

PARACETAMOL (Safety)
Is considered as a very safe

analgesic & anti pyretic

It is safe from neonate to old
age, pregnant even lactation
women.
It is very cheap analgesic, and
the only analgesic which can be
used for long term treatment .

The mystery as how

paracetamol exerts an
analgetic effect without
affecting COX-1 and COX2?

PARACETAMOL
Although paracetamol has been using for more than
100 years, but the mechanism of action still
controversial.
1. What is the mechanism of action of
paracetamol?
2. Which endogenous analgesic system are
influenced by paracetamol?
3. Is paracetamol is NSAID?
4. Is paracetamol safe for liver disease or taking
anticoagulants?
5. Which formula has the best analgesic efficacy?
6. Which route of administrates has the better
pharmacokinetic.

POSSIBLE MECHANISM
OF ACTION
1.
2.
3.
4.
5.

Inhibition of cycloaxygenase
isoenzymes
Interaction with the endogenous
opioid pathway
Activation of the serotoninergic
pathway.
Inhibition of NO production
Modulation in endogen
cannabinoid system

ENKEPHALIN
GABA
NOREPINEPHRI
NE

SEROTONIN

ENKEPHALIN
ENKEPHALIN
SEROTONIN
SEROTONIN

Inhibition of NO synthesis

NMDA-R

WIND-UP
Ca++

+
sGC

NOS

PKGI

Glutamate

NO

Activation of endogenous
cannabinoids

As conclusion, we may
conclude that;
Analgesic

effect of paracetamol
involves a self-synergistic
interaction between spinal and
supraspinal sites with recruitment of
endogenous opiod pathways.
Paracetamol is an analgesic and
antipyretic drug and has no or very
little anti-inflammatory effect which
work centrally.

Metabolism of
Paracetamol
Large Dose
Enzyme Inducers
Alcoholism
Poor Oxygenation
Cytochrome P450
Deacetylation
5%

Liver

Kidney

Glucuronide
Conjugation (90%)

Para-aminophenol
NAPQI
(PAP)
(N-acetyl-p-benzo-quinon
imine)
Liver
Non toxic
Glutathione
Oxidation
Damage
Metabolite
Conjugation
Kidney
Damage

Malnutrition
Low protein diet
Fasting
Excretion
Alcoholism
PBQI
Drugs (e.g., statins, phenytoin)