Nonopioid Analgesics and Adjuvants

1
Etiology and Pathophysiology of Various Pain
Syndromes
2
Nociception

• The detection of tissue damage by specialized
  transducers connected to A-delta and C-fibers

3
Pain

• An unpleasant sensory and emotional experience
  which we primarily associate with tissue damage
  or describe in terms of such damage, or both

4
Classification of Pain Nociception

• Proportionate to the stimulation of the
  nociceptor
• When acute
• Physiologic pain
• Serves a protective function
• Normal pain
• Pathologic when chronic

5
Classification of Pain Neuropathic Pain

• Sustained by aberrant processes in PNS or CNS
• Disproportionate to the stimulation of nociceptor
• Serves no protective function
• Pathologic pain

6
Classification of Pain Mixed Pain

• Nociceptive components
• Neuropathic components
• Examples
• Failed low-back-surgery syndrome
• Complex regional pain syndrome

7
Classification of Pain Idiopathic Pain

• No underlying lesion found yet, despite
  investigation
• Pain disproportionate to the degree of clinically
  discernible tissue injury

8
Normal Central Pain Mechanisms
9
Peripheral and Central Pathways for Pain
Adapted with permission from Fields HL, Price DD.
In Harrington A, ed. The Placebo Effect. An
InterdisciplinaryExploration. Cambridge, Mass
Harvard University Press 1997106.
10
Pain-Inhibitory and Pain-Facilitatory Mechanisms
Within the Dorsal Horn
0
C
A-DELTA
A-BETA
_ _


Neuronal circuitry within the dorsal
horn. Primary afferent neuron axons synapse onto
spinothalamic neurons and onto inhibitory and
excitatory neurons.
STTNEURON


TO BRAIN
11
Rating of First and Second Pain Intensity

Adapted with permission from Cooper BY, et al.
Pain. 198624103 and from Lee KH, et al. In
Fields HL, Dubner R, Cervero F, eds. Proceedings
of the Fourth World Congress on Pain. New York,
NY Raven Press 1985204.
12
Mechanisms ofPathologic Pain
13
Mechanisms of Pathologic Pain General
Considerations

• Pain-processing mechanisms function abnormally
• Examples neuropathic pain syndromes
• Nociception is sustained by chronic injury
• Example arthritis

14
Mechanisms of Pathophysiologic Pain Peripheral
Processes

•  Injured or diseased nerve(s)
• Growth of axonal sprouts
• Formation of ectopic foci

15
Mechanisms of Pathophysiologic Pain Central
Sensitization Processes

• Repeated impulse activity in C nociceptive
  neurons produces sensitization of STT neurons
  over time
• Sensitization of STT neurons leads to
• Increased spontaneous impulse activity
• Enhanced responses to impulses in nociceptive and
  non-nociceptive primary afferents
• Causes hyperalgesia, allodynia, and spontaneous
  pain

16
Temporal summation of second pain (second pain
summation is a result of repeated input from
C-fiber).
Temporal summation of responses of a dorsal horn
(STT) neuron to repeated C-fiber stimulation and
the effects of the NMDA-receptor antagonist
ketamine.
Reproduced with permission from Price DD, et al.
In Fields HL, Liebeskind JC, eds.
Pharmacological Approaches to the Treatment of
Chronic Pain New Concepts and Critical Issues.
Seattle, Wash IASP Press 199466.
17
Mechanism of Central Sensitization Associated
With Tonic C Nociceptor Input
0
A-DELTA
A-BETA
C
Tonic activity in C nociceptors
_ _



STTNEURON


Enhanced postsynaptic effects by NMDA-receptor
sensitization




TO BRAIN
18
Intracellular Mechanisms of Sensitization
Reproduced with permission from Mao J, et al.
Pain. 199561361.
19
Loss of Inhibitory Interneuron Function
0
C
A-DELTA
A-BETA
Tonic activity in C nociceptors
_ _


STTNEURON


Enhanced postsynaptic effects by NMDA-receptor
sensitization




TO BRAIN
20
Brain-to-Spinal-Cord Modulation of Pain
21
cell
Adapted with permission from Fields HL, Price DD.
In Harrington A, ed. The Placebo Effect. An
InterdisciplinaryExploration. Cambridge, Mass
Harvard University Press 1997108.
22
Mechanisms of Neuropathic Pain

• Noninflammatory states
• Inflammatory states

23
Pathophysiology of Neuropathic Pain

• Ectopic activity in the peripheral pathways,
  including axons and DRG
• CNS mechanisms

24
Radicular and Discogenic Neuropathic Pain
Mechanisms

• Ectopic activity of the nerve root nervi nervorum
  
• Sensitization and ectopic activity of the
  nociceptors innervating spinal periosteal
  structures, ie, annuli and ligaments
• Possible role of abnormal nociceptors overgrown
  within the intradiscal space, postsurgical
  epidural scars, degenerated facet joints
• CNS sensitization and reorganization

25
Neuropathic Pain Central Mechanisms

• Peripheral neuropathic events can be complicated
  by temporary or long-term CNS changes, such as
  central sensitization and then reorganization of
  the pain pathways at the dorsal horn level

26
Neuropathic Pain and SMP

• Some neuropathic pains are sustained, at least in
  part, by sympathetic efferent activity
• SMP
• Expression of alpha-adrenergic receptors on
  injured C-fibers may be a relevant mechanism of
  SMP, but others are possible
• Clinical findings consistent with CRPS signal an
  increased likelihood of SMP

27
Nociceptive Pain
Neuropathic Pain
PNS peripheral nervous system
PNS
Peripheral sensitization

Healthy nociceptors
Abnormal nociceptors
CNS
CNS central nervous system
Central sensitization
Normal transmission
Central reorganization
Physiologic state
Pathologic state
Pappagallo M. 2001.
28
Nociceptive Pain

• Sensitization and activation of healthy
  nociceptor endings and recruitment of silent
  nociceptors
• Soup of inflammatory algogenic agents, such as
  protons, prostaglandins, bradykinin, serotonin,
  adenosine, histamine, cytokines

29
Low Back Pain and Sciatica Nociceptive/
Inflammatory Pain Mechanisms

• Activation and sensitization of the nerve root
  nervi nervorum from root compression/traction
• Sensitization of the nociceptors of the annulus
  fibrosus, periosteal spinal structures, and
  ligaments, due to acute inflammation, eg, status
  post trauma
• Hyperalgesia (deep spinal and dermatomal) due to
  central sensitization

30
Fibromyalgia Syndrome Pathophysiology

• Central-nervous-system abnormalities
• Muscle pathology
• Psychopathology
• Genetic predisposition

31
Myofascial Pain Syndrome Pathophysiology

• Current pathophysiologic knowledge relies
  significantly on clinical examination
• Histologic studies of trigger points have not
  been particularly helpful
• Local ischemic factors due to prolonged muscle
  contraction may play a role in the development of
  the pain
• Denervation supersensitivity has been suggested
  by some to be the cause

32
Pathophysiology of Pain Conclusion

• Neuronal plasticity
• Nociceptor, spinal cord, brain
• Pain-facilitatory and pathophysiologic mechanisms
• Wind-up phenomenon
• Central sensitization
• Modulating mechanisms
• Ascending
• Descending