Transcript Pain

Neurobiology of Pain :
Clinical application
Kongkiat Kulkantrakorn, MD.
Neurology division, Faculty of Medicine
Thammasat University
The beginning and the end of pain
Unrelieved Pain
USA Survey 1999: “40% 0f Chronic
(moderate to severe) pain pts. reported that their pain
is
“Out of Control”
and
“They had not found adequate relief”
despite advanced in new pain medications
Inadequate pain control due to
Attitude of doctor, nurse, and
patient
Fear of narcotic usage
Knowledge deficits
Laws and regulations
PAIN
 Subjective response to nociceptive input to brain
Components
 Motivational-Affective:
Emotional
 Sensory-Discriminative
Nociception
 Awareness of the
stimulation of
nociceptors by a noxious
stimulus
Achieve pain control
Earlier is better
Perceptual categories
Pricking (First pain)
Quality: Sharp
Temporal: Initial pain sensation; Brief
PNS axons: Aδ fibers
CNS pathway: Somatosensory to thalamus & cortex
Burning (Second pain)
Qualities: Dull; Aching; Unpleasant
Temporal: Later, more long-lasting pain sensation
PNS axons: C fibers
CNS: Reticular formation; Periaqueductal gray;
Hypothalamus; Central thalamus
What is a Nociceptor?
• A number of receptors/channels that sense damage
• VR1 vanilloid receptor family - capsaicin/ATP
• ASICs - respond to low pH/mechanical?
• P2X receptors - respond to ATP
• Chemical sensors - prostaglandins, 5HT, Bk etc - peripheral
sensitization & inflammation
ATP
capsaicin
heat
mechanical?
COX1
COX2
H+
cold
PGs warm ATP
VRs ASICs EPs TRPs P2X
Na+, K+,
Ca2+
channels
DRG
sensitize, activate
C-fibre
SENSATIONS
SP & CGRP
peripheral
endings
low
intensity
non-noxious
stimuli
high intensity
noxious
stimuli
dorsal root
ganlgia
heavily
myelinated
fast conducting
thinly myelinated
intermediate
conducting
unmyelinated
slow conducting
I
I Io
I Ii
III
IV
A
WDR
VI
A
X
C
V II
INPUTS
V I II
REFLEXES
V
IX
INFLAMMATION/NOCICEPTIVE
Peripheral Sensitization
Central Sensitization
Damaged Zone
ALLODYNIA
HYPERALGESIA
Sensitization and activation
COX1 - COX2
BK2 - BK1
PGs, H+
CNS
ATP
NGF
blood
vessel
C-fibre
SP, CGRP
BK
5HT
Vasodilation+plasma extravasation
Transmitter
release - neuronal
excitability
NEUROPATHY
Ectopic activity
Central
Sensitization
HYPERALGESIA
ALLODYNIA
Sympathetic
sprouting
Nerve
Injury
Neurochemical
alterations
CNS
Na+ channels
Ephaptic transmission
Transmitter
release
Multiple mediators at the site of injury
J Pain 2000;1:344.
C-fiber
a2

m
SP
Ca++
m

Increase
Ca++ influx
5-HT3
Glu
SP
5-HT2
GABAB
Glu
Na+
a2
NMDA AMPA GABAB GABAA
5-HT3 5-HT2
Increase
Na+ influx
Dorsal horn
Peripheral Sensitization
Macrophage
Skin
Mast
cell
6h 12h
PGS
TRPV1
Tissue
damage
Cox-2
AA
PG
EP/IP
H+
IL1, IL6
TNFa
Ca2+
COX-2
Sensitive
PKC
PKA
(SNS/SNS2)
Primary sensory neuron
peripheral terminal
There are both prostanoid and non-prostanoid sensitizers
Tissue damage
Hyperalgesia
PERIPHERAL
ACTIVITY
Nerve damage
Spontaneous
pain
Allodynia
CENTRAL
SENSITIZATION
Decreased
threshold to
peripheral
stimuli
Increased
Expansion of spontaneous
activity
receptive
field
Pain Sensitization
10
Hyperalgesia
Normal
Pain
Response
Pain Intensity
8
6
4
Injury
Allodynia
2
0
Stimulus Intensity
Gottschalk and Smith. Am Fam Physician. 2001.
Pain perception: Located in
Thalamus & Cortex
Psychophysical features
Components: Location; Intensity; Character; Duration
Location: 1° & 2° somatosensory cortex
Affective features
Components: Unpleasantness & Rejection
Location: Limbic cortex (Cingulate & Insula)
Ascending pathway: Dorsal horn; Parabrachial nucleus;
Amygdala
Monoamines & GABA after Nerve Injury
Midbrain
Brainstem
• Spinal transmission can
also be modulated from
supraspinal mechanisms
5-HT
5HT1 inhibitory
5HT2 & 3 excitatory
Noradrenaline
a2-adrenergic Rs inhibitory
• Use a wide range of
neurotransmitters
Spinal
cord
GABA
Tonic inhibition, GABAA/B
Analgesic classification
1. Narcotics
no ceiling effect except partial agonists and mixed
agonist -antagonist
2. Non-narcotics
NSAIDs/Coxibs
ceiling effect
3. Adjuvant analgesic or coanalgesics
tricyclic antidepressants
antiepileptics
steroids
bisphosphonates
Analgesic ladders
ความปวดจากมะเร็ง
Pain persisting or
increasing
Non - opioid
+ Adjuvant
Pain persisting or
increasing
Strong - opioid
+ Non - opioid
+ Adjuvant
Weak - opioid
+ Non - opioid
+ Adjuvant
ความปวดเฉียบพลัน
Multimodal Analgesia
AN E XAM PLE
Opioid
  doses of each analgesic
 Improved anti-nociception
Potentiation
due to synergistic/
additive effects
 May  severity of side effects
NSAIDs,
COX-2 inhibitors,
regional blocks,
α2-agonist
of each drug
Adapted from Kehlet H, Dahl JB. Anesth Analg., 1993;77:1048–1056.
Clinical application
 Pharmacology
Around the clock dosing
vs PRN dosing
 Development of new
drugs, preparation
COX-2 inhibitors
Tramadol
Long acting opioids
 Opioid receptors
Pharmacogenomics
Variable responses
NSAIDS/COX II inhibitor
Acetaminophen, Clonidine