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Pharmacological Treatment of Pain- EE

Pharmacological Treatment of Pain- EE


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Published by api-3723461
הרצאה 20- 10.7.2008
הרצאה 20- 10.7.2008

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Published by: api-3723461 on Oct 17, 2008
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Basic Understanding of Pain


Elon Eisenberg MD
Pain Relief Unit, Rambam Medical Center, The Technion – Israel Institute of Technology, Haifa, Israel

Mechanistic Classification of Pain

• • • •

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
• Free nerve endings • High threshold • Polymodal • Receptive fields

Pain Transmission

Pain Transmission
A-delta Myelinated 1.0-35 m/s First pain Sharp pain C fibers Unmyelinated 0.3-1.0 m/s Second pain Dull pain

Synaptic Transmission

Primary afferent Substance P

Post synaptic neuron NK Receptor

Pain Pathways

Pain Imaging

Pain Modulation

Gate Control Theory

Pain C-fiber

+ _

Light touch

Aβ-fiber Primary afferent

Spinal cord



Descending Pathways
______________________________________________________________________________________ _

Pain Modulation

Primary afferent Substance P Endorphin

Post synaptic neuron NK Receptor 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

Epidural Blocks

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


Prostaglandines Free radicals

Inflammation-Induced Phenotypic Changes
Substance P CGRP Glutamate Cytokines Free radicals


Central Sensitization

Danysz et al; 1995

The Two Phases of Acute Pain
40 35 30 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

Pain Index

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 5

NSAID/ NMDA ant. Injection

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


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:
___________________________________________________________________ _

• Spontaneous pain • Hyperalgesia / allodynia • Loss of sensation

Post-Mastectomy Pain Syndrome
__________________________________________________________________ Intercosto-brachial nerve

Post Herpetic Neuralgia

(Chronic Constrictive Injury (CCI

Neuropathic Pain Mechanisms

• • • • •

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 increased

Primary excitatory afferent nerve fiber

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


Central sensitization

Primary afferent
Glutamate Substance P CGRP

Post synaptic neuron
NMDA Receptor NK Receptor

Sympathetic Sensory Coupling

Janig & McLachlan 1994↑ DRGαTH staining; Devor 1994→

Loss of Large Fiber Inhibition
__________________________________________________________________ _

Pain C-fiber

+ _

Light touch

Aβ-fiber Primary afferent

Spinal cord



Spinal Cord Reorganization
Before nerve section

After nerve section

Cortical Reorganization

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

Balanced effects on 5-HT and NE at starting doses Adequate potency to ensure effectiveness at starting dose Site selectivity to limit side effects

5-HT Reuptake Transporter (Blocked) 5-HT

NE Reuptake Transporter (Blocked)


Theoretical Representation

Allodynia in CRPS

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

Dysfunctional Pain

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