PAIN
Lynn Fitzgerald Macksey
CRNA, MSN
The emotional experience of pain is based on the
individual’s subjective experience.
Emotional pain is associated with
ACTUAL or POTENTIAL tissue damage
Situational, behavioral, and
emotional factors all play a role
Expectations
Motivations
all strongly modify nociceptive input
Does the same stimulus or damage cause
the same sensation in all people?
We now know…
…the old concept of
linear pain transmission
implied a fixed relationship
between a stimulus and perception.
Pain is whatever
the person says
it is!
4 PHYSIOLOGIC PROCESSES IN
SENSORY PAIN
1. Transduction
2. Transmission
3. Interpretation/Perception
4. Modulation
Let’s review this
process quickly….
First order neuron:
brings pain
information
to the CNS via the
nociceptors
to the dorsal horn of
the spinal cord
Second order neuron:
synapses with the first
order neurons in the
dorsal horn –
picks up
excitatory NT, crosses
the midline and heads
toward the
spinothalamic tract
(STT).
Third order neuron:
meets up at the
spinothalamic pathway
and carries pain
neurotransmitters to
midbrain, brainstem,
thalamus/hypothalamus,
limbic system and then
to cerebral cortex.
1. Transduction
Pain begins with the
stimulation of
peripheral nerve fiber
receptors called
nociceptors.
Nociception is caused
by noxious thermal,
mechanical, or
chemical stimuli.
Nociceptors carry the
pain stimulus to the
spine.
Transduction
peripheral
nociceptors
carry pain
towards
spinal cord.
Nociceptors – 2 main types
Type-A delta nerve fibers
Small, myelinated nerve fibers; carries impulse quickly.
Sharp or fast pain; stabbing, shooting pain
Type-C nerve fibers
Unmyelinated nerve fibers; slower pathway than A fibers
Dull or slow pain; throbbing, burning, and achy.
Constitute nearly 90% of peripheral sensory fibers
2. Transmission
First order neuron
First order neurons
…arrive in
the
dorsal horn
the first six
Rexed laminae
--and
to the
substantia
gelatinosa
Neurotransmitters
endogenous chemicals
carried from a pre- to
post-synaptic receptor
across the synapse.
2 excitatory neurotransmitters (NT)
Other excitatory NT besides
glutamate and substance P
Hydrogen
Histamine
Prostaglandin
Bradykinin
Potassium
Serotonin
Norepinephrine
Acetylcholine
Transmission
After picking up the NT
at the 1st order
neuron synapse,
second order neurons
cross the midline
close to their level of
origin and carry these
NTs to the
contralateral
spinothalamic tract
(STT)
After synapsing with the
2nd order neurons of
the STT……
Third order neurons
travel to the thalamus
…and other key areas of
the brain
From the STT,
the impulse goes
to
raphe nuclei,
reticular system,
and
periaqueductal
gray matter of
the brain…
3. INTERPRETATION AND PERCEPTION
…and from there,
pain
neurotransmitter
messages
project out to the
cerebral cortex.
Modulation
Modulation of pain
occurs in…..
supraspinal structures
and in the
spinal cord
Modulation
MEDULLA/MIDBRAIN produce
ENDOGENOUS OPIOIDS
and
INHIBITORY NEUROTRANSMITTERS
which travel down the
descending pathways
Modulation
 Endogenous opioids aka Endorphins, betaendorphin, dynorphin, enkephalin, opiopeptins are a type of inhibitory neurotransmitter
 Endorphins initiate a series of physiologic
functions resulting in cellular hyperpolarization
and inhibition of excitatory neurotransmitter
release and cephalad transmission of pain
impulses
 ENDORPHINS INHIBIT SUBSTANCE P and
GLUTAMATE and other excitatory NT.
Modulation
 Remember back to excitatory NT…
Inhibitory NT are released in the same
way and block the tendency of that
neuron to fire.
Examples of inhibitory NT
 serotonin, norepinephrine, dopamine,
glycine, enkephalin, and galanin,
somatostatin, and gammaaminobutyric acid (GABA);
acetylcholine, is an inhibitory NT but it is also an
excitatory NT…depending on the stimulus.
Dorsal Horn and Lamina II
 dorsal horn is the principal site
of pain modulation
 substantia gelatinosa is the
major site of action of opioids.
 This is the point at which the
peripheral nervous system
synapses with the CNS and
where many different
neurotransmitters are effectors
The first-order neuron travels
____ and to_____?
Peripheral nociceptors to the dorsal
horn of the spinal cord
The dorsal horn of the spinal cord
gray matter is made up of?
a. the first six Rexed lamina
b. Lissauer’s tract
c. 1st and 2nd order neurons
d. the start of the 3rd order
neurons
A: the first six Rexed lamina
These first six lamina receive all afferent neural activity
and represent the principal site of modulation of pain
by ascending and descending neural pathways.
Rexed Lamina II in the dorsal horn
gray matter is also called?
a. motor horn (anterior)
b. spinothalamic tract
c. substantia gelatinosa
d. intermediolateral column
c. substantia gelatinosa
The substantia gelatinosa is believed to?
a. play a role in nociceptive input
b. receive stimuli from wide dynamic range
(WDR) neurons
c. the area of the spinal cord where the secondorder neuron begins its path
d. the area of the spinal cord where the firstorder neuron begins its path
a. play a role in nociceptive input
The second order neuron travels
____ and to_____?
After synapsing and picking up the
neurotransmitters at the dorsal root
ganglion, second order neurons
cross the midline close to their level of
origin and carry these chemicals to the
contralateral spinothalamic tract
(STT)
The spinothalamic tract sends stimulus to?
a. nucleus raphe magnus
b. amygdala nuclei
c. reticular formation
d. periaqueductal gray
1. a, b, c
2. all but b
3. a and d
4. all of the above
answer: 2; all but the amygdale nuclei. STT
does send to the nucleus raphe magnus,
reticular formation, the periaqueductal gray,
as well as to the thalamus.
The third-order neuron travels from
____ and to_____?
Spinothalamic tracts to the nucleus
raphe magnus, reticular
formation, the periaqueductal
gray, as well as to the thalamus.
WHAT HAPPENS IN THE BODY
WITH PAIN
 Neuroendocrine









catecholamines
cortisol
angiotensin II
ADH
aldosterone
adrenocorticotropic hormone
growth hormone
glucagon
lower levels of insulin
Pain
 CV
 Release of catecholamines from
sympathetic nerves and adrenal medulla
 Release of aldosterone and cortisol from
adrenal cortex
 Release of ADH from hypothalamus &
activation of renin-angiotensin system
 Salt/water retention
 Tachycardia, myocardial work
 Hypertension
Pain
 Pulmonary









 skeletal muscle tension
decrease lung compliance
splinting
hypoventilation
atelectasis
VQ ratio abnormality
hypoxemia
respiratory failure
increased respiratory rate
Pain
 GI
 pain-induced hyperactivity may cause
inhibition of GI
 postoperative ileus, nausea and vomiting
 GU
 reflex inhibition of visceral smooth muscle
 urine retention
Pain
 Coagulation
  platelet adhesiveness
  fibrinolysis
 Decreased immune function
POSTOPERATIVE STRESS
SYNDROME
 Postoperative pain is one of the elements
of the acute postoperative stress
syndrome that includes increased levels
of stress hormones which include:




Adrenocorticotrophic hormone (ACTH)
Cortisol
Catecholamines
Interleukins
 Along with: decreased insulin release
and fibrinolysis
POSTOPERATIVE STRESS
SYNDROME
 These hormonal changes lead to
increased myocardial oxygen
consumption and associated risks of
myocardial ischemia and infarction,
hypertension, increased coagulability,
decreased regional blood flow,
increased risk of infection, depression,
and loss of sleep.
Inflammatory response
When we talk about pain
transmission, we must also
talk about the inflammatory
response.
Inflammatory response
INFLAMMATION is a part of the
pain response
The inflammatory effects
can be greater in
magnitude than the initial injury.
Mediators of inflammation
 Histamine- cause moderate vasodilation and
considerable increase in vascular permeability, (from
mast cells and connective tissue release)
 Serotonin (5-HT) - causes some vasodilation, and
increase in vascular permeability. (from blood products).
Serotonin– both excitatory & inhibitory
 Bradykinin- causes considerable vasodilation and
pain, with small increase in vascular permeability.
(activation of clotting cascade)
 Prostaglandins- cause considerable vasodilation and
chemotaxis, with small increase in vascular permeability
and pain. (released from damaged membranes)
 Leukotrienes- cause a considerable vascular
permeability and chemotaxis. (released from injured
tissue/membrane)
Inflammation: Eicosanoids
prostaglandins, prostacyclins,
thromboxanes and leukotrienes
 These eicosanoids are ligands that
bind to the cell surface;
they exert complex control mainly in
inflammation, and as messengers in
the central nervous system.
Cyclooxygenase Pathway
 Naturally
occurring
mediators of
inflammation…
AND PAIN!
Arachidonic
acid
is converted by
cyclooxygenase
compounds
to synthesize
specific
eicosanoids
--prostaglandins,
prostacyclins, &
thromboxane
Cyclooxygenase Pathway
 Two main forms of cyclooxygenase
(though a 3rd has been identified):
 COX-1 and COX-2
 Cox-1 and 2 are the targets of nonsteroidal anti-inflammatory drugs
(NSAIDs) and non-opioid analgesics
COX-1
 COX-1 is a constituative
(produced all the time) enzyme in
the gastric mucosa, renal
parenchyma and platelets.
 Protects the inner lining of the stomach
and the gastric mucosa.
 Causes platelet aggregation
 Mediates renin release and
maintenance of renal blood flow
The inhibition of COX I
is undesirable.
Inhibition of COX I
Why is inhibiting COX 1 undesirable?
When the COX-1 enzyme is blocked,
inflammation is reduced, but
*the protection of the lining of the
stomach also is lost. Can cause
ulceration and bleeding from the
stomach and the intestines.
*platelet function inhibited……bleeding
*hypertension, salt and water retention,
hyperkalemia can occur
COX-2
 COX-2 is present constitutively in
small amounts, but is highly inducible
(must be turned on) at sites of
inflammation.
 Expression varies markedly
depending on stimulus.
Because COX II is only present at
inflammation then….
The inhibition of COX II
is desirable.
Inhibition of COX II
COX II enzyme is located in areas involved in
inflammation…a COX II blocker inhibits
generation of prostaglandins thereby
inhibiting inflammation, pain, and fever..
 COX II is not located in the stomach….
and there are fewer GI complications.
Understanding pain
and how drugs work
Receptor-Ligand Interaction
Drugs affect receptor sites in two ways -
Affinity
…the ability of a
drug to bind
to a receptor
Efficacy
….the capacity of a drug
to produce an effect.
Agonist
An agonist will produce the
maximum possible effect of
binding with the receptor.
 Strong agonists (eg. morphine,
methadone) - act as complete agonists at
receptors;
 Mild-moderate agonists (eg. codeine;
propoxyphene [Darvon]; tramadol
[Ultram]) - has less intrinsic efficacy
Partial agonist
AKA mixed agonist-antagonist
Effect is
based on
their
concentration
and on the
presence of a
full agonist.
 If administered alone, it will act
as a partial agonist.
 If administered with a small dose
of a full agonist, the two will be
additive up to the maximum of
the partial agonist
 If administered with a large dose
of a full agonist, the partial
agonist will act as an antagonist
to the agonist.
Antagonist
 produces no direct effect when binding with
the receptor; blocks or dampens agonist
responses.
 Examples: eg. naloxone [Narcan],
naltrexone [ReVia] act as "pure"
competitive antagonists at opiate receptors.
 occupy opiate receptors without
producing a pharmacological effect;
will precipitate rapid withdrawal symptoms
in addicts.
Antagonist
Antagonists have affinity for a receptor
…
But no efficacy!!
Mixed agonist-antagonist
DRUG
Use
Receptors
Nalbuphine
(Nubain)
Used to antagonize respiratory
depressant effects of full
agonists while maintaining
analgesia.
Also used to treat pruritus due to
neuraxial opioids.
Partial Mu, and Kappa agonist;
provides analgesia,
sedation. Can
precipitate withdrawal
symptoms in opioid
tolerant patients.
Butorphanol
(Stadol)
Used to antagonize respiratory
depressant effects of full
agonists while maintaining
analgesia.
Effective in treating postoperative
shivering.
Partial Mu, and Kappa agonist;
has increased sedative
properties due to kappa
Post-op dose 3mg
Buprenorphine
(Buprenex)
Used to antagonize respiratory
depressant effects of full
agonists while maintaining
analgesia.
Mu agonist, Kappa antagonist.
In small to medium doses, is
more potent than
Morphine.
Overdose cannot be
treated with
naloxone.
Notes
OR dose 3mg/kg
followed by 0.25mg
boluses;
for pruritus – dose 5-10
mg every 3 hours
How Do Pain Treatments Work
What do we use???
Pre-emptive analgesia
 It is thought that preventing pain prevents
the excitability of the sympathetic nervous
system (flight or flight) that we now know
leads to subsequent functional changes to
the nerves….
this all leads to a reduced analgesic need.
 What we can use…non-opioid analgesics,
COX-2 inhibitors, nerve blocks, etc.
Pain intensity & management
Pain Intensity
Mild
Moderate to
severe
Pain management
Surgery examples
COX-2 inhibitors (pre and
postop)
Local anesthesia infiltration
Single injection blocks
Oxycodone, hydrocondone
PRN
Carpal tunnel release
Hardware removal
COX-2 inhibitors (pre and
postop)
Intraarticular local anesthetic
infiltration
Continuous nerve blocks
PCA opioids x 24 hours
Oxycodone PRN and prior to
physical therapy
Total joint replacement
long-bone fracture
ORIF
ACL repair
Pain intensity & management
Pain Intensity
Severe
Pain management
PREOP
COX-2 inhibitors
(pre and postop)
Preoperative clonidine
Intra-articular local
anesthetic infiltration
Continuous nerve blocks
POSTOP
PCA opioids x 24 hours
Oxycodone PRN and
prior to physical tx
Surgery examples
Thoracic, open
heart surgery,
open abdominal
surgery
Pain Intensity
Severe
Pain management
Decrease the original opioid dose and
introduce an additional opioid at low
dose.
IV Acetaminophen (Tylenol)
NMDA antagonists: subanesthetic doses of
•
ketamine
•
nitrous oxide
•
methadone
•
tramadol
Muscle relaxants
Benzodiazepines
A Multimodal Approach
Simultaneous use of a
combination of ≥2
analgesics that act at
different sites within the
central and peripheral
nervous systems can be
used in an effort to:
Opioids1
Alpha-2 agonists1
Acetaminophen1
Anti-inflammatory
agents1
• Ketamine2
•
•
•
•
Ascending
input via
spinothalamic
tract
• Reduce pain
• Minimize opioid use and
related side effects
Descending
modulation
Dorsal
horn
Peripheral
nerve
Coxibs=cyclooxygenase inhibitors.
NE=norepinephrine.
NSAIDs=non-steroidal anti-inflammatory drugs.
• Local anesthetics
(epidural)1
• Opioids1,3
• Alpha-2 agonists3
• NMDA antagonists3
• Local
anesthetics
(peripheral
nerve block)1
• Local
anesthetics
(field block)1
Pain
• NSAIDs,
coxibs1
Peripheral
nociceptors
Local Anesthetics
 relieve pain by blocking the
sodium channels from within
the nerves, this blocks the
transmission of nociceptive
impulses from reaching the
dorsal horn of the
spinothalamic tract.
 LA can be given peripherally
and by neuraxial anesthesia
(epidural and spinal).
COX 1 Inhibitors
Diclofenac (Voltaren®,
Cataflam®)
Diflunisal (Dolobid®)
Etodolac (Lodine®)
Flurbiprofen (Ansaid®)
Naproxen (Anaprox®,
Naprosyn®)
Ibuprofen (Motrin® and
others)
Indomethacin (Indocin®)
Ketorolac (Toradol®)
Meclofenamate
(Meclomen®)
Mefenamic acid
(Ponstel®)
Meloxicam (Mobic®)
COX-2 Inhibitors
 Celecoxib
(Celebrex)
Valdecoxib (Bextra)
and
Rofecoxib (Vioxx)taken off market
NSAIDs
All NSAIDS have same
mechanism of action in common:
the principal effect is
inhibition of cyclooxygenase
resulting in the inhibition of
prostaglandin synthesis.
Certain effects may also be related to
altered synthesis of the four families
of eicosanoids.
NONOPIOID ANALGESICS
Also considered COX inhibitors
 Irreversibly inhibit thromboxane A2
(platelet aggregate stimulator and
vasoconstrictor)
 Examples include:
 Aspirin (acetylsalicylic acid)
also considered an
NSAID
 Tylenol (acetaminophen)
(nonacetylated salicylate)
Where COX
inhibitors
work
Block the
cyclooxygenase
pathway…
but arachidonic
acid already
formed
Steroids
Inhibits
inflammatory
response.
Steroidal antiinflammatory
effects are
more profound
than COX
inhibitors.
Corticosteroids - block Phospholipase A2
Opiates
Opiates are drugs built on same
structures as MSO4.
The synthetic opioids are not
structurally related to Morphine. i.e.:
Fentanyl, Meperidine
How do opioids work
Opioids relieve pain by
attaching to opioid
receptors dispersed
throughout the CNS
and other tissues.
Receptor stimulation
inhibits the
presynaptic release
and postsynaptic
response to
nociceptive NT's such
as acetylcholine and
substance P.
Dorsal Horn and Lamina II
 The dorsal horn is the principal site
of pain modulation for both
ascending and descending pathways.
 Opioid analgesics-3 major effects



Inhibit release of pain
neurotransmitters
Hyperpolarize postsynaptic neuron
making it less likely to fire an action
potential
Exerting an anti-hyperalgesia effect
on the afferent neuron

 the substantia gelatinosa, is
believed to play a major role in
modulating nociceptive input and is
the major site of action of opioids.
Opioid receptors
Receptor
Mu-1
μ
Agonist
Morphine
synthetic opioids
(Fentanyl, etc.),
phenylpiperidin,
endorphine
Works by
Opioid
couples
to K+.
Conductance
Receptor
activation,
inhibits NT
release &
Hyper
polarizes
Cell
membrane
Major
action
Analgesia
(supraspinal
:
Brain- in
limbic
system,
hypothalams,
and
thalamus);
Euphoria,
well-being
Side effects
Sedation,
Respiratory
depression,
miosis,
bradycardia,
pruritis,
Urinary
retention,
NAUSEA AND
VOMITING,
constipation,
bradycardia,
Diuretic
(suppresses
ADH)
Notes
Low-abuse
potential
Antagonist
Naloxone
Nalbuphine
Buprenorphine
Mu-2
μ
Morphine
synthetic opioids
(Fentanyl, etc.),
phenylpiperidine,
endorphins
Analgesia
(spinal);
Euphoria,
Respiratory
depression
Depression
of
ventilation,
Marked
constipation,
Diuretic
(suppresses
ADH), miosis
High risk of
Physical
dependence
Naloxone
Kappa
Κ
Dynorphin
Nalbuphine
Butorphanol
Pentazocine
Inhibits
Ca++
effect
Analgesia
(spinal &
supraspinal;
Dysphoria
sedation,
miosis,
Diuretic
(suppresses
ADH), miosis
Low-abuse
potential
Naloxone
Delta
δ
Enkephalins
Butorphanol
Pentazocine
Analgesia
(spinal &
supraspinal),
Antidepressant
effects
Depression of
ventilation,
some
constipation,
Urinary
retention
Physical
dependence
Naloxone
Little is know about
These receptors, not
an Opioid receptor.
Sigma
σ
Pentazocine
Action
unknown
Dysphoria,
delirium,
mydriansis,
hallucinations,
tachycardia,
hypertension
Effects of sigma
Receptor stimulation
include:
hypertonia (increased
muscle
tension)
tachycardia
tachypnea
mydriasis (pupil
dilation)
Euphoria or dysphoria
anti-depressant effect
Epsilon
ε
Endorphin
Decrease
Stress
response
do not
appear to
be related to
analgesia;
exact
role unknown
Pharmacologic adjuvants
 Antiepileptics:
Gabapentin, Valproate,
and Phenytoin
 Antidepressants:
Amitriptyline,
Desipramine, and
Nortriptyline
 Alpha-2 adrenergic
Agonists: Tizanidine
and Clonidine
 Benzodiazepines:
Diazepam, lorazepam,
and clonazepam
 Corticosteroids:
Prednisone and
Dexamethasone
Pharmacologic adjuvants
 NMDA receptor:
Dextromethorphan
and Ketamine
 Miscellaneous:
Baclofen and
Calcitonin
 Muscle
relaxants:
Cyclobenzaprine,
carisoprodol, and
methocarbamol
Consequences of inadequate
pain relief
The issue of postoperative pain is the
most distressing factor for most
patients going for surgery.
Patients have the right
to adequate analgesia.
References
Miller’s Anesthesia
Barash Clinical Anesthesia
Stoelting’s Anesthesia and Co-Existing Disease
Morgan, Mikhail, & Murray
Clinical Anesthesiology
 Evers & Maze Anesthetic Pharmacology

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The End