Pharmacological Treatment Of Pain- Ee

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 Nociceptors • 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

Nociception

Light touch

Aβ-fiber Primary afferent

+ _

WDR

Spinal cord

P

A

Descending Pathways ______________________________________________________________________________________ _

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 _____________________________________________________________

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 K

+

Prostaglandines Free radicals

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

+

Central Sensitization ________________________________________________________________

Danysz et al; 1995

Pain Index

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

First Phase

Second Phase

The Two Phases of Acute Pain 2nd phase abolished by NSAIDs/NMDA ant. 40 35

Pain Index

30 25 20 15 10 5

NSAID/ NMDA ant. Injection

0 0

3

6

Formalin Injection

9

12

15 18

21 24

27

30 33

36 39

42 45

Time

First Phase

Second Phase

48 51

54 57

60

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 ___________________________________________________________________ ++

Ca

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

Nociception

Light touch

Aβ-fiber Primary afferent

+ _

WDR

Spinal cord

P

A

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)

SNRI

NE 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 _________________________________________________________________

Thank You