Pain

Pain and
and Analgesic
Analgesic
Pathways
Pathways

Robert
Robert B.
B. Raffa,
Raffa, Ph.D.
Ph.D.
Professor
Professor of
of Pharmacology
Pharmacology
Temple
Temple University
University
School
School of
of Pharmacy
Pharmacy & & School
School of
of Medicine
Medicine
 Current Knowledge

• Different ‘types’ of pain, not just different

degrees of pain
• Multiple chemical mediators of pain
• Optimal
Optimal therapy
therapy matches
matches the
the analgesic(s)
analgesic(s)
with
with the
the type(s)
type(s) of
of pain
pain
 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
 Normal Pain Pathways
cortex

thalamus

Tissue injury
• histamine
• bradykinin
• etc.
lateral spino-
dorsal root thalamic tract
ganglion

primary
afferent Fig 3-25
 Normal Pain Pathways

PAG
(periaqueductal gray)
locus ceruleus
raphe nuclei

Enkephalin-containing
interneuron

Fig 3-25
 Primary (1o) Afferents

‘sharp’ ‘dull’
localized vague

Aδ C
 REVIEW QUESTION

Which is/are TRUE?

1. Pain can be beneficial
2. Pain can be harmful
3. Nociception is normal
4. C-fibers transmit sharp, localized pain
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.
Current Analgesics Options

• NSAIDs: 1970’s
• opioids: 1970’s
• tramadol: 1980’s & 1990’s
• COX-2 inhibitors: 1990’s
• acetaminophen: unknown
• combinations
• adjuncts
 WHO Analgesic ‘Ladder’

Step 3
Severe Strong opioids (e.g., morphine)
with or without non-opioids

Step 2
Moderate Weak opioids (e.g., codeine)
with or without non-opioids

Step 1
Non-opioids (e.g., NSAIDs,
Mild
acetaminophen = paracetamol)
Underutilization and Control
Sites of Action

NSAIDs

Aa PGs
COX
Sites of Action

Local
Anesthetics
(voltage-gated
Na+ channels)
 Sites of Action

Opioids
(µ , δ , κ )
Sites of Action

Acetaminophen ?
 REVIEW QUESTION

The WHO analgesic ladder is a guide to

the proper dose of analgesic:
1. True
2. False
 ‘Resistant’ Pains

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

Pharmacologic management
• Acute attack
– analgesics (e.g., NSAIDs, APAP)
– ‘triptans’ (5-HT agonists)
• Prophylaxis
– ß blockers
– anticonvulsants
– Ca22++ channel blockers
– etc.
 Neuropathic Pain
Common types
• diabetic neuropathy
• post-herpetic neuralgia
• ‘phantom limb’
• etc.
Pharmacologic management
• opioids
• tramadol
• topical anesthetics
• antidepressants
• anticonvulsants
 Possible Mechanisms
•• ‘Central
‘Central sensitization’.
sensitization’. Overactivity
Overactivity of of aa 22oo neuron
neuron inin the
the dorsal
dorsal
horn
horn leads
leads to
to enhanced
enhanced pain transmission characterized by aa
lowered
lowered threshold
threshold for
for activation
activation andand expanded
expanded receptive
receptive fields,
fields,
leading
leading to
to the
the activation
activation of
of key
key excitatory
excitatory aminoamino acid
acid receptors
receptors
such
such as
as the
the N-methyl-
N-methyl-DD-aspartate
-aspartate (NMDA)
(NMDA) receptor.
receptor.
•• Disinhibition.
Disinhibition. Reduced
Reduced activation
activation of of central
central inhibitory
inhibitory inputs
inputs
from
from endogenous
endogenous opioid,
opioid, 5-HT,
5-HT, and
and norepinephrine
norepinephrine pathways.
pathways.
•• Sympathetic
Sympathetic activation.
activation. Sympathetic nerve nerve endings sprout
from
from aa nearby
nearby blood
blood vessel
vessel toward
toward thethe site
site of of injury
injury and
and can
can
enhance
enhance signal
signal transmission
transmission in in the
the DRG.
DRG. Catecholamine
Catecholamine
release
release and
and up-regulation
up-regulation of of adrenoceptors
adrenoceptors on on free
free nerve
nerve
endings
endings also
also contribute
contribute toto sympathetically
sympathetically mediatedmediated pain.
pain.
•• Peripheral
Peripheral sensitization.
sensitization. Injury
Injury toto peripheral
peripheral nerves
nerves may
may lead
lead to
to
hyperexcitability
hyperexcitability ofof peripheral
peripheral nerve
nerve terminals
terminals (nociceptors).
(nociceptors).
This
This may bebe due toto altered
altered expression
expression of of Na
Na++ channels,
channels, Ca Ca2+2+
channels,
channels, oror adrenoceptors
adrenoceptors in in peripheral
peripheral nerves
nerves and and DRG.
DRG.
 Mechanisms of Pain
Normosensitivity
 Mechanisms of Pain
Central Sensitization
 Mechanisms of Pain
Neuropathic
 Mechanisms of Pain
Hyperalgesia
 Mechanisms of Pain
Allodynia
 Combination
Combination Analgesics
Analgesics
Possible rationales
No
No single
single perfect
perfect analgesic
analgesic
–– Complementary PK
Complementary PK
–– Multiple sites/mechanisms of action target multiple pain pathways
Multiple sites/mechanisms of action target multiple pain pathways
–– Potentially synergistic analgesia
Potentially synergistic analgesia
–– Comparable efficacy, but reduced AE profile
Comparable efficacy, but reduced AE profile
––

Raffa, RB. J Clin Pharm Ther. 2001;26:257-64.

 REVIEW QUESTION

‘Triptans’ are most associated with:

1. Diabetic neuropathy
2. Migraine headache
3. Neuropathic pain
 REVIEW QUESTION

Central sensitization and up-regulation

are the same thing:
1. True
2. False
REVIEW QUESTION

Almost everyone experiences:

1. Hyperalgesia
2. Allodynia
end