Pathophysiology of Acute &
Chronic Pain
Steven Stanos, DO
Center for Pain Management
Rehabilitation Institute of Chicago
Dept. of PM&R, Northwestern
University Medical School
Feinberg 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
Nociceptive vs. Neuropathic Pain
Other “Mixed”
Pain Types?
Nociceptive
Pain
(Inflammatory?)1
Postoperative
pain
Mechanical
low back pain
Arthritis
Sickle cell
crisis
Sports/exercise
injuries
Neuropathic
Pain2,3
CRPSII*
Postherpetic
neuralgia
(PHN)
Trigeminal
neuralgia
Neuropathic
low back pain
Central poststroke pain
Distal
polyneuropathy
(e.g., diabetic, HIV)
*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.
The BIOMEDICAL Model
• Pain as a
sensory event
reflecting
underlying
disease or
tissue damage
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.
Gate Control Theory
A. Sensory
B. Affective
C. Evaluative
Melzack R, Wall PD. Science. 1965;150:971-976.
Enteroceptive Sensations
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Pain
Thirst
Hunger
Thermoception
• Neurophysiologic changes
• Neurochemical changes
Biological Functions of Pain
Sherrington (1906)
Exteroceptive:
Escape and avoidance of
external threats
protection of injured or
Interoceptive:
dysfunctional tissues that
disrupt homeostasis
Price DD et al. Pain 2003, 106.
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
The Role of Plasticity
in Chronic Pain
Injury
Acute Pain
Normal Healing
Pain Relief
Healing With Plasticity
Allodynia
Hyperalgesia
Chronic
Pain
Adapted from Marcus DM. Am Fam Physician. 2000;61:1331-1338.
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.
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, the
central nervous system, or both
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
Physiology of Pain Perception1-3
Brain
Perception
Descending
Pathway
Ascending
Pathway
Spinal
Cord
C-Fiber
α-β Fiber
α-δ 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
Kidd, Urban. Br J Anaesthesia 2001;87(1).
Pathologic vs. Physiologic
Classification of Fibers in
Peripheral Nerves
Lloyd /Hunt
Diameter
(µm)
Letter
System
Conduction
velocity
(m/sec)
Myeli
n
I-a
12-20
-
70-120
+
I-b
-
12-20
-
70-120
+
12-20
A-α
70-120
+
II
6-12+
A-β
30-70
+
-
2-10
A-γ
10-50
+
III
1-6
A-δ
5-30
+
-
<3
B
3-15
+
IV
<1.5
C
0.5-2.0
No
Adapted from Nolte J. The human bran. St.Louis: Mosby, 1999:213.
Receptor/ ending
Muscle spindle
primary endings
Golgi Tendon organs
Muscle efferents
(extrafusal)
Encapsulated
endings;Merkel
Muscle efferents
(intrafusal)
A-δ specific &
polymodal; cold; hair;
visceral (+/-)
Preganglionic
autonomic
C-nociceptors; C-polymodal;
warmth, mechano;postganglioic
autonomic; enteric nerve fibers
Conduction Velocity: Aδ & C fibers
• Aδ (Fast pain)1
• C-fibers (Slow pain)1
• Age related
impairment in fast
pain fibers2
1. Julius D, Basbaum A, Nature 2001(413).
2. Chakour M,, et al. Pain 1996; 64:143.
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 and
mechanical stimuli (polymodal)
• Threshold for firing may decrease
Kidd, Urban. Br J of Anaesth 87, 2001.
Cutaneous
C-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)
Caterina, Cur Op in Neurobiology (9), 1999.
A-δ
• Medium diameter
• Fast conducting
• Lightly myelinated
• Polymodal
Type I
Long response latency
> 50°C
Persistent pain
2. Type II
Short response
43°C
Initial burn
Primary Afferent C & Aβ Fibers
Sensation Mediated
Fibre Threshold Principal
Class For
Transmitters
Activation
SP/NKA
C
High
CGRP
EAA
Aβ
Low
EAA
Millan, Progress in Neurobiology, 1999.
Receptors Physiological Pathological
Engaged
NK
CGRP
NMDA
AMPA
mGlu
Noxious
(pain)
Highly noxious
(hyperalgesia)
Cold Allodynia
(pain)
AMPA
Innocuous
(no pain)
Mechanical
allodynia
Receptor types on sensory neurons
Transduction mechanism
Example
Cellular effect
Ligand-gated channel
Capsaicin-heat
H , 5HT, ATP
Glutamate, GABA-A
Excitation
G-protein linked
GABA-B
Opiated, Adenosine
Adrenoreceptors
NPY, 5HT
Inhibition of
transmitter &
peptide release
Bradykinin(B2)
Histamine (H1)
Adrenoreceptors (α2)
PGE2
NGF (Trk A)
Excitation
and/or
sensitization
Tyrosine kinase linked
Bevan S. Textbook of Pain, 4th ed. Wall, Malzack, 1999.
Control of gene
expression
Ion Channels
• Dynamic, constantly changing
• Plasticity reflects sensitivity needed for
survival
• Injury: amygdala, hippocampus, and DRG
• Normal peripheral nerves (resist)
• Demyelination: density
Receptors
• Capsaicin/ Vanilloid
• Purinergic (P2X)
Ion Channel Linked Receptors
Receptors
• Vanilloid (VR-1)
• Acid-sensing (ASIC)
• Purinergic (P2X)
• Cannabinoid
Kidd BL, Urban LA, Br J of Anaesthesia (1). 2001.
Ion Channels
• Sodium
– TTX-S
– TTX-R
• Calcium
Caterina. Cur Op in Neurobiology (9), 1999.
Nociception in Other Organs
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Less differentiation
Autonomic component
Poorly localized
Referred pain
Absence of Aβ in viscera
Skeletal muscle: group III, group IV
Joint: group III & group IV respond to
stretch
Visceral Pain
Psychophysics
• Not evoked from all
viscera
• Not always linked to
injury
• Referred to body wall
• Diffuse & poorly
localized
• Intense motor &
autonomic reactions
Cervero F, Laird J, Lancet 353, 1999.
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
Siddal, Cousins. Neural Blockade in Clinical Anesthesia and Management of Pain, Third Ed.,1998.
Milan MJ, Progress in Neurobiology 66, 2002.
Inflammation
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Redness (rubor)
Heat (calor)
Swelling (tumor)
Loss of function (function lasea)
Pain (dolor)
Inflammation
• Macrophages:
– Cytokines(IL1, IL6, TNF-α)
– 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 Scand 45, 2001.
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.
Hyperalgesia
pain threshold
pain to suprathreshold
stimuli
Spontaneous pain
Sensitization
threshold for response
response to
suprathreshold stimuli
Spontaneous activity
Peripheral Sensitization
Tissue Damage
Inflammation
Sympathetic Terminals
SENSITIZING ‘SOUP’
Hydrogen Ions
Noradrenaline
Bradykinin
Leukotrienes
Histamine
Potassium
Prostaglandins
5-HT
Woolf, Chong. Anesth. Analgesia (77), 1993.
Purines
Cytokines
NGF
Neuropeptides
Peripheral Sensitization
SKIN
Plasma Extravasation
Vasodilation
Macrophage
Mast
Cell
TNF-α
IL-6
LIF
Tissue
Damage
Pressure ?
Heat
5-HT3 Histamine PGE2
VR1
H+
5-HT3 H1
Bradykinin
EP
H+
IL1ß NGF ATP
B1/B2
IL1-R TrkA P2X ASIC
Ca2+
(PKC)
PKA
PKC
TTXr
(SNS/SNS2)
TTXs
Gene
Regulation
TTXr
Sub P
Adapted from Woolf CJ, et al. Science. 2000;288:1765-1768.
Peripheral
Nerve
Terminal
Central Sensitization: wind up
With permission. Jensen TS et al. Acta Anaesth Scand, 45, 2001.
Mechanisms of Nociceptive
Central Pain
• Autosensitization of receptors
• Ectopic firing of DRG cells
• Calcium-induced molecular cascades from
excess glutamate
• Phenotypic change of A-β cells and DRG
• Changes in gene expression of sodium
channels and neuropeptides
• Anatomic changes at dorsal horn
Schwarzman et al. Neurological Review, 58, 2001.
With Permission. Woolf,2000.
Mechanisms of nociceptive central pain
1. Autosensitization of receptors
2. Ectopic firing of DRG cells
3. Calcium-induced molecular cascades
from excess glutamate
4. Phenotypic change of A-β cells and DRG
5. Changes in gene expression of sodium
channels and neuropeptides
6. Anatomic changes at dorsal horn
Schwarzman et al. Neurological Review, 58, 2001.
Neuropathic Pain Is Defined
as…
…Pain caused by a lesion or dysfunction
of the nervous system1
• Nerve sensitization or damage
can be located in the peripheral
or central nervous system1
• Manifests with sensory symptoms
and signs2
• May have both positive and
negative 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
Sensitization
Sensory function after nerve injury with spontaneous firing along axon
To Brain
No
Stimulus
Nociceptor
Dorsal Horn
Neuron
Pain
Sensation
Central sensitization occurs as a result of increased nociceptor drive or disinhibition
after nerve injury, leading to exaggerated dorsal horn response
Inhibitory Input Is
Downregulated
To
Brain
Innocuous
Stimulus
Dorsal Horn
Neuron
Increased Nociceptor Drive
Adapted from Woolf CJ, Mannion RJ. Lancet. 1999;353:1959-1964.
Innocuous
or Noxious
Stimulus
Dorsal Horn
Neuron
Disinhibition
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
Beydoun A, Backonja. J Pain Symp Management 2003.
Temperature
Thermosensation
Julius D, Proc 10th Word Conference of Pain, 2003.
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
<17 C
Noxious cold
Szalassi et al. Nature Rev 2007;6.
Thermosensation
Cold
Heat
• 10-15% C & A-delta
• Specificity vs. modulation
of excitatory & inhibitory
channels
• K, Na, Ca channels
• CMRI (cold- and mentholsensitive receptor) cloned
• TRP (transient receptor
potential)
• Capsaicin
• Vanilloid receptor
subtype 1 (VR1 or
TRPV1)
• Thermal activation
threshold ~43°C
• Polymodal, influenced by
a variety of substances
Julius D, Proc 10th Word Conference of Pain, 2003.
Capsaicin
genus Capsicum:
mildest (bell) to hottest (habanero)
Capsaicin: 16,000,000 SHU
Classic:
habanero: 200,000 SHU
• Activates, desensitize (Ca²), 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. Gut 52, 2003.
W. Clin J Pain 16(2), 2000.
Robbins
TRPV Channels:
Szalassi et al. Nature Rev 2007;6.
Menthol: natural analgesic
• Mentha species
• peppermint plant, cornmint oil,
citronella, eucalyptus & Indian
turpentine oil
• “coolness”: stimulation of cold
receptors by (-) Calcium currents of
neuronal membranes, increasing
pain thresholds
• Activation of central “κ” Opioid
system
Galeotti N. Neuroscience Letters 322 (2002).
McKeny, Nature 416, 2002.
Pain Neurochemistry
Transmission via
spinothalamic tract
to brain
Dorsal
horn
Ion fluxes
(H+/ K+)
Dorsal root
ganglion
Tissue injury
Bradykinin
Prostaglandins
Leukotrienes
Spinal cord
Substance P
To brain
Histamine
Substance P, aspartate,
neurotensin, glutamate
Sensitized
nociceptor
Neuromatrix
Apkarian AV, et al. J of Neuroscience, 24(46), 2004.
Price DD. Science 2000.
Price DD. Science. 2000;288:1769-1772.
Price DD. Science. 2000;288:1769-1772.
“Pain Matrix”
Moseley GL. Man Ther. 2003;8(3):130-140.
“Pain Matrix”
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Anterior cingulate cortex (ACC)
Insular cortex (IC)
Thalamus
Sensorimotor cortex (SSI, SSII)
Cerebellum
Moseley GL. Man Ther. 2003;8(3):130-140.
Petrovic P, et al. Science 2002;295:1737-1740.
Petrovic P, et al. Science. 2002;295:1737-1740.
Opioid Systems
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Reynolds: (1969)
Endogenous opioid system
PAG & NMM: “funnel”
Homeostatic and
behavioral 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.
Tracey, 2008
INJURY
Tissue Damage
PERIPHERAL
ACTIVITY
SYMPTOMS
Spontaneous
Hyperalgesia
Allodynia
CENTRAL
SENSITIZATION
Decreased
threshold to
peripheral stimuli
Nerve Damage
Pain
Expansion of
Receptive field
Increased
Spontaneous
activity
Summary: “a gain in pain”
• Nociceptive vs. Neuropathic pain
• Chronic changes in the nervous system
may not be reversible
• Understanding of channels and receptors
evolving
• Medications and therapies targeted at
specific mechanisms
• Pain is not just a passive transfer of input
along a fixed system