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Pain and Analgesic Pathways

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tramadol: 1980's & 1990's. COX-2 inhibitors: 1990's. acetaminophen: unknown. combinations ... tramadol. topical anesthetics. antidepressants. anticonvulsants ... – PowerPoint PPT presentation

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Title: Pain and Analgesic Pathways


1
Pain and Analgesic Pathways
  • Robert B. Raffa, Ph.D.
  • Professor of Pharmacology
  • Temple University
  • School of Pharmacy School of Medicine

2
Current Knowledge
  • Different types of pain, not just different
    degrees of pain
  • Multiple chemical mediators of pain
  • Optimal therapy matches the analgesic(s) with the
    type(s) of pain

3
Types of Pain
  • Nociceptive
  • normal physiology (mechanisms known)
  • beneficial
  • treated with conventional analgesics (NSAIDs,
    acetaminophen, opioids)
  • unrelieved, it becomes deleterious
  • Neuropathic
  • aberrant physiology (mechanisms unknown)
  • poor quality of life
  • difficult to treat

4
Normal Pain Pathways
cortex
thalamus
  • Tissue injury
  • histamine
  • bradykinin
  • etc.

lateral spino- thalamic tract
dorsal root ganglion
primary afferent
Fig 3-25
5
Normal Pain Pathways
PAG (periaqueductal gray)
locus ceruleus
raphe nuclei
Enkephalin-containing interneuron
Fig 3-25
6
sharplocalized
Primary (1o) Afferents
dullvague
Ad
C
7
REVIEW QUESTION
  • Which is/are TRUE?
  • Pain can be beneficial
  • Pain can be harmful
  • Nociception is normal
  • C-fibers transmit sharp, localized pain

8
Multiple types in injury
In many injuries and chronic disorders (e.g.,
arthritis, cancer), there are multiple sources
and types of tissue injury and, thus, multiple
sources and causes (types) of pain.
9
Current Analgesics Options
  • NSAIDs 1970s
  • opioids 1970s
  • tramadol 1980s 1990s
  • COX-2 inhibitors 1990s
  • acetaminophen unknown
  • combinations
  • adjuncts

10
WHO Analgesic Ladder
Step 3 Strong opioids (e.g., morphine) with or
without non-opioids
Severe Moderate Mild
Step 2 Weak opioids (e.g., codeine) with or
without non-opioids
Step 1 Non-opioids (e.g., NSAIDs, acetaminophen
paracetamol)
11
Underutilization and Control
12
Sites of Action
13
Sites of Action
Local Anesthetics (voltage-gated Na channels)
14
Sites of Action
Opioids (m, d, k)
15
Sites of Action
Acetaminophen ?
16
REVIEW QUESTION
  • The WHO analgesic ladder is a guide to the
    proper dose of analgesic
  • True
  • False

17
Resistant Pains
  • Migraine
  • Neuropathic pain
  • Sickle cell pain
  • etc.

18
Migraine
  • Periodic, pulsatile headaches. Familial disorder
    that usually begins in childhood or early
    adulthood and tends to decrease in frequency in
    later life.
  • Possible causes (1) humoral disturbance that
    alters vascular responsiveness which in turn
    elicits pain, or (2) a neurological disturbance
    in the meninges, from which pain and vasomotor
    changes result. More specifically, could be due
    to vascular changes triggered by 5-HT release, to
    a neuronal abnormality, or excess activity of
    peptidergic nerve terminals in meningeal vessels.
    The release of 5-HT also leads to local
    inflammatory response and the release of other
    mediators (e.g., bradykinin and prostaglandins)
    that act on nociceptive nerve terminals, causing
    pain and also releasing neuropeptides which
    further reinforce and prolong the pain. Afferent
    nerve terminals in blood vessel walls may become
    hypersensitive to vascular distension, thus
    accounting for the fact that many anti-migraine
    drugs are vasoconstrictors.

19
Migraine
  • Pharmacologic management
  • Acute attack
  • analgesics (e.g., NSAIDs, APAP)
  • triptans (5-HT agonists)
  • Prophylaxis
  • ß blockers
  • anticonvulsants
  • Ca2 channel blockers
  • etc.

20
Neuropathic Pain
  • Common types
  • diabetic neuropathy
  • post-herpetic neuralgia
  • phantom limb
  • etc.
  • Pharmacologic management
  • opioids
  • tramadol
  • topical anesthetics
  • antidepressants
  • anticonvulsants

21
Possible Mechanisms
  • Central sensitization. Overactivity of a 2o
    neuron in the dorsal horn leads to enhanced pain
    transmission characterized by a lowered threshold
    for activation and expanded receptive fields,
    leading to the activation of key excitatory amino
    acid receptors such as the N-methyl-D-aspartate
    (NMDA) receptor.
  • Disinhibition. Reduced activation of central
    inhibitory inputs from endogenous opioid, 5-HT,
    and norepinephrine pathways.
  • Sympathetic activation. Sympathetic nerve
    endings sprout from a nearby blood vessel toward
    the site of injury and can enhance signal
    transmission in the DRG. Catecholamine release
    and up-regulation of adrenoceptors on free nerve
    endings also contribute to sympathetically
    mediated pain.
  • Peripheral sensitization. Injury to peripheral
    nerves may lead to hyperexcitability of
    peripheral nerve terminals (nociceptors). This
    may be due to altered expression of Na channels,
    Ca2 channels, or adrenoceptors in peripheral
    nerves and DRG.

22
Mechanisms of Pain
Normosensitivity
23
Mechanisms of Pain
Central Sensitization
24
Mechanisms of Pain
Neuropathic
25
Mechanisms of Pain
Hyperalgesia
26
Mechanisms of Pain
Allodynia
27
Combination Analgesics
Possible rationales
  • No single perfect analgesic
  • Complementary PK
  • Multiple sites/mechanisms of action target
    multiple pain pathways
  • Potentially synergistic analgesia
  • Comparable efficacy, but reduced AE profile

Raffa, RB. J Clin Pharm Ther. 200126257-64.
28
REVIEW QUESTION
  • Triptans are most associated with
  • Diabetic neuropathy
  • Migraine headache
  • Neuropathic pain

29
REVIEW QUESTION
  • Central sensitization and up-regulation are the
    same thing
  • True
  • False

30
REVIEW QUESTION
  • Almost everyone experiences
  • Hyperalgesia
  • Allodynia

31
end
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