Pain and Analgesic Pathways

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Pain and Analgesic Pathways

• Robert B. Raffa, Ph.D.
• Professor of Pharmacology
• Temple University
• School of Pharmacy School of Medicine

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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

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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

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Normal Pain Pathways
cortex
thalamus

• Tissue injury
• histamine
• bradykinin
• etc.

lateral spino- thalamic tract
dorsal root ganglion
primary afferent
Fig 3-25
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Normal Pain Pathways
PAG (periaqueductal gray)
locus ceruleus
raphe nuclei
Enkephalin-containing interneuron
Fig 3-25
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sharplocalized
Primary (1o) Afferents
dullvague
Ad
C
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REVIEW QUESTION

• Which is/are TRUE?
• Pain can be beneficial
• Pain can be harmful
• Nociception is normal
• C-fibers transmit sharp, localized pain

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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.
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Current Analgesics Options

• NSAIDs 1970s
• opioids 1970s
• tramadol 1980s 1990s
• COX-2 inhibitors 1990s
• acetaminophen unknown
• combinations
• adjuncts

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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)
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Underutilization and Control
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Sites of Action
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Sites of Action
Local Anesthetics (voltage-gated Na channels)
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Sites of Action
Opioids (m, d, k)
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Sites of Action
Acetaminophen ?
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REVIEW QUESTION

• The WHO analgesic ladder is a guide to the
  proper dose of analgesic
• True
• False

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Resistant Pains

• Migraine
• Neuropathic pain
• Sickle cell pain
• etc.

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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.

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Migraine

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

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Neuropathic Pain

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

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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.

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Mechanisms of Pain
Normosensitivity
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Mechanisms of Pain
Central Sensitization
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Mechanisms of Pain
Neuropathic
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Mechanisms of Pain
Hyperalgesia
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Mechanisms of Pain
Allodynia
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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.
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REVIEW QUESTION

• Triptans are most associated with
• Diabetic neuropathy
• Migraine headache
• Neuropathic pain

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REVIEW QUESTION

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

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REVIEW QUESTION

• Almost everyone experiences
• Hyperalgesia
• Allodynia

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end