Pathophysiology of

Chronic Pain
Yuneldi Anwar
Department Neurology
Medical Faculty of North Sumatera

Biopsychosocial Model of Pain

Overall functional status

Physiology of Pain Perception1-3

Brain

Perception

Descending
Pathway

Ascending
Pathway
Spinal
Cord

C-Fiber
- Fiber
- Fiber

Conduction
Peripheral
Nerve

Transduction

Dorsal
Horn

Dorsal
Root
Ganglion

Injury

1. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, MN: McGraw-Hill; 2000.
2. Irving GA, Wallace MS. Pain Management for the Practicing Physician. New York, NY: Churchill Livingstone; 1997.
3. Woolf CJ, et al. Ann Intern Med. 2004;140:441-451.

Transmission/
Modulation

NOCICEPTION
Nocious Stimuli
mechanical thermal chemical electrical
Tissue damage
Release of mediators
Hydrogen and potassium ions,
neurotransmitters, kinins, prostaglandins

Stimulation of nociceptors
Transmission to CNS
via afferent pathways
Robert W. Gereau IV, PhD, and Judith P. Golden, PhD. Peripheral Mechanisms and Persistent pain, 2014

Stage of Nociception
Perception

3.Modulation

2.Transmission

1.Transduction

Net result of three events the

subjective experience of pain
Process by which impulse travel from the
brain back down to the spinal cord to
selectively inhibit (or sometimes amplify)
pain impulses
Communication of the nerve impulse from
the periphery to the spinal cord, up the
spinothalamic track to the thalamus and
cerebral cortex
Conversion of noxious, or harmful
stimuli (mechanical, thermal, chemical)
activation nociceptor into nervous
impulse, or action potential

Peripheral Chemical Mediators of

Pain

Nociceptor
Free nerve ending
Least differentiated
Cell body at dorsal root
ganglia and trigeminal
ganglia
Synapse in dorsal horn
of spinal cord
On local interneuron
On projection neuron

A & C fiber

Stage of Nociception
Perception

3.Modulation

2.Transmission

1.Transduction

Net result of three events the

subjective experience of pain
Process by which impulse travel from the
brain back down to the spinal cord to
selectively inhibit (or sometimes amplify)
pain impulses
Communication of the nerve impulse from
the periphery to the spinal cord, up the
spinothalamic track to the thalamus and
cerebral cortex
Conversion of noxious, or harmful
stimuli (mechanical, thermal, chemical)
into nervous impulse, or action
potential

Classification of Peripheral Nerves

10

Targets of Primary Afferent Neurons in the

posterior gray (dorsal) horn

11

Stage of Nociception
Perception

Net result of three events the

subjective experience of pain

3.Modulation

Process by which impulse travel from the

brain back down to the spinal cord to
selectively inhibit (or sometimes amplify)
pain impulses

2.Transmission

Communication of the nerve impulse from

the periphery to the spinal cord, up the
spinothalamic track to the thalamus and
cerebral cortex

1.Transduction

Conversion of noxious, or harmful

stimuli (mechanical, thermal, chemical)
into nervous impulse, or action
potential

Endogenous Mechanisms of Analgesia

(Modulation of Pain)
Endogenous Opioids
Descending analgesic system
Gate control theory of pain

13

Descending fibre

Endorphins
in the synapse

Presynaptic
neuron

Opioids block secretion of Glutamate

through opiate receptor
Pain signal
from periphery
Termination of
pain signal
Glutamate

Signal from
brain to inhibit
pain signal

Opiate
receptor

Glutamate
Receptor (non-NMDA)

Postsynaptic
neuron

14

Ronald Melzack and Patrick Wall, 1965

ACUTE PAIN
Tissue
injuries

Healing

Subside pain

CHRONIC
/PERSISTENT PAIN
Tissue
injuries
Healing

Does not
Subside pain

Patologic condition

Definition of Chronic Pain

Pain that has lasted longer than three to six
months (Debono, DJ; Hoeksema, LJ; Hobs, RD.
August 2013 )
Acute pain pain that lasts less than 30 days,
Sub acute pain that lasts from one to six
months, Chronic pain that lasts more than
six months (Thienhaus, O.; Cole, B.E. (2002).
A popular definition Pain that extends
beyond the expected period of healing(Turk,
DC, Okifuji, A. 2001 )

Nociceptive pain is a crucial defensive

mechanism that warn an individual of recent,
ongoing, or imminent damage to the body and
is produced as the physiological out come of of
normal fungtioning of the PNS and CNS. By
contrast, chronic pain, wich is inflammatory
or neuropathic, is the result of aberrant
fungtioning of the PNS or CNS, wich has been
pathologically modified

Michael W. Salter, MD, PhD. Neurobiology of Acute and

Persistent Pain: Spinal cord Mechanism, 2014

General differences
between acute and chronic pain
Acute pain

Chronic pain

Reasonable, possibly even a lifeprotecting function

Pain that lasts beyond the commonly

expected healing time

A warning sign that makes one

aware of a danger

No reporting, protective, or
healing function

Perception of pain triggers an

appropriate protective reaction

Becomes a free-standing
pain disease

Promotion of wound healing through

rest

Physical, psychological, and social

attrition

Relatively simple psychological

processing

Poor acceptance from colleagues

Examples: Pains from arthrosis, osteoporosis,
rheumatoid arthritis,
tumor pains, peripheral arterial blockage
disease, post-herpes neuralgia, postamputation

Good acceptance from colleagues

Examples: post-traumatic or
post-operative pain, toothache

21
Working Group A.M.A.D.E.U.S. Basic Course in Treatment of Chronic Pain Cologne 2003

Type or Category of Pain

3. Disfunctional
clear that
no somatic disorder
is present

1. NociceptiveInflamatorik
Caused by activity
in neural pathways
in response to potentially
tissue-damaging stimuli

fracture /
Postoperative
Ongoing or
impending injury

4. Mixed type
Caused by a
combination of both
primary injury or
secondary effects

2. Neuropathic
Initiated or caused by
primary lesion or
dysfunction
in the nervous sys.

sprain
Inflamation /
Infection
Muscle Stretch

strangulated
(scar tissue)

Myofascial pain

inflamed (infection )

Infiltrated or compressed
(tumors)

The Assessment of the Patient with Pain, Steven Richeimer, M.D. Director USC Pain Management, USC Medical Center, Los Angeles, CA, USA, 2007

NOCICEPTIVE PAIN
Noxius Pheripheral Stimuli
Heat

Pain
Autonomic Response
Witdrawal Reflex

Cold

Brain

Intense
Mechanical
Force

Nociceptor sensory neuron

Heat
Cold
Modifikasi Meliala, 2005

Spinal cord

NOCICEPTIVE PAIN

INFLAMMATORY PAIN
Inflammation
Macrophage

Spontaneous Pain
Pain Hypersensitivity
Reduced Threshold : Aliodyna
Increased Response : Hyperalgesia

Mast Cell
Neutrophil
Granulocyte

Brain

Nociceptor sensory neuron

Tissue Damage
Prostaglandin
Sitokin
Bradikinin
Substansi P
Modifikasi Meliala, 2005

Spinal cord

FROM ACUTE TO CHRONIC PAIN

Activation, Modulation and Modification

Voscopoulos C , and Lema M Br. J. Anaesth. 2010;105:i69-i85

Peripheral Mediators of Inflammation

Thermal/
SP: vascular permeability; CGRP: long-lasting vasodilation

What is Neuropathic pain?

Definition:
Pain arising as a direct consequence of a lesion or disease
affecting the somato sensory NERVE system

Characterized by:
Pain often described as pinprick sensation, numbness,

electric shock-like or burning and alodinia

The painful region may not necessarily be the same as the site of injury.

Almost always a chronic condition (e.g. post herpetic neuralgia, post

stroke pain)
Responds poorly to conventional analgesics

Pathophysiology of Neuropathic Pain

Peripheral mechanisms

Peripheral Neuron
hyperexcitability

Central mechanisms
Loss of
inhibitory controls

Central Neuron
hyperexcitability
(central sensitization)

NeP

Pathophysiology of Chronic Pain

Central sensitization
Wind- up phenomena
Genetic factor
Microglial activation
Neuroplasticity

CENTRAL SENSITIZATION
Increased spontaneous
discharge

Central Sensitization
result from low and
high nociceptive
stimulation
increased excitability
neurons at DH

Increased receptive fielf

size possibly celluler
basis of secondery
hyperalgesia
Increased resposnsiveness
to innocuous stimulation
possibly celluler basis of
allodynia

Microglia and Astrocyte activation

Immune cells in spinal
cord contribute to
alteration in neuronal
hyperexitability
(Marchand, F, Perretti, M,
McMahon, SB, 2005 )

Injury to PNS or
Inflammation in spinal
cotd and brain
increasing excitability
of spinal nociceptive
neurones through
removal on an
inhibitory influence, or
disinhibition ( Sherman,
SE, Loomis ,CW, 2004 )

Genetic Factor
Mutation inactivation of spesific sodium
channel unable to feel pain (Fertleman CR,
Baker MD, Parker, KA, et al. 2006 )
Other mutation ifluence modify the kinetic
of sodium channel perception of persistent
pain ( Yang Y, Wang Y, Li S, et al, 2004)

Neuroplasticity
Chronic pain disease affecting brain structure
and function (neuroplasticity) , MRI studies have
showns abnormality anatomical and functional
connectivity involving area related to the
processing of pain (Geha PY, Baliki MN, Harden
RN, et al ;2008)

Neuronal Plasticity and Pain

Normal adaptive function
Neurons detecting and transmitting pain
display plasticity
A capacity to change function, chemical profile,
or structure
A response to painful stimuli and inflammation
A contributor to altered sensitivity to pain

When persistent can lead to permanent neuropathic

pain
Woolf CJ, et al. Science. 2000;288:1765-1768.

Choice of Assessment Tool

Visual Analog Scale (VAS)

Numeric Pain Rating Scale (NPRS)

Faces Pain Rating Scale (untuk anak)

ID PAIN : Screening tool to help differentiate

nociceptive from neuropathic pain
Neuropathic pain screening questionnaire
Patients (N = 586) with non-headache chronic pain A second
multicenter study (N = 384) evaluated reliability and validity.
89-item questionnaire 6 items
ID Pain appeared to accurately indicate the presence of a
neuropathic component of pain (74,2%)
Portenoy R et al. Curr Med Res Opin. 2006 Aug;22(8):1555-65.

CONCLUSIONS

Pain includes a complex mechanism