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

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.

Injury

Peripheral Nerve

Brain

Descending Pathway

Ascending Pathway

Spinal Cord

Dorsal Horn

Dorsal Root

Ganglion

C-Fiber

- Fiber

- Fiber

Conduction

Transduction

Transmission/Modulation

Perception

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

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

Stage of Nociception

Peripheral Chemical Mediators of Pain

7

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

8

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

Stage of Nociception

10

Classification of Peripheral Nerves

Targets of Primary Afferent Neurons in the posterior gray (dorsal) horn

11

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

Stage of Nociception

Endogenous Mechanisms of Analgesia (Modulation of Pain)

Endogenous Opioids

Descending analgesic system

Gate control theory of pain

13

Opioids block secretion of Glutamate through opiate receptor

Endorphins in the synapse

Pre

syn

apti

c

ne

uro

n

Postsynaptic neuron

Glutamate

Glutamate Receptor (non-NMDA)

Pain signal from periphery

Signal from brain to inhibit pain signal

Opiate receptor

Termination of pain signal

14

Descending fibre

Ronald Melzack and Patrick Wall, 1965

Tissue injuries

Healing

Subside pain

ACUTE PAIN

Tissue injuries

Healing

Does not Subside pain

CHRONIC /PERSISTENT 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

21

Acute pain

Reasonable, possibly even a life-

protecting function

A warning sign that makes one

aware of a danger

Perception of pain triggers an

appropriate protective reaction

Promotion of wound healing through

rest

Relatively simple psychological

processing

Good acceptance from colleagues

Examples: post-traumatic or

post-operative pain, toothache

Chronic pain

Pain that lasts beyond the commonly

expected healing time

No reporting, protective, or

healing function

Becomes a free-standing

pain disease

Physical, psychological, and social

attrition

Poor acceptance from colleagues

Examples: Pains from arthrosis, osteoporosis,

rheumatoid arthritis,

tumor pains, peripheral arterial blockage

disease, post-herpes neuralgia, post-

amputation

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

fracture /

Postoperative

Ongoing or

impending injury

sprain

Inflamation /

Infection

Infiltrated or compressed

(tumors)

strangulated

(scar tissue)

Muscle Stretch

inflamed (infection )

Type or Category of Pain

3. Disfunctional clear that

no somatic disorder

is present 1. Nociceptive-

Inflamatorik Caused by activity

in neural pathways

in response to potentially

tissue-damaging stimuli

2. Neuropathic Initiated or caused by

primary lesion or

dysfunction

in the nervous sys.

4. Mixed type

Caused by a

combination of both

primary injury or

secondary effects

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

Myofascial pain

Heat

Cold

Intense

Force

Mechanical

Heat

Cold

Pain

Autonomic Response

Witdrawal Reflex

Nociceptor sensory neuron

NOCICEPTIVE PAIN

Noxius Pheripheral Stimuli

Spinal cord

Brain

Modifikasi Meliala, 2005

NOCICEPTIVE PAIN

Macrophage

Neutrophil

Granulocyte

Tissue Damage

Spontaneous Pain

Pain Hypersensitivity Reduced Threshold : Aliodyna

Increased Response : Hyperalgesia

Nociceptor sensory neuron

INFLAMMATORY PAIN

Inflammation

Spinal cord

Mast Cell

Brain

Modifikasi Meliala, 2005

Prostaglandin Sitokin Bradikinin Substansi P

FROM ACUTE TO CHRONIC PAIN

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

Activation, Modulation and Modification

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

NeP

Central mechanisms

Peripheral mechanisms

Peripheral Neuron hyperexcitability

Loss of inhibitory controls

Central Neuron hyperexcitability

(central sensitization)

Pathophysiology of Chronic Pain

Central sensitization

Wind- up phenomena

Genetic factor

Microglial activation

Neuroplasticity

CENTRAL SENSITIZATION

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

Increased spontaneous discharge

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)

Faces Pain Rating Scale (untuk anak)

Numeric Pain Rating Scale (NPRS)

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.

Pain includes a complex mechanism

CONCLUSIONS