1 Pathophysiology Acute Chronic Pain

7/30/2019 1 Pathophysiology Acute Chronic Pain

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Pathophysiology of Acute &Chronic Pain

Steven Stanos, DOCenter for Pain Management

Rehabilitation Institute of Chicago

Dept. of PM&R, Northwestern

University Medical SchoolFeinberg School of Medicine


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Nociceptive vs. Neuropathic

Receptors and channels

Inflammation

Peripheral Sensitization

Central Sensitization

Temperature Sensation

Plasticity & Brain Changes

Muscle Pain

Cytokines: the Future


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Nociceptive vs. Neuropathic Pain

*Complex regional pain syndrome type II.

1. Portenoy RK, Kanner RM. In: Pain Management: Theory and Practice. Philadelphia, PA: FA Davis Company; 1996:4.

2. Merskey H, Bogduk N, eds. Classification of Chronic Pain. 2nd ed. Seattle, WA: IASP Press; 1994.

3. Galer BS, Dworkin RH.A Clinical Guide to Neuropathic Pain. Minneapolis, MN: McGraw-Hill; 2000.

Other Mixed

Pain Types?

Nociceptive

Pain

(Inflammatory?)1

Neuropathic

Pain2,3

Postoperative

pain

Mechanical

low back pain

Sickle cellcrisis

Arthritis

Postherpetic

neuralgia

(PHN)

Neuropathic

low back pain

CRPSII*

Sports/exercise

injuries

Central post-

stroke pain

Trigeminal

neuralgia

Distal

polyneuropathy

(e.g., diabetic, HIV)


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The BIOMEDICAL Model

Pain as a

sensory event

reflecting

underlying

disease or

tissue damage


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Gate Control Theory

Melzack R. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of

Pain. 3rd ed. Philadelphia, Penn: Lippincott Williams & Wilkins; 1998.


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Gate Control Theory

Melzack R, Wall PD. Science. 1965;150:971-976.

A. Sensory

B. Affective

C. Evaluative


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Enteroceptive Sensations

Pain

Thirst

Hunger Thermoception

Neurophysiologic changes Neurochemical changes


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Biological Functions of Pain

Sherrington (1906)

Exteroceptive:

Interoceptive:

Escape and avoidance ofexternal threats

protection of injured or

dysfunctional tissues thatdisrupt homeostasis

Price DD et al. Pain 2003, 106.


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Physiological Pain

Initiated and by specialized sensory

nociceptors innervating peripheral tissues

and responding only to noxious stimuli

Projects to spinal cord and cortex

Activates reflex withdrawal, increase in

arousal, emotional, autonomic and

neurohumoral responses


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ChronicPain

Hyperalgesia Allodynia

The Role of Plasticity

in Chronic PainInjury

Acute Pain

Healing With PlasticityNormal Healing

Pain Relief

Adapted from Marcus DM.Am Fam Physician. 2000;61:1331-1338.


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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.


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Pain Pathophysiology

Nociceptive pain Believed to be related to ongoing activation of an

intact nervous system by tissue injury

Somatic Visceral

Neuropathic pain Believed to be related to aberrant somatosensory

processing in the peripheral nervous system, thecentral nervous system, or both


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Nociception

Transduction: detection of noxious or

damaging stimuli

Conduction: passage of resulting sensory

input from peripheral terminals to the

spinal cord

Transmission: synaptic transfer of input

to neurones within specific laminae of DH


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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

DescendingPathway

Ascending

Pathway

Spinal

Cord

Dorsal

Horn

Dorsal

Root

Ganglion

C-Fiber

- Fiber

- Fiber

Conduction

Transduction

Transmission/

Modulation

Perception


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Kidd, Urban. Br J Anaesthesia 2001;87(1).


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Pathologic vs. Physiologic


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C-nociceptors; C-polymodal;

warmth, mechano;postganglioic

autonomic; enteric nerve fibers

No0.5-2.0C


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Conduction Velocity: A & C fibers

A (Fast pain)1

C-fibers (Slow pain)1

Age relatedimpairment in fast

pain fibers2

1. Julius D, Basbaum A, Nature 2001(413).

2. Chakour M,, et al. Pain 1996; 64:143.


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20/66Kidd, Urban.Br J of Anaesth 87, 2001.

Receptors

Non-painful stimuli: Specificity for a particular stimulus

High degree of gain to amplify weak signals

Rapid adaptation to increasing intensities

Painful stimuli:

Specificity less important

High threshold receptors: thermal, chemical andmechanical stimuli (polymodal)

Threshold for firing may decrease


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Caterina, Cur Op in Neurobiology (9), 1999.

CutaneousC-fiber

Small diameter Slow conducting

Unmyelinated

1. Proinflammitory peptides

Subst P

CGRP

Lamina I/II

* tissue inflammation

(NGF)2. Specific enzymes/ Lectin IB4

*chronic neuropathic pain

(GDNF)

A-

Medium diameter Fast conducting

Lightly myelinated

Polymodal

Type I

Long response latency

> 50C

Persistent pain

2. Type II

Short response

43C

Initial burn


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Millan,Progress in Neurobiology, 1999.

Primary Afferent C & A Fibers

Sensation MediatedFibre

Class

Threshold

For

Activation

Principal

Transmitters

Receptors

Engaged

Physiological Pathological

C High SP/NKACGRP

EAA

NK

CGRP

NMDA

AMPA

mGlu

Noxious

(pain)

Highly noxious

(hyperalgesia)

Cold Allodynia

(pain)

A LowEAA AMPA Innocuous

(no pain)

Mechanical

allodynia


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Receptor types on sensory neurons

Transduction mechanism Example Cellular effect

Ligand-gated channel Capsaicin-heat Excitation

H , 5HT, ATP

Glutamate, GABA-A

G-protein linked GABA-B Inhibition of

Opiated, Adenosine transmitter &

Adrenoreceptors peptide release

NPY, 5HT

Bradykinin(B2) ExcitationHistamine (H1) and/or

Adrenoreceptors (2) sensitization

PGE2

Tyrosine kinase linked NGF (Trk A) Control of gene

expression

Bevan S. Textbook of Pain, 4 th ed. Wall, Malzack, 1999.


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Dynamic, constantly changing

Plasticity reflects sensitivity needed for

survival

Injury: amygdala, hippocampus, and DRG

Normal peripheral nerves (resist)

Demyelination: density

Ion Channels


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Receptors

Capsaicin/ Vanilloid Purinergic (P2X)


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Ion Channel Linked Receptors

Receptors

Vanilloid (VR-1)

Acid-sensing (ASIC) Purinergic (P2X)

Cannabinoid

Ion Channels

Sodium

TTX-S TTX-R

Calcium

Kidd BL, Urban LA,Br J of Anaesthesia (1). 2001.


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Caterina. Cur Op in Neurobiology(9), 1999.


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Nociception in Other Organs

Less differentiation

Autonomic component

Poorly localized Referred pain

Absence of A in viscera

Skeletal muscle: group III, group IV Joint: group III & group IV respond to

stretch


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Cervero F, Laird J,Lancet353, 1999.

Visceral PainPsychophysics

Not evoked from all

viscera

Not always linked to

injury

Referred to body wall

Diffuse & poorly

localized

Intense motor &autonomic reactions

Neurobiology

Not all innervated by

sensory receptors

Functional properties of

afferents

Viscerosomatic

convergence in CNS

Few sensory visceral

afferents, diverge CNS

Warning system,

capacity for

amplification


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Siddal, Cousins. Neural Blockade in Clinical Anesthesia and Management of Pain, Third Ed.,1998.


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Milan MJ, Progress in Neurobiology66, 2002.


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Inflammation

Redness (rubor)

Heat (calor)

Swelling (tumor) Loss of function (function lasea)

Pain (dolor)


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Inflammation

Macrophages:

Cytokines(IL1, IL6, TNF-)

Nerve Growth Factor

Damaged Cells: ATP and protons

Mast Cells:

Histamine, serotonin, prostaglandins, arachidonic

acid metabolites Upregulation of receptors

VR1, SNS, SNS-2 & Peptides

Phenotypic Switch ( A-fiber into C-fiber)

Jensen et al.Acat Anaesthesiol Scand45, 2001.


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Inflammation

Short-term

Modifications in excitation & sensitization of

peripheral sensory terminals

Longer-term

Changes in properties of afferents

Decrease in threshold for firing

Increase in excitability of spinal neurons

Mamet et al. J of Neuroscience, 22(24), 2002.


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Hyperalgesia Sensitization

pain threshold threshold for response

pain to suprathreshold response to

stimuli suprathreshold stimuli

Spontaneous pain Spontaneous activity


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SENSITIZING SOUP

Hydrogen Ions Histamine Purines

Noradrenaline Potassium Cytokines

Bradykinin Prostaglandins NGF

Leukotrienes 5-HT Neuropeptides

Tissue Damage

Woolf, Chong.Anesth. Analgesia (77), 1993.


Inflammation Sympathetic Terminals


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SKIN


PeripheralNerve

Terminal

Pressure ?

Plasma ExtravasationVasodilation

Heat5-HT3 PGE2

Bradykinin

VR1 5-HT3 EP B1/B2

IL1

MastCell

Macrophage

(PKC)

TNF-IL-6LIF

IL1-R TrkA

H+

PKC

TTXr(SNS/SNS2)

Sub P

GeneRegulation

TTXr

TTXs

H+

P2X ASIC

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

TissueDamage

ATPNGF

H1

Histamine

Ca2+

PKA


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Central Sensitization: wind up


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With permission. Jensen TS et al.Acta Anaesth Scand, 45, 2001.

M h i f N i i


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Mechanisms of Nociceptive

Central Pain Autosensitization of receptors

Ectopic firing of DRG cells

Calcium-induced molecular cascades fromexcess glutamate

Phenotypic change of A- cells and DRG

Changes in gene expression of sodiumchannels and neuropeptides

Anatomic changes at dorsal horn

Schwarzman et al.Neurological Review, 58, 2001.


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With Permission. Woolf,2000.


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Mechanisms of nociceptive central pain

1. Autosensitization of receptors

2. Ectopic firing of DRG cells

3. Calcium-induced molecular cascadesfrom excess glutamate

4. Phenotypic change of A- cells and DRG

5. Changes in gene expression of sodiumchannels and neuropeptides

6. Anatomic changes at dorsal horn

Schwarzman et al. Neurological Review, 58, 2001.

N thi P i I D fi d


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Neuropathic Pain Is Defined

asPain caused by a lesion or dysfunction

of the nervous system1

Nerve sensitization or damage

can be located in the peripheralor central nervous system1

Manifests with sensory symptoms

and signs2

May have both positive andnegative sensory and motor symptoms and

signs2

1. Merskey H, Bogduk N, eds. Classification of Chronic Pain. 2nd ed. Seattle, WA: IASP Press; 1994.2. Backonja MM.Anesth Analg. 2003;97:785-790.

Examples of Peripheral vs Central


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Examples of Peripheral vs. Central

Sensitization

Adapted from Woolf CJ, Mannion RJ. Lancet. 1999;353:1959-1964.

Sensory function after nerve injury with spontaneous firing along axon

No

StimulusPain

SensationNociceptorDorsal Horn

Neuron

To Brain

Central sensitization occurs as a result of increased nociceptor drive or disinhibitionafter nerve injury, leading to exaggerated dorsal horn response

Disinhibition

Innocuous

or Noxious

StimulusDorsal Horn

Neuron

To

Brain

Increased Nociceptor Drive

Innocuous

StimulusDorsal Horn

Neuron

Inhibitory Input Is

Downregulated

P i t t P i Di


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Persistent Pain as a Disease

Entity: Increase peripheral input: increase DH

firing

Increase firing: increased NMDA, Ca,

PKC, Nitric Oxide

Increase PKC, Ca: genetic changes

Increase NO: decreased GABA neurons

Increase Neurotrophins: sprouting

Cousins, MJ, 2009 AAPM


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Beydoun A, Backonja. J Pain Symp Management2003.


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Temperature

Th ti


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Thermosensation

Julius D, Proc 10th Word Conference of Pain, 2003.


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Thermosensation

TRP channel family

TRV2 >53 C Noxious heat

TRPV1 (Vanilloid) >43 C Heat, capsaicin, acid

TRPV3/TRPV4 >30-40 C Warm

TRPM8 (CMRI) >25 C Cold, menthol

TRPA1


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Thermosensation

Cold 10-15% C & A-delta

Specificity vs. modulation

of excitatory & inhibitory

channels K, Na, Ca channels

CMRI (cold- and menthol-

sensitive receptor) cloned

TRP (transient receptorpotential)

Heat Capsaicin

Vanilloid receptor

subtype 1 (VR1 or

TRPV1) Thermal activation

threshold ~43C

Polymodal, influenced by

a variety of substances

Julius D,Proc 10th Word Conference of Pain, 2003.


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Capsaicin

genus Capsicum:

mildest (bell) to hottest (habanero)

Capsaicin: 16,000,000 SHU habanero: 200,000 SHU

Classic:

Activates, desensitize (Ca), and exert neurotoxic

effects on polymodal nociceptors

release of Subst P & CGRP, nerve degeneration

(NGF), loss of intraepidermal fibers

pharmacological & functional desensitization via

VR1 receptor

Anand P. Gut52, 2003. Robbins

W. Clin J Pain 16(2), 2000.

TRPV Ch l


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TRPV Channels:

Szalassi et al. Nature Rev2007;6.


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Menthol: natural analgesic

Mentha species

peppermint plant, cornmint oil,

citronella, eucalyptus & Indian

turpentine oil

coolness: stimulation of coldreceptors by (-) Calcium currents of

neuronal membranes, increasing

pain thresholds

Activation of central Opioid

system

Galeotti N. Neuroscience Letters 322 (2002). McKeny, Nature 416, 2002.


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Pain Neurochemistry

To brain

Dorsal

horn

Substance P, aspartate,

neurotensin, glutamate

Spinal cord

Dorsal root

ganglion

Tissue injury

Bradykinin

Leukotrienes

Ion fluxes

(H+/ K+)

Prostaglandins

Transmission viaspinothalamic tract

to brain

Substance P

Histamine Sensitized

nociceptor


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Neuromatrix


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Apkarian AV, et al. J of Neuroscience, 24(46), 2004.


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Price DD. Science 2000.

Price DD. Science. 2000;288:1769-1772.


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Price DD. Science. 2000;288:1769-1772.


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Pain Matrix

Moseley GL. Man Ther. 2003;8(3):130-140.


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Pain Matrix

Anterior cingulate cortex (ACC)

Insular cortex (IC)

Thalamus

Sensorimotor cortex (SSI, SSII)

Cerebellum

Moseley GL. Man Ther. 2003;8(3):130-140.


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Petrovic P, et al. Science 2002;295:1737-1740.


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Petrovic P, et al. Science. 2002;295:1737-1740.


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Opioid Systems

Reynolds: (1969)

Endogenous opioid system

PAG & NMM: funnel

Homeostatic andbehavioral adjustments

Mason P. J Neurophysiol. 2005;94:1659-1663.

Finniss DB, Benedetti F. Pain. 2005;114:3-6.

Petrovic P, Ingvar M. Pain. 2002;95:1-5.


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Tracey, 2008


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INJURY SYMPTOMS

Tissue Damage

Nerve Damage

HyperalgesiaSpontaneous

PainAllodynia

PERIPHERAL

ACTIVITY

CENTRAL

SENSITIZATION

Decreasedthreshold to

peripheral stimuli Expansion of

Receptive field

Increased

Spontaneous

activity


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Summary: a gain in pain

Nociceptive vs. Neuropathic pain

Chronic changes in the nervous systemmay not be reversible

Understanding of channels and receptorsevolving

Medications and therapies targeted at

specific mechanisms Pain is not just a passive transfer of input

along a fixed system

Documents

1 Pathophysiology Acute Chronic Pain