Physiological Pain

A. Husni Tanra
Department of Anesthesiology,
Intensive Care and Pain Management
Faculty of Medicine
University of Hasanuddin
Makassar
Objective
After this lecture, participants are able to know :
1. Short history of Pain

2. Definition of Pain

3. Mechanism of Pain

4. Nociceptive Pain Perceptin

Before Eve was created from Adam's Rib, Adam was put into sleep
 INTRODUCTION
Concept of pain has a long history.
• Ancient greek time (9 Century BC, Hormer, Plato,
Aristoteles)
• Descrates  Cartesian Mechanistic Model (1664)
• Muller  Specific nerve energies (1842)
• Beecher  emotional factor (1959)
• Melzack & Wall  Gate control theory (1965)
• Merskey  definition of pain (IASP) (1979)
• Woolf  plasticity of the nervous system. (1991)

Pain Pain is
as alarm protector A disease entity it self
or symptom of disease A self sustaining disease
 What is Pain?
“Arrows shot by the Gods”
Homer
“Passion of the Soul”
Aristotle
“Pain & Pleasure arise from within the body”
Plato

The word “pain” derives from latin word “poena”

meaning “punishment”.
During the 17th century
Rene Descartes (1664)  Mechanistic concept

Cartesian model
• One unit of pain stimulus would produce one unit
of pain.
• Pain system was a straight through channel from
the peripheral to the brain.
• NS is just like
– “a church bell system”
– “a hard wire system”
• Body and mind are distinctly separate
(“cogito, ergo sum” = “ I think, therefore I exist”)
Descartes (17th Century)

First ideas….

Pain was faithfully transmitted

from periphery to brain
A pure stimulus response relationship
1840 MULLER from Berlin proposed
Doctrine of Specific Nerve Energies

• Stating that there are

specific pathways for the
five senses.
• Brain receives information
only by way of the sensory
nerves
Muller
In the 19th century, two scientist;
Bell and Magendig found that :

Charles BELL Francous MAGENDIE

DORSAL ROOTS IS SENSORY in FUNCTION

where VENTRAL ROOTS IS MOTOR FUCTION
Progress in understanding pain
MELZACK and WALL
‘Gate Control Theory’

1965-
 1965 MELZACK and WALL
Introduce Hypothesis of
“GATE CONTROL THEORY”

Brain

GATE CONTROL SYSTEM

Aβ
-
+ +
ACTION
SG DHN SYSTEM
- - +

The beginning of “MODULATION”

 1979 MERSKEY (psychiater) pain
definition, which was accepted by IASP

PAIN IS “AN UNPLEASANT SENSORY AND

EMOTIONAL EXPERIENCE ASSOCIATED WITH
ACTUAL OR POTENTIAL TISSUE DAMAGE, OR
DESCRIBED IN TERM OF SUCH DAMAGE”.

The problem lies in the word unpleasant.

Pain is more than unpleasant.
 What is Pain?...Definition…

• Scientific : Pain is unpleasant sensory and

emotional experience ascociated with
actual or potential tissue damage or
describe in term of such damage.
(Merskey 1979).Accepted by IASP

• Clinical : “Pain is whatever the experiencing

person says. (Mc Caffery 1997)
“Pain is what ever the pateint says”
Definisi Nyeri

Definisi oleh IASP :

Nyeri adalah “Perasaan yang tidak
menyenangkan dan pengalaman emosionil
akibat adanya kerusakan jaringan yang nyata
atau berpotensi rusak atau tergambar
sebagai adanya kerusakan semacam itu”

(Merskey, 1979).
 Definisi Ini Bermakna
1. Syarat utama u disebut nyeri yakni adanya rasa tidak
menyenangkan, tanpa itu bukan nyeri, walaupun tdk
semua yg tidak menyenangkan itu hrs nyeri.
2. Nyeri adalah perasaan sensoris dan pengalaman
emosional yang tidak menyenanagkan.
3. Nyeri terjadi akibat adanya kerusakan jaringan yang nyata
atau berpotensi mengalami kerusakan  yg pertama
disebut NYERI AKUT (PAIN WITH NOCICEPTION) yg
terakhir disebut NYERI FISIOLOGIK  withdrawel reflex.
4. Nyeri juga dapat dirasakan tanpa adanya kerusakan
jaringan yang nyata  NYERI KRONIK (PAIN WITHOUT
NOCICEPTION).
Klassifikasi Nyeri
Sampai saat ini belum ada
kesepakan yg umum yg
disepakati oleh para ahli.

Tissue damage – inflammation

or nociceptive pain
Nerve damage
– neuropathy
-central neuropathic pain
-peripheral neuropathic pain

 Cancer pain

Acute pain
Chronic pain

Mild
Moderate
Severe
 KLASIFIKASI NYERI
Yang umum digunakan adalah

Menurut waktu  Nyeri akut & kronik

NYERI
Menurut patofisiologinya :
 Nyeri fisiologik
 Nyeri klinis ( nyeri patofisiologik)
1. Nyeri nosiseptif
2. Nyeri neuropatik
• Perifer
• Sentral
3. Nyeri psikogenik / idiopatik
 Acute Pain

Acute Pain is the normal predicted

physiological response to an adverse
chemical, thermal or mechanical stimulus
…., associated with surgery, trauma and
acute illness.”

( Federation of State Medical Boards of US )

 Nyeri Akut

Nyeri Yang Terjadi Akibat Adanya

Kerusakan Jaringan Yang Nyata.
- Adaptive pain (patophysilogic pain)
- Maladaptive pain (patological pain )
 Acute Pain

Somatic pain Visceral pain

 constant  constant
 sharp aching  dull aching
 well localized  poorly localized
 usually with nausea and
vomit
occasional colicky or cramp
 often referred to
cutaneous sites
Referred Pain

Figure 10-13: Referred pain

 Klassificasi serabut saraf
perifer
Neuron Afferen Primer
Mempunyai badan sel unipolar yang
berlokasi pada radix ganglion dorsalis

Diklasifikasikan berdasarkan ukuran

serabut dalam 3 group mayor (A, B, C).

Group A selanjutnya disubklasifikasikan

dalam 4 subgroup (Aα, Aβ, Aγ, dan Aδ
 Classification of peripheral nerve fibers
Fiber Innervations Mean Mean
Group diam conduc
(mn) Velocity
(m/sec)
A  (m) Primary muscle spindle, motor to skeletal 15 100
muscles
A (M) Cutaneous touch and pressure afferents 8 50
A (M) Motor to muscle spindles 6 20
A (M) Mechanoreceptors and nociceptors <3 15
B (M) Sympathetic preganglionic 3 7
C (UM) Mechanoreceptors, nociceptors and 1 1
sumpathetic preganglion fibers
 Pain Afferent neurons
A myelinated fiber
Responds to noxious stimuli
C unmyelinated fiber

Both have
free nerve
endings

Aα myelinated fiber Responds

to
Aβ myelinated fiber innocous
stimuli
INNOCUOUS STIMULUS
A fiber
Mg NMDA

AMPA

Glu
NK Em
AMPA
Mg
NMDA

NK
C fiber

Urban et.al., 1994

 NOXIOUS STIMULUS
A fiber
Mg NMDA

AMPA

Glu
NK Em
Mg AMPA

NMDA

NK
C fiber

Urban et.al., 1994

PATHOLOGICAL PAIN
A fiber Mg

NMDA

AMPA

Glu
Em
NK
Mg AMPA

NMDA

NK
C fiber
Urban et.al., 1994
 Nociceptors
1. Mechanothermal nociceptors
Ad fibers respond to mechanical and thermal
stimuli, display a rapid conduction velocity.( first
pain, well localized )
2. Polimodal nociceptors
C fibers respond to mechanothermal and chemical
stimuli, display a slow conduction velocity.( second
pain, diffuse)
• Exist in many tissues, skin, muscle, pariosteum,
joints, and viscera, except brain.
 NOCICEPTION
Between noxious stimulus and perception
of pain lies a complex series of
electrophysioloc event, collectively
termed NOCICEPTION
4 physiologic processes are involved:
1. Transduction
2. Transmission
3. Modulation
4. Perception
 TRANSDUCTION
Transduction Mechanical
denotes the
process whereby
Heat
noxious stimuli are
translated into
electrical activity at Chemical
nociceptors site.
 Transduction Process

Ca2+

K+
K+

Na+

1. Transduction 3. Propagation
2. Spike Initiation 4. Transmitter Release

Modified Meliala, 2006

 TRANSMISSION

• Propagation of impulses throughout

the sensory nervous system. Or
• Passage of signal from periphery to
the central NS.
 There are two sensory afferent neurons
1. Large myelinated A fibers, very fast conduction velocity.
Respond to innocuous stimuli
2. Small myelinated A & C unmyelinated fibers, have slow
conduction velocity. Respond to noxious stimuli

Large
fibers A

Dorsal root
ganglion Dorsal Horn
A
Small
fibers
C Peripheral sensory
Nerve fibers
 Physiological Pain
NOXIOUS INNOCUOUS
STIMULUS STIMULUS

A C fiber A

DHN DHN

INNOCUOUS SENSATION
PAIN
First Pain Touch
Second Pain Tactile
Pressure
Afferent Synaptic in DHN

Substantia
Marginal layer
gelatinosa
A Medial

A

C
Lateral

Nucleus
proprius
 Medula Spinalis
(kornu posterior)
Dahulu : dikenal sebagai “SIMPLE RELAY
STATION” Untuk transmisi Nyeri
Sekarang : Sebagai tempat interaksi yang
kompleks antara
 Serabut-serabut Eksitatori
 Serabut-serabut inhibitori

MODULASI NYERI
 WIDE DYNAMIC RANGE SPINAL
NEURON
Glutamate
C
(Subs P)

A NMDAr
Glutamate
A
Glutamate
+ “Wind-up” Brain
Gene induction

Inhibitory
GABA
-
Fibers
Glycine
Opioids
NA, 5HT
 MODULATION
• The process whereby endogenous
analgesic system (opioid, serotonergic,
and noradrenergic) can modify nociceptive
transmission
 Spinal Cord
SPINAL CORD (DHN) is the key point of
modulation
• The place where afferent input is processed.
• Where interaction between excitatory and inhibitory
system.
• NOCICEPTION IS BORN IN DORSAL HORN,
BUT WE DON’T CALL IT PAIN TILL IT
REACHES THE BRAIN (Dr. Ken Casey)
Modulation
 Descending Modulating
Pathways
Ascending pathways is modulated by descending
modulating pathways in several higher centers;
 CEREBRAL CORTEX
 THALAMUS
 MIDBRAIN/ BRAINSTEM
 Periaqueductal gray (PAG)
 Nuclei raphe magnus (NRM)
 Locus ceruleus (LC)
 Sub ceruleus
 SPINAL CORD
SEROTONIN
NEOREPINEPHRINE
 Two Kind of Stimuli
Nociceptor Noxious/ Innocuous

DHN Modulation

Facilitatory/ excitatory Inhibitory

Pain No Pain

Pain stimulus is not perfect terminology

 Pain

Inhibition
CNS Excitation

Nociception
 Nociception Without Pain

Pain
X
Inhibition
CNS Excitation

Example: Stress Induced Analgesia

Nociception
 Pain Without Nociception

Pain

Inhibition
CNS Excitation

X Example: Phantom pain

Nociception
 Pain Perception

Depends on the balance between:

 Excitatory system
 Inhibitory system
(Cognitive, emotional, behavior)
Beecher

Pain perception depend on the meaning of injury

 Perception Pain
Pathway/ Perception
Pain

Medulation
Descending
modulation Dorsal Horn

Ascending
input
Dorsal root
ganglion
transmission

Transduction
Spinothalamic
Peripheral
tract
nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Perception Perception
Final process to
create the final Pain
Brain
subjective and Perception

emotional
experience that
we call pain
How pain perception is processed, no body knows and
Where pain perceptions in the brain still unclear.
 Neuron III Persepsi

Transduksi

Fisik
Transmisi

Transmisi Modulasi Neuron II

Suhu

Neuron I
Kimiawi
 TAKE HOME MESSANGE
1. -Pain is a very subjective feeling
-Pain is what ever the patient says
2. -Only nociceptive pain is respond to NSAID
(cox1 or cox2)
3. -Neurophatic pain do not respond to NSAID
but it may respond to anti depresunt or anti
convulsait may be opioid
4. - Chronic pain, is pain beyoud naciceptive,
accure after headling process, diffecult to heat
and reduced quality of life.
Facial expression of pain drawn by Sir Charles Bell
 Controversy between physical and
psychological (emotional) component during
ancient greek time
• Hormer, thought of pain as due to arrows shot by
god.
• Aristoteles, pain was not a sensation but
emotional  “passion of soul”.
• Plato , pain was perceived in the heart due to
impact violent on the soul.
• Galen, investigated that the brain was the center
of sensation.
• The word “pain” derives from latin word “poena”
meaning “punishment”.
 Definition of Pain
According to IASP
Pain is “an unpleasant sensory and emotional
experience associated with actual or
potential tissue damage or described in term of
such damage” (Merskey, 1986).
• Pain is a complex interaction that involves:

1. Cognitive, in formulation of pain

2. Emotional , the consequence of pain

3. Behavioral , the way we response to cog & emotion aspects
 INFLAMMATION/NOCICEPTIVE
Peripheral Sensitization Central Sensitization

Damaged Zone ALLODYNIA

HYPERALGESIA

Sensitization and activation

COX1 - COX2
BK2 - BK1

PGs, H+

ATP CNS
NGF C-fibre
blood SP, CGRP Transmitter
vessel release - neuronal
BK
excitability
5HT
Vasodilation+plasma extravasation
 Inflammation Tissue
1
Painful stimulus
Prostaglandins
produced in response to
tissue injury; increase
Pain-sensitive tissue
sensitivity of nociceptor
(pain)
2
Prostaglandin
1 Blood Nociceptor then releases
Substance P
Mast cell vessel substance P, which dilates
blood vessels and increases
Histamine release of inflammatory
mediators, such as
Bradykinin
Bradykinin (redness & heat)
Substance P
2
3 3
Substance P also promotes
Nociceptor degranulation of mast cells,
which release histamine
(swelling)
 Perception Pain Perception
Pain

Medulation
Descending
modulation Dorsal Horn

Ascending
input
Dorsal root
ganglion
transmission

Transduction
Spinothalamic
Peripheral
tract
nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
 Persepsi Nyeri
•Sangat tergantung dari MODULASI mulai dari :
– Korteks Serebri
– Hipotalamus
– Otak Tengah
– Batang Otak, dan
– Medulla Spinalis
•Yang dipengaruhi oleh berbagai faktor :
– Genetik, kelamin
– Pendidikan
– Motivas
– Budaya
– Tafsiran dari trauma
– dll
 Neurotransmitters
• There are many neurotransmitters in
presynaptic at DHN, but 2 are very
important;
• Glutamate (AA) and Substance P (peptide)
– AA mediate rapid short-duration depolarization
– Peptide delayed and long acting depolarization
Presynaptic & Post Synaptic Receptors

Dorsal Horn Neurons

 Cortical structures
• It has been long to divide higher neural
center in pain processing into 2 parts:
– Somatosensory cortex  sensory
discriminative pain
– Cingulate cortex  affective pain
• However, this is maybe an
oversimplification, the role of cortex in
PAIN PERCEPTION remains unclear.
( Philip Siddal )
 DESCENDING INHIBITION
BRAIN DESCENDENS

5HT

ENK
AFFEREN

SP-GLUTAMAT
NEURON TRANSMISI

Kornu Dorsalis

Meliala, 2005
 WIDE DYNAMIC RANGE SPINAL
NEURON
Glutamate
C
(Subs P)
A NMDAr
Glutamate
A
Glutamate
+ Brain
“Wind-up”
Gene induction

Inhibitory GABA
-
Fibers Glycine
Opioids
NA, 5HT
 Descending Pain Control
Cortex
Brain Hypothalamus
Thalamus

Releases
• Endogenous opioids
Midbrain PAG • GABA
• NE

Releases
Brain stem NRM • Serotonin
• NE

Inhibit
Spinal cord DHN • WDR neurons Analgesia
• NS neurons
From this definition, some conclusions can be obtained;

1. PHYSIOLOGICAL PAIN, is a normal sensation, elicited by

potential tissue damage  Withdrawal reflex

2. PATHOPHYSIOLOGICAL PAIN, is an abnormal

sensation :
 Due to actual tissue damage  inflamed pain = clinical pain =
acute pain. e.g. : postoperative pain
 Due to nervous system damage  neuropathic pain

3. PATHOLOGICAL PAIN,
 Described in intern of such damage  CHRONIC PAIN
 Chronic pain is now consider as “a disease of entity”. Causing
suffering, reducing QOL
 Primary Afferent Fibers
C Fiber & A are afferent fibers that respond to
noxious stimulus, while A do not respond to
noxious stimuli, but it’s very important for normal
sensation
Without A, all noxious stimuli will perceive as
burning pain

A
Chronic pain ?

Chronic pain is a pain that persists

beyond normal tissue healing time,
which is assumed to be three months.
The International Association for study of pain (IASP)
panthom pain
 PATHOPHYSIOLOGY OF
CHRONIC PAIN

• Pathophysiology in CNS - “central sensitization”

• “Rewiring” in spinal cord dorsal horn
• Genetic changes in dorsal horn neurons
• Death of neurons: inhibitory deficit
• Inhibition of normal motor activity, muscle
wasting
• Sympathetic dysfunction, tropic changes
 CONSEQUENCE of
CHRONIC PAIN

• Fear - avoidance behaviour

• Anxiety and sleep disturbance
• Depression, helplessness, irritability,
suicidal risk
• CNS toxicity due to inappropriate drug use
• Loss of job, family and community status
 CHRONIC PAIN IS A DISEASE
ENTITY

- Is a major problem of public health

- lead to emotional distress and suffering
(insomnia, anxiety, depression,can not work, etc)

- Is really a killer for quality of life

 sensations Spinal cord
A
I
Dorsal root C II
III
Peripheral A/
IIV
nerve
A V

inputs VI X

VII
IX

reflexes VIII
 Neurotransmitters in DHN
Tachykinin (Substance P, Neurokinin A)
Presynaptic neurons Glutamate

Ca2+ Na+
Na+/Ca2+

NK1 NK2 NMDA

AMPA

Mg2+
G G
Na+
Ca2+
Ca2+
Depolarisasi

Protein Kinase C
Postsynaptic neurons
Normal condition
R

Physiological pain

Pathological condition

S
Physiological pain
Dorsal Horn
• Approximately 70% of
pain fibres enter in the
dorsal root
• 30% double back and
enter the ventral
("motor" root).

Ten Grey Matter Laminae

• Lamina I - marginal
zone
• Lamina II - substantia
gelatinosa
• Lamina V - part of
"nucleus proprius of
dorsal horn" (with IV,VI)
• Laminae VII and VIII -
intermediate spinal
grey matter (with X)
 The Dorsal Horn

• Different functional classes of 1° afferents have

specialised central axon arbor morphology &
their DH termination zones are mostly
segregated into different laminae
• Termination of 1° afferents
– A: Laminae I, V & X
– C : Laminae I, II (substantia gelatinosa), V
– A: Laminae III, IV, V
 Pain is negleted subject
• Pain as a proper subject has long been
neglected by medical science
• Pain is like death, it reminds us too much
of our failures as physician
• Pain is like sex, it was seen as too private
for objective analys
• Pain was never mentioned as a topic in
my medical school, residency, or
fellowship training

David Nelson, Neuroanatomy of Pain : November 18, 2001

 Pain is a real perception
• Unlike other diseases such as blind,
parkinsons, alzheimer, etc
• Pain can not be seen, what you have to do
is to listen the patient
• Pain is whatever the patient says
 Pain Physiology
1. Transduction
– Activation of nociceptors by mechanical, thermal or
chemical stimuli
2. Transmission
– Passage of signal from periphery to centre
3. Modulation
– Modification of signal
4. Perception
– Awareness of noxious stimulus
 Transmission
• A Fibres
– Convey “First pain” responses from periphery to the dorsal
horn
– Thinly myelinated  5 - 30 m/sec
• C Fibres
– Convey “Second pain” to DH
– non-myelinated  0.5 – 2 m/sec
• Aβ Fibres
– large myelinated fibres  40-70 m/sec
– Convey signals from peripheral vibration / pressure / touch
receptors. (ie non-noxious)
– Non noxious stimuli can reduce transmission of A & C
signals in the cord (eg rubbing the injured part, TENS to
reduce pain)
– Non-noxious stimuli perceived as noxious (Allodynia) when
cord connections are “rewired” following nerve damage
 Receptors-Nociceptors
• Peripheral Receptors:
– High threshold mechano-thermal Nociceptors.
– Polymodal Nociceptors (thermal, chemical,
mechanical)
• exist in many tissues (but not in the brain)
• Visceral Nociceptors
– Chemical & mechano-thermal
– “Silent”- sensitised by inflammation
– Wide Dynamic Range-polymodal
• Intensity encoded from innocuous to noxious
stimuli
 Transmission
Brain Pain Perception

Descending control
pathway from base
of brain

Encephalin
Encephalin interneuron
interneuron Dorsal
Dorsal Root Horn Dorsal
Ganglion Brainstem Horn

Nociceptive
Dorsal Root
transmission
Ganglion
via ascending
pain pathways
Spinal Cord (spinothalamic tract)

Nociceptor sensitization Spinal Cord

 sensitivity to norepinephrine
Nociceptor
heat / cold, local ion fluxes
evoked
Nociceptor mechanical stimulation Nociceptor discharges

Adapted from Goldstein A. Hospital Practice 1978 1:32

 NYERI NOSISEPTIF VS
NYERI NEUROPATIK
Nyeri Nosiseptif Tipe campuran Nyeri Neuropatik
Disebabkan oleh Timbul akibat Diawali/disebabkan oleh
kerusakan jaringan atau kombinasi trauma lesi / disfungsi susunan
organ primer atau efek saraf
sekunder

Sakit kepala
Artritis Neuralgia post herpes (headache)
Nyeri pasca
operasi
Sickle cell Radikulopati menyertai
crisis Low Back Pain Neuralgia
Nyeri punggung
bawah mekanik trigeminal
Trauma olahraga
Nyeri Kanker Neuropatik
Polineuropati distal (mis. DM, HIV)
Mekanisme Nyeri Nosisepsi

Dimulai dari adanya stimulus noksius

(fisik, suhu atau kimiawi) diterima oleh
nosiseptor yang ada di kulit, otot,
perios, visera atau pleura, dll. dan
dilanjutkan olen neuron pertama.
Multimodal Analgesia
A.Husni Tanra
 Multimodal Analgesia
( Balanced Analgesia )
Polypharmacologic intervention nociception
at discreet points in the nociceptive pathways
and processes.
Or polypharmacologic manipulation of
– Transduction  NSAIDs (COX1 & COX2)
– Transmission  Local anesthetics
– Modulation  Opioid or NMDA antagonist

Using 2 or more drugs which different actions

 Multimodal Analgesia
Except for a very mild surgery, no single drug may
produce optimal analgesia without adverse effect

Multimodal analgesia, is the best method for

postoperative pain management.
“Combination of analgesic that act by different
mechanisms result in synergic analgesia”
 Benefits of Multimodal
Analgesia

Opioids
• Reduced doses of each
analgesic
• Improved pain relief due
Potentiation to synergistic or additive
effects
• May reduce severity of
side effects of each drug
NSAIDs,
acetaminophen,
nerve blocks
1Kehlet H et al. Anesth Analog. 1993;77:1048-1056.
Nature Of Postoperative Pain
Nociceptor
sensitisation
Somatic
Pain Referred
muscle, fascia, pain
ligament

Postop
pain Reflex
Visceral response
Pain Muscle
spasm

Cortical Cutaneous
Responses Somatic
pain
Different Surgical Procedures have
Characteristic Pain Profiles

Different types Different pain

of pain intensity

Different
procedures

Different risks
and benefits of Different
analgesic location of
techniques pain
Analgesic Choice and Requirement
Depending On:

• Type of surgery
• Duration of surgery
• Extent of surgery
• Surgeon him/ herself
 Different surgery different
method & drugs
1. Thorax Surgery is very severe pain
 Epidural (LA + opioid) + NSAID / COX 2. Site at
Th5 - 6
 Acetaminophen (COX 3) is a basic for multimodal
analgesia.
2. Upper abdominal Surgery is also very
severe pain.
 Epidural (LA + opioid) + NSAID / COX 2. Site at
Th9 - 10
 Acetaminophen (COX3) is recommended as a basic
for multimodal analgesia.
Different surgery different method & drugs

3. Gyneocologic Surgery less severe pain

 Systemic opioid + NSAID / COX 2 is recommended
but,
 Epidural (LA + opioid) is preferable +
Acetaminophen (COX3) is a basic for multimodal
analgesia. Site at Th12 - L1
4. Prostat Surgery usually not so severe
pain
 Systemic opioid + NSAID / COX 2
 Acetaminophen (COX3) is a basic for multimodal
analgesia
 Epidural (LA + Opioid) at site at L1 - 2
Step Ladder of Multimodals
Analgesia
Step 3 Severe Postoperative Pain
Step 1 and Step 2 Strategies
AND
Local Anesthetic Peripheral Neural Blockade
(With or Without Catheter)
Use of Sustained Release Opioid Analgesics
Step 2 Moderate Postoperative Pain
Step 1 Strategy
AND
Intermittent Doses of Opioid Analgesics
Step 1 Mild Postoperative Pain
Nonopioid Analgesic
Acetaminophen, NSAIDs, or COX-2 Specific Inhibitors
AND
Local Anesthetic Infiltration
Modification of WFSA analgesic ladder
Crews JC, JAMA 2002;288:629-32
 Paracetamol (COX3)
 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
 Paracetamol has a little effect on COX 1 &
COX 2
 Work centrally decrease pain & fever
 Basic component of multimodal analgesia
 Some Drugs Are Superior to Others

Ketorolac Parecoxib
(First injection COX 1 ) (First injectable COX 2 )

• Potent analgesic • Potent analgesic

• Effect of bleeding time • No effect of bleeding time
• Induce GI bleeding • Improve GI motility
• No interaction with midazolam • No interaction with midazolam
or propofol or propofol
• Cheap • Expensive
• Preemptive? • Good for preemptive
Not All Drugs Have Same Effect to All
Surgery

Paracetamol
(COX-3)

Good for: Not so good for:

Oral surgery Episiotomy
Dental extraction Orthopaedic surgery
 Multimodal Analgesia
OPIOID
- Systemic
PERCEPTION - Epidural
- Subarach
Pain Ketamin, Tramadol

COX-2, COX-3
LOCAL ANESTHETIC
MODULATION - Epidural
Descending
modulation Dorsal Horn - Subarachnoid
Ascending Dorsal root
input ganglion

TRANSMISSION LA
COX-1
COX-2
Spinothalamic
Peripheral
tract TRANSDUCTION
nerve

Trauma
Peripheral
nociceptors

No single drug can produce optimal analgesia without adverse effect

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
 Multimodal Analgesia
Parecoxib
Ketamine
Ibuprofen
ivNMDA
iv
Cox-2 agents antagonists

NSAIDs Better analgesia

iv
– Synergy
Multimodal – Additivity
Reduce side effects
Paracetamol
iv

NorAdr & iv Local Anaesthesia

Opioids 5HT antagonists
iv
Jin et al. J Clin Anesth;13:524, 2001
Tramadol
Kehlet et al. Anesth Analg;77:1048. 1998
Woolf CJ, Science, 288:1765-1768, 2000
 Balanced Analgesia

as bad as
too little too much
analgesia analgesia

- Decrease mobility - Somnolence

- Hypoventilation - PONV
- Chronic pain - Inability to mobility
- Tromboembolism

TITRATION IS
Balanced analgesia
IMPORTANT
 Multimodal Analgesia
Thorax Surgery
PERCEPTION
Abdominal Surgery
Gynecologic Surgery COX 2
Pain Prostate Surgery

MODULATION Epidural LA + Opioid

Descending COX1
modulation Dorsal Horn
Ketorolac
Ascending Dorsal root (Remopain)
input ganglion

TRANSMISSION

Spinothalamic
Peripheral
TRANSDUCTION
tract
nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
 Tips From dr. D. Nelson
Marin General Hospital

• Using combine of COX-2 +

Cox-3 inhibitors as post
operative pain management
• Celebrex 400 mg/ once daily,
taken 2-3 hrs before surgery
• Paracetamol 500 mg q 4 hrs
after surgery
• The result was so fantastic, no
pain at all.

Good for minor orthopedic surgery or ambulatory surgery

• Giving : - parecoxib (COX2-inhibitor), combine
- Paracetamol (COX3)
Before induction of anesthesia or surgery may
produce long effective analgesia

COX2-inhibitor + COX3 Strong Synergism

• Continuous treatment with multimodal will be the

most effective method of treating post op pain
Role of Precoxib (Dynastat)
• The existence of COX2 injection brought a new era of
– Multimodal analgesia
– Pre-emptive analgesia
• Complete nerve block can not prevent central
sinsitization
• Tissue damage (surgery) or inflammation may induce
COX2 prostaglandin
(via humoral) to induce control sensitization
• Only precoxib can inhibit COX2-iso enzyme both
peripherally and centrally
 Psychological Approach
interventions should be used in combination with
pharmacologic therapies to prevent or control
acute pain.
Individuals differ considerably in how they respond
to noxious stimuli; much of this variance is
accounted for psychological factors.

Cognitive, behavioral, or social

Pain has two dimensions: physical & psycological.
 Psychological Preparation of
Surgical Patients
Procedural information, description of what will take place

Sensory information, sensations that will be experienced

Pain treatment information, plan for administering sedative

and analgesic medication

Instructional information, teach patients pre and

postoperative exercises

Reassurance, reassure those who are mentally, emotionally, or

physically unable to cooperate

(Henrik Kehlet, Postoperative Pain ACS Surgery, 2005)

 Take Home Message
• Postoperative pain is the most understood form
of pain that we know.
• MULTYMODAL ANALGESIA is the best
method.
• Different surgery may has different method.
• Combination :
– Pre-emptive analgesia
– Multimodal analgesia
– Perioperative rehabilitation
Is a new concept to increase effective analgesia
and outcome of surgical patients
Super Thanks for Your attention !
Ascending Descending
pathways pathways
Ascending Descending
pathways pathways
 Acute Pain

• “Pain of recent onset & probable limited

duration.
• It usually has an identifiable temporal and
causal relationship to injury or disease.”
Ready & Edwards 1992
Some Drugs Are Superior to Others

Parecoxib
(First injectable COX 2 )

• Potent analgesia & anti-inflammation

• No effect on bleeding time
• Improve GI motility
• No interaction with midazolam or propofol
• Can be used as preemtive analgesia
 Pain: The Fifth Vital Sign™

• Pulse
• Blood pressure Pain:
The Fifth
• Temperature Vital Sign™

• Respiratory rate

•American Pain Society (APS) has redefined PAIN as the 5th vital sign
•Health care professional has to assess patients for pain every time

June 2005
Response

Pain threshold

Stimulus
intensity

Hyperalgesia Allodynia
Increased SENSATION OF Reduced PAIN THRESHOLD
PAIN
 OPIOID RECEPTORS
Mu and Delta opioid receptors
• linked to potassium channels
• increased potassium flux  hyperpolarizes the
cell and reduces excitability
• located pre and postsynaptically
• presynaptic actions inhibit glutamate release
• enkephalin is the preferred ligand

• Mu receptors influenced by CCK

• Delta receptors more potent against thermal
stimuli?
OPIOID RECEPTORS
Kappa opioid receptors

• located postsynaptically
• inhibit calcium channel activity
• regulate WDR excitability
• dynorphin is the preferred ligand

• possible anti-analgesic effect

• dynorphin derived from intrinsic
dorsal horn neurons
 Differences of PO Pain
• Abdominal Procedures
- Pain after major and upper abdominal operation is
severe
- Combined regimen of epidural local anesthetics and
opioids plus systemic NSAID or COX-2 inhibitors is
recommended
• After Gynecologic Operations
- Systemic opioids plus NSAID or COX-2 inhibitors are
recommended
• Prostatectomy
- Pain is usually nor severe and may be treated with
systemic opioids combined with NSAID or COX-2
inhibitors and acetaminophen
- How ever, blood loss and thromboembolic
complication are reduced when epidural local
anesthetics are administered
 Better Pain Management Protocols
are Required
Limited use of fixed
pain therapy plans

Pain management Choice of analgesia Pain management

relies on systemic may be made too late: differs between
opioids and is not in ward, when patient hospitals and
procedure-specific complains countries

Sub-optimal postoperative pain management

Salamat, po
Overcoming
Pain
Management

Multidisciplinary Approach
 Pain Neurochemistry
Transmission via Tissue injury
Ion
spinothalamic tract Dorsal fluxes
to brain Horn (H+/ K+)
Dorsal
root Prostaglandins Bradykinin
ganglion

leukotrienes

Spinal Cord

Substance P

To brain
Histamine
Sensitized
nociceptor
Substance P, aspartate,
neurotensin, glutamate
 Sensitization
10

8 Hyperalgesia Normal
Pain
Pain Intensity

Response
6 Injury
Allodynia
Hyperalgesia—
4 heightened sense of
pain to noxious stimuli
2 Allodynia—pain
resulting from normally
painless stimuli
0

Stimulus Intensity

Gottschalk A et al. Am Fam Physician. 2001;63:1979-84.

Sub-optimal pain management can
have serious consequences…
Acute postoperative pain
Inadequate pain
management

Clinical and Decreased

psychological changes mobilisation
Induction of
chronic pain
Increased risk of
deep vein thrombosis, pulmonary embolism,
myocardial infarction and coronary ischaemia

Mortality/morbidity, longer hospital stay, re-admission, decreased quality of life,

decreased patient satisfaction and increased health costs

Ballantyne et al. Anesth Analg 1998;86:598;

Wu et al. Anesth Analg 2003;97:1078;
Pavlin et al. Anesth Analg 2002;95:627;
Anesthesiology 2004;100:1573;
Perkins et al. Anesthesiology 2000;93:1123
 Epidural and Subarachnoid
Opioids
Opioids injected into the epidural or subarachnoid space
cause segmental spinally mediated analgesia by binding to
opioid receptors in the dorsal horn of the spinal cord

The lipid solubility of an opioid determines its access to the

dorsal horn via (1) diffusion through the arachnoid
granulations and (2) diffusion into spinal ridiculer artery
blood flow.

Opioids with low lipid solubility have a slow onset of action

and a long duration of action.
Opioids with high lipid solubility have a quick onset of
action but a short duration of action
Penanganan nyeri postop sebaiknya dikerjakan secara Tim
dengan menyertakan Dokter Spesialis Anestesiologi dan
Perawat.
Agar anelgesia optimal dicapai dengan dosis minimal.
Dosis minimal = efek samping yang sangat minimal

Physicians prescribe analgesics, pharmacists facilitate

access to appropriate analgesics and nurses implement
pain relief methods and identify the need for changes.

Basic of Pain Management in Adults, Chris Pasero.RN.MS: Margo

McCaffery.RN.MS.FAAN. Pain Management Educator and Consultant Rocklin, CA
Surgical outcomes are best divided into four
major sub-groups :
a) Patient satisfaction;
b) Morbidity and mortality of surgery, surgical
stress and anesthesia;
c) Side effects of peri-operative medication;
d) Duration of stay in hospital and intensive
therapy areas.
Good postoperative pain management, can
impact to all of these end points.
 Conventional NSAIDs and COX-2
Inhibitors
NSAIDs are minor analgesics.
The anti-inflammatory effect makes it suitable for
postoperative pain associated with inflammation.
They may have central analgesic effects and thus
analgesic efficacy after all kinds of operations.

Conventional NSAIDs inhibit both COX-1 and

COX-2 .

Newer agents specifically inhibit COX-2.

The analgesic efficacy is comparable to
conventional NSAIDs but with fewer side effects
 What is Pain?
• Pain is a subjective feeling
• Pain is what the patients said
• Post operative pain is “the
expected, undesirable byproduct
of all surgical procedures”
 Pain Transmission
Brain Pain Perception

Descending control
pathway from base
of brain

Encephalin
Encephalin interneuron
interneuron Dorsal
Dorsal Root Horn Dorsal
Ganglion Brainstem Horn

Nociceptive
Dorsal Root
transmission
Ganglion
via ascending
pain pathways
Spinal Cord (spinothalamic tract)

Nociceptor sensitization Spinal Cord

 sensitivity to norepinephrine
Nociceptor
heat / cold, local ion fluxes
evoked
Nociceptor mechanical stimulation Nociceptor discharges

Adapted from Goldstein A. Hospital Practice 1978 1:32

 Mechanisms of Action of
Opioid
Opioids produce analgesia and other physiologic effects
by binding to specific receptors in the peripheral and
central nervous system.
These receptor-binding interactions mediate a wide array
of physiologic effects

Five types of opioid receptors :

mu, delta, kappa, epsilon, and sigma receptors.
Most commonly used opioids bind to mu receptors

The mu1 receptor is responsible for opioid-induced

analgesia.
The mu2 receptors are related to the respiratory
depression, cardiovascular effects and inhibition of GI
motility
What is Pain?
“Pain is an unpleasant sensory and
emotional experience associated actual or
potential tissue damage, or described in
terms of such damage” (IASP 1979)

“Pain is always subjective.

Many people report pain in the absence of
tissue damage, if they report it in the same
way as pain caused by tissues damage.
It should be accepted as pain”
So, pain is what the patient says
Characteristic of Postop Pain

 Postoperative pain is pain of recent

onset and limited duration.
 It usually has an identifiable temporal
and causal relationship to injury
 It is “self-limiting”.

(IASP acute pain task force)

 Analgesia and the Pain Pathway

Pain Opioids
2 agonists
Centrally acting analgesics
COX-2–specific inhibitors
Traditional NSAIDs
Ascending
input Descending
modulation
Local anesthetics
Dorsal Opioids
horn 2 agonists

Dorsal root
ganglion
Spinothalamic
tract
Local anesthetics

Peripheral
Peripheral nociceptors
nerve Local anesthetics
Cox-2–specific inhibitors
Traditional NSAIDs
Trauma

Adapted from Gottschalk A, Smith DS. Am Fam Physician 2001;63:1979-84

 Multimodal Analgesia
OPIOID
- Systemic
PERCEPTION - Epidural
- Subarach
Pain Ketamin, Tramadol, 
agonist
LOCAL ANESTHETIC
COX-2, COX-3
- Epidural
MODULATION -Subarachnoid
Descending
modulation Dorsal Horn -Peripheral nerve block
Ascending Dorsal root
input ganglion

TRANSMISSION LA
COX-1
COX-2
Spinothalamic
Peripheral
tract TRANSDUCTION
nerve

Trauma
Peripheral
nociceptors

No single drug can produce optimal analgesia without adverse effect

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
 TISSUE INJURY

Prostaglandins
Bradykinin

Leukotriens

PAIN Histamine

NSAID
 Primary Hyperalgesia
Immuno Cells
Cell injury
Kinins Cytokines Cannabioids
H+ Neurotrophins Opioids
K Histamine Adenosine
5HT
Prostaglandin
Bradikynin

Nociceptor NO
Kinins
Vasculature
Neuropeptides
Primary Afferent Neurones

Prostaglandins
Sympathetic Efferent Neurones
 Inflammation Tissue
1
Painful stimulus
Prostaglandins
produced in response to
tissue injury; increase
Pain-sensitive tissue
sensitivity of nociceptor
(pain)

Prostaglandin 2
1 Blood
Substance P Nociceptor then releases
Mast cell vessel
substance P, which dilates
Histamine blood vessels and increases
release of inflammatory
Bradykinin mediators, such as
Substance P Bradykinin (redness & heat)
2
3 3
Substance P also promotes
degranulation of mast cells,
Nociceptor
which release histamine
(swelling)
 NSAID ? History
• 1893, Felix Hoffman (ahli kimia Jerman, bapaknya
menderita RA) menemukan asetilsalisilat (aspirin)
– Tahun yang sama ditemukan Parasetamol
– Keduanya dikenal sbg analgesik biasa (usual analgesic)
• 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  disebut
Cox3
 Five Cardinal
Signs of
Inflammation

HEAT REDNESS SWELLING PAIN LOSS OF FUNCT

 Apa itu prostaglandin?
• Merupakan salah satu dari eicosanoid (local hormon) yg penting
untuk normal physiology dan pathophisiologic condition

Normal physioloy Pathol. condition

• Blood clotting • Inflamation process
• Ovulation • Pain
• Initiation of labor • Swelling
• Bone metabolism
• Nerve growth & development
• Wound healing
• Kidney function
• Blood vessel tone
• Immuneresponse, dll
• Disebut prostaglandin,karena pertama ditemukan dalam cairan
prostat.
• Prostaglandin diproduksi lokal untuk kebutuhan lokal diberbagai
organ tubuh
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.

Cox2
Paracrine AA
AA  PGs PGs Cox1

PGs

Autocrine
Autocrine PGs

Epithelial cell Neighboring cell

• Cortisone & Thyroxin are released from a single site but have broad
systemic effect, it is called as:
– endocrine
 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
Cox2 = enzym induceble at the site of inflammation
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.
 COX-1 vs COX-2

COX-1 COX-2

 Constitutive  Inducible (in most tissues)

 Present in most tissues  Induced mainly at sites of
 Synthesizes prostaglandins inflammation by cytokines
(PGs) that regulate  Synthesizes PGs that mediate
physiologic processes inflammation, pain, and fever
 Especially important in  Constitutive expression
– gastric mucosa primarily in
– kidneys – brain
– platelets – kidneys
– vascular endothelium – ovaries

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

DuBois RN et al. FASEB J. 1998;12:1063-73.
The Differences Between COX-1 and COX-2

ARACHIDONATE

COX-1 COX-2

prostaglandins prostaglandins

• “Constitutive” • “Inducible”
• Expressed: • Expressed:
– GI mucosa – Site of injury
– Kidneys – inflamation
– Platelets – CNS
– Vascular
endothelium
 Arachidonic Acid

Cyclooxygenase-1 NSAIDS
Cyclooxygenase-2

PGG2

PGH2

PGF2.. PGD2 PGE2 PGI2 TXA2

 Cyclooxygenase (COX) in Platelets1

Inhibitors of
Platelet COX-1
COX-1

(-)

Thromboxane A2
Increased
bleeding

Platelet
aggregation

1Schafer AI. Effects of nonsteroidal antiinflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol. 1995;35:209-219.
 Cyclooxygenase (COX) in Gastric Mucosa1

Inhibitors of
Mucosal COX-1
COX-1

(-)

PGE2 and PGI2

Increased risk
of GI ulcers

Mucosal
protection

1Scheiman JM. Gastroenterol Clin N Am. 1996;25:283.

 Risk of GI Complications
and Death With Traditional
NSAIDs
• Risk of GI complications and death
is 3 to 10 times higher in users of
traditional NSAIDs vs. non-NSAID
users
•  107,000 hospitalizations and
16,500 deaths annually related
to traditional NSAID use among
people with arthritis
• Even 1 week of traditional NSAID
use can cause ulcers

1. Hawkey CJ. BMJ. 1990;300:278-84. 2. Gabriel SE, et al. Ann Intern Med. 1991;115:787-96. 3. Henry D, et
al. BMJ. 1996;312:1563-66. 4. Griffin MR, et al. Ann Intern Med. 1991;114:257-63. 5. Langman MJS, et al.
Lancet. 1994;343:1075-78. 6. Singh G. Am J Med. 1998;105 (suppl 1B):31S-38S. 7. Goldstein JL, et al. Am J
Gastroenterol. In press.
COX 2 selective inhibitors :
Proven decreased gastrointestinal side
effects
Similar caution for renal impaired and
elderly patients
No significant platelet inhibitory effect
Worries of increased thrombotic events
Response

Pain threshold

Stimulus
intensity

Hyperalgesia Allodynia
Increased SENSATION OF Reduced PAIN THRESHOLD
PAIN
 Why COXIBs?
• Benefits :
– Anti-inflammatory analgesic1
– No effect on platelet aggregation2
– Non-narcotic safety profile1
– Effective relief of pain on movement2
– Multimodal efficacy2
• Enhanced analgesic effect
– Lower risk of GI side effects3
1Power I et al. Surg Clin North Am. 1999;79(2):275-295.
2Noveck RJ et al. Clin Drug Invest. 2001;21(7):465-476.
3Needleman P et al. J Rheumatol. 1997;24(Suppl 49):6-8.
Weighing the Benefits and the Risks:
Celebrex versus NSAIDS
“WINNER”: product whose benefits exceed its risk at a reasonable cost
for the amount of benefit achieved;
“Loser”: product with excessive risk or excessive cost relative to benefit.
(Am J Cardiol 2002;89(15):971-972)

CELEBREX NSAIDS

CELEBREX

?
(less GI toxicity)
NSAIDS
CELEBREX
(prevent clotting) (Adverse events
remain controversial)
NSAIDS
(cause GI bleeding,
ulceration etc.)

(Harv Heart Lett Dec 2001; 12(4):2-4; Am J Med 2001;110(3A):6S-12S)

 Benefits of Multimodal
Analgesia

Opioids
• Reduced doses of each
analgesic
• Improved pain relief due
Potentiation to synergistic or additive
effects
• May reduce severity of
side effects of each drug
NSAID,(Cox1&Cox2)
acetominophen,
nerve blocks
1Kehlet H et al. Anesth Analog. 1993;77:1048-1056.
THERE IS NO IDEAL DRUG,
BUT IDEAL DOCTOR WHO
CAN CHOOSE THE BEST
DRUG FOR PATIENT
 Modulation
SPINAL CORD (DHN) is the key point of
modulation
• The place where afferent input is processed.
• Where interaction between excitatory and inhibitory
system.
• NOCICEPTION IS BORN IN DORSAL HORN,
BUT WE DON’T CALL IT PAIN TILL IT
REACHES THE BRAIN (Dr. Ken Casey)
 phospholipids

arachidonic acid

COX LOX
COX-2 COX-1
cyclic
endoperoxides 5-HPETE

PGI2
inhibits platelet TXA2 LTA4
aggregation, stimulates platelet
vasodilator, aggregation,
vasoconstriction LTB4
hyperalgesia chemotaxis

PGD2 PGF2alfa LTC4 brochoconstriction

PGE2
inhibits platelet bronchoconstriction increase
vasodilator, myometrial contr. vascular
aggregation,
vasodilator hyperalgesia hyperalgesia permeability
LTD4

LTE4
 Arachidonic Acid Cascade
Membrane phospholipids

Phospholipase A2
Arachidonic acid
COX-1 COX-2
Prostaglandin G2

Prostaglandin H2

Tissue-specific isomerases

Prostacyclin THX A2 PGD2 PGE2 PGF2

THX =
thromboxane. Adapted from FitzGerald GA et al. N Engl J Med. 2001;345:433-42.
 Mechanism of Prostanoids
Arachidonic acid

Cyclooxygenase  Anti-inflammatory
 Analgesic
X  Antipyretic
 Gastrointestinal toxicity
 Renal toxicity
Prostanoids

Mediate
Support renal and
inflammation, pain,
platelet function Protect and fever
gastroduodenal
mucosa
 Categorization of Pain
Acute Pain
Relatively brief duration
(hours to weeks)
A symptom of injury or
disease
Postsurgical pain, trauma,
select disease processes
Protection mechanism 
has biological meaning
Turk DC et al. Bonica’s Management of Pain. 2001:17-25.
Chronic Pain
Longer in duration (months to
years)
Persistent beyond nociception
Occur after healing
Usually accompanies a disease
process or injury
OA, RA, LBP, shoulder pain, pain
associated with malignancy
No biological meaning  suffering
 CLINICAL PAIN

(INFLAMATION PAIN)
Low Intensity Stimulus

Ab Fiber
Ad Fiber

PNS
CNS

Hyperexitable
DHN
DHN

PAIN
 ANATOMI DAN
FISIOLOGI NYERI
 Terdapat Dua Serabut
Afferen Sensoris primer

1. HIGH TRESHOLD PRIMARY AFFERENT

– Small myelinated A Memberikan respon
– Small unmyelinated C stimuli noksius

2. LOW TRESHOLD PRIMARY AFFERENT

– Large myelinated A  memberikan respon
stimuli innoksius
 Serabut Afferen Primer
Walaupun tidak ada serabut nyeri pada saraf tepi atau saraf
sentral,secara anatomi dan fisiologi terdapat serabut perifer
afferen yang memberikan respon terhadap stimuli noksius.
Serabut-serabut afferen ini adalah myelinated A and
unmyelinated C fibers. A tidak memberikan respon terhadap
stimuli noksius, namum serabut ini sangat penting untuk sensasi
normal

A

Tanpa A, setiap noksius stimuli akan dirasakan sebagai

burning pain
 PERSEPSI

Pain Pathway
Cortex

(Descending Inhibition)
MODULASI
Thalamocortical
projections

TRANSMISI

TRANSDUKSI

Spinothalamic
tract
Aferen
primer
Noxious
stimulus
 Medula Spinalis

Dahulu : dikenal sebagai “SIMPLE

RELAY STATION” Untuk transmisi
Nyeri
Sekarang : Sebagai tempat interaksi yang
kompleks antara
 Serabut-serabut Eksitatori
 Serabut-serabut inhibitori

MODULASI NYERI
 Serabut Eksitatori & Inhibitori
Serabut Eksitatori

C Glutamate
(Subs P)
A Glutamate
A
Glutamate + OTAK
WDR & NS
Serabut GABA
-
Glycine
Inhibitori Opioids
NA, 5HT
Presynaptic & Post Synaptic Receptors

Dorsal Horn Neurons