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Basic Understanding of Pain

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Elon Eisenberg MD

Pain Relief Unit, Rambam Medical Center,


The Technion – Israel Institute of Technology, Haifa, Israel
Mechanistic Classification of Pain
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• Nociceptive pain
• Inflammatory pain
• Neuropathic Pain
• “Dysfunctional” pain
Nociceptive pain
• A useful, protective, adaptive feature of the
sensory nervous system.

• It is associated with withdrawal response to


potentially hazardous stimuli in the
environment.
Descartes’ (1664) Concept of
Pain Pathways
Pain Processes

• Transduction
• Transmission
• Modulation
Pain Transduction

Nociceptors
• Free nerve endings
• High threshold
• Polymodal
• Receptive fields
Pain Transmission
Pain Transmission
A-delta C fibers
Myelinated Unmyelinated
1.0-35 m/s 0.3-1.0 m/s
First pain Second pain
Sharp pain Dull pain
Synaptic Transmission

Primary afferent Post synaptic neuron


Substance P NK Receptor
Pain Pathways
Pain Imaging
Pain Modulation
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Gate Control Theory
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Pain
Nociception
C-fiber +
Light touch
WDR
Aβ-fiber _

P
Primary afferent Spinal cord

A
Descending Pathways
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_
Pain Modulation

Primary afferent Post synaptic neuron


Substance P NK Receptor
Endorphin Opiate receptor
Nociceptive Pain –Clinical Implications

• Trauma
• Diagnostic procedures
• Surgery
• Labor
Nociceptive Pain - Potential Interventions

• Neural blocks
- Peripheral
- Central
• General anesthesia
• Pain modulation
- Local stimulation
- Opioids
Nerve Blocks
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Epidural Blocks
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Nociceptive Pain - Summary
• Nociceptive pain results from the exposure of high
threshold primary sensory neurons in the periphery to
noxious stimuli
• The sensory neurons express highly specialized
transduction proteins that detect extreme temperature,
irritant chemical, intense mechanical stimuli and
convert them into electrical activity.
• The resulting pain is perceived within milliseconds
and dissipates quickly with the removal of the stimulus.
Inflammatory Pain ((1
• Pain that is associated with tissue damage and
active inflammation.
• The inflammatory response recruits and activates
leukocytes, which produce inflammatory mediators,
cytokines, and chemokines – that a alter neuronal
sensitivity.
• This sensitization process occurs over a period of
seconds to days from the initial tissue damage.
•Sensitization lowers the activation threshold of
nociceptors.
Inflammatory Pain ((2
• This results in spontaneous pain, allodynia and
hyperalgesia.
• Molecules associated with inflammation may also
change gene expression levels within nociceptors
leading to altered transmitters, receptors, or ion
channels (phenotypic changes)
• Additionally, central sensitization – a state of
enhanced excitability in the spinal cord in which
peripheral inputs to the CNS are amplified –also
occurs. This contributes to pain sensitivity outside
of the area of damage (secondary hyperalgesia)
Sensitization of Primary Afferent
Substance P
Cytokines
K
+

Prostaglandines
Free radicals
Inflammation-Induced Phenotypic Changes
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Substance P
CGRP
Glutamate
Cytokines
Free radicals
K
+
Central Sensitization
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Danysz et al; 1995


The Two Phases of Acute Pain
40
35
30
Pain Index

25
20
15
10
5
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Time

Formalin Injection First Phase Second Phase


The Two Phases of Acute Pain
2nd phase abolished by NSAIDs/NMDA ant.
40

35

30
Pain Index

25

20

15

10

NSAID/ 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
NMDA
ant. Time
Injection

Formalin Injection First Phase Second Phase


Inflammatory Pain –Clinical Implications

• Post-operative pain
• Rheumatoid arthritis
• Infection (i.e. ear)
• Pancreatitis
Inflammatory Pain - Potential Interventions

• Anti-inflammatory drugs
• Steroids
• Free radical scavengers
• Substance P blocking agents
• Pain modulation
Neuropathic Pain
• Is a combination of pain and loss of function that
originates from damage to the nervous system.
• In contrast to nociceptive pain, there is no change
in nociceptive transduction sensitivity at the
periphery.
• Rather, a series of profound changes occur at
multiple levels of the nervous system.
Neuropathic Pain: Signs & symptoms:
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_

• Spontaneous pain
• Hyperalgesia / allodynia
• Loss of sensation
Post-Mastectomy Pain Syndrome
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Intercosto-brachial nerve
Post Herpetic Neuralgia
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(Chronic Constrictive Injury (CCI
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Neuropathic Pain Mechanisms
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• Sensitization of primary afferent (Neuroma; DRG)


• Neurogenic inflammation
• Central sensitization
• Sympathetically maintained pain
• Loss of large fiber inhibition
• Central Reorganization
Ectopic Discharges
Injured nerve fibers develop increased expression of Na+ channels

Na+ channel
expression Primary excitatory afferent nerve fiber
increased

Conduction frequency amplified

Na+ = sodium ion. England et al. Neurology 1996;47:272-76. Ochoa et al. Brain. 1980;103:835-853
Taylor. Curr Pain Headache Rep. 2001;5:151-161. Sukhotinsky et al. Eur J Pain. 2004;8(2):135-43
Ectopic Discharge
Central Sensitization
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++
Ca

Central
sensitization

Primary afferent Post synaptic neuron


Glutamate
NMDA Receptor
Substance P NK Receptor
CGRP
Sympathetic Sensory Coupling
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Janig & McLachlan 1994↑


DRGαTH staining; Devor 1994→
Loss of Large Fiber Inhibition
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_

Pain
Nociception
C-fiber +
Light touch
WDR
Aβ-fiber _

P
Primary afferent Spinal cord

A
Spinal Cord Reorganization
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Before nerve section

After nerve section


Cortical Reorganization
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Neuropathic Pain - Potential Interventions

• Reducing ectopic discharge: Na+ channel


blockers, antiepileptic drugs, sympathetic
blockers
• Blocking the release of neurotransmitters
• Blocking glutamate (NMDA) and other (?)
receptors
• Pain modulation: opioids, antidepressants, neural
stimulation
Pregabalin Modulates Hyperexcited Neurons

*Does not affect Ca++ influx in normal neurons


Duloxetine (Cymbalta)
A Balanced SNRI at the Synaptic Level
5-HT Reuptake
♦ Balanced effects Transporter
on 5-HT and NE (Blocked)
at starting doses 5-HT
♦ Adequate potency
to ensure
effectiveness at
NE Reuptake
starting dose
Transporter
(Blocked) SNRI
♦ Site selectivity to
limit side effects

NE

Theoretical Representation
Allodynia in CRPS
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Dysfunctional Pain
• Much less is known about it.
• Heightened pain sensitivity in the absence of
noxious stimuli, peripheral pathology or
inflammation, and lesion to the nervous system.
• Abnormal function of intact nervous system.
• Includes: fibromyalgia, tension-type headaches,
IBS, and migraine.
…Wrong Object
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Dysfunctional Pain
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Thank You