The emotional experience of pain is based on the individuals
subjective experience. Emotional pain is associated with ACTUAL or
POTENTIAL tissue damage
Slide 6
Situational, behavioral, and emotional factors all play a
role
Slide 7
Motivations Expectations all strongly modify nociceptive
input
Slide 8
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.
Slide 9
Pain is whatever the person says it is!
Slide 10
4 PHYSIOLOGIC PROCESSES IN SENSORY PAIN 1.Transduction
2.Transmission 3.Interpretation/Perception 4.Modulation
Slide 11
Lets review this process quickly.
Slide 12
First order neuron: brings pain information to the CNS via the
nociceptors to the dorsal horn of the spinal cord
Slide 13
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).
Slide 14
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.
Slide 15
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.
Slide 16
Transduction peripheral nociceptors carry pain towards spinal
cord.
Slide 17
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
Slide 18
2. Transmission First order neuron
Slide 19
First order neurons arrive in the dorsal horn the first six
Rexed laminae --- and to the substantia gelatinosa
Slide 20
Neurotransmitters endogenous chemicals carried from a pre- to
post-synaptic receptor across the synapse.
Slide 21
2 excitatory neurotransmitters (NT)
Slide 22
Other excitatory NT besides glutamate and substance P Histamine
Prostaglandin Bradykinin Potassium Hydrogen Serotonin Acetylcholine
Norepinephrine
Slide 23
Transmission After picking up the NT at the 1 st 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)
Slide 24
Slide 25
After synapsing with the 2nd order neurons of the STT Third
order neurons travel to the thalamus and other key areas of the
brain
Slide 26
Slide 27
From the STT, the impulse goes to raphe nuclei, reticular
system, and periaqueductal gray matter of the brain
Slide 28
and from there, pain neuro- transmitter messages project out to
the cerebral cortex. 3. INTERPRETATION AND PERCEPTION
Slide 29
Modulation Modulation of pain occurs in.. supraspinal
structures and in the spinal cord
Slide 30
Modulation MEDULLA/MIDBRAIN produce ENDOGENOUS OPIOIDS and
INHIBITORY NEUROTRANSMITTERS which travel down the descending
pathways
Slide 31
Modulation Endogenous opioids aka Endorphins, beta- endorphin,
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.
Slide 32
Modulation Remember back to excitatory NT Inhibitory NT are
released in the same way and block the tendency of that neuron to
fire.
Slide 33
Examples of inhibitory NT serotonin, norepinephrine, dopamine,
glycine, enkephalin, and galanin, somatostatin, and gamma-
aminobutyric acid (GABA); acetylcholine, is an inhibitory NT but it
is also an excitatory NTdepending on the stimulus.
Slide 34
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
Slide 35
The first-order neuron travels ____ and to_____? Peripheral
nociceptors to the dorsal horn of the spinal cord
Slide 36
The dorsal horn of the spinal cord gray matter is made up of?
a. the first six Rexed lamina b. Lissauers 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.
Slide 37
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
Slide 38
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 second- order
neuron begins its path d. the area of the spinal cord where the
first- order neuron begins its path a. play a role in nociceptive
input
Slide 39
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)
Slide 40
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.
Slide 41
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.
Slide 42
WHAT HAPPENS IN THE BODY WITH PAIN Neuroendocrine
catecholamines cortisol angiotensin II ADH aldosterone
adrenocorticotropic hormone growth hormone glucagon lower levels of
insulin
Slide 43
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 GI pain-induced hyperactivity may cause inhibition of GI
postoperative ileus, nausea and vomiting GU reflex inhibition of
visceral smooth muscle urine retention
Slide 46
Pain Coagulation platelet adhesiveness fibrinolysis Decreased
immune function
Slide 47
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
Slide 48
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.
Slide 49
When we talk about pain transmission, we must also talk about
the inflammatory response. Inflammatory response
Slide 50
INFLAMMATION is a part of the pain response The inflammatory
effects can be greater in magnitude than the initial injury.
Slide 51
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)
Slide 52
Inflammation: Eicosanoids prostaglandins, prostacyclins,
thromboxanes and leukotrienes TThese eicosanoids are ligands that
bind to the cell surface; they exert complex control mainly in
inflammation, and as messengers in the central nervous system.
Slide 53
Cyclooxygenase Pathway Naturally occurring mediators of
inflammation AND PAIN!
Slide 54
Arachidonic acid is converted by cyclooxygenase compounds to
synthesize specific eicosanoids - - - prostaglandins,
prostacyclins, & thromboxane
Slide 55
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 non- steroidal anti-inflammatory drugs (NSAIDs) and
non-opioid analgesics
Slide 56
Slide 57
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
Slide 58
The inhibition of COX I is undesirable.
Slide 59
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 inhibitedbleeding *hypertension, salt and water
retention, hyperkalemia can occur
Slide 60
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.
Slide 61
Because COX II is only present at inflammation then. The
inhibition of COX II is desirable.
Slide 62
Inhibition of COX II COX II enzyme is located in areas involved
in inflammationa COX II blocker inhibits generation of
prostaglandins thereby inhibiting inflammation, pain, and fever..
CCOX II is not located in the stomach. and there are fewer GI
complications.
Slide 63
Understanding pain and how drugs work Receptor-Ligand
Interaction Drugs affect receptor sites in two ways -
Slide 64
Affinity the ability of a drug to bind to a receptor
Slide 65
Efficacy .the capacity of a drug to produce an effect.
Slide 66
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
Slide 67
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.
Slide 68
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.
Slide 69
Antagonist Antagonists have affinity for a receptor But no
efficacy!!
Slide 70
Mixed agonist-antagonist DRUG UseReceptorsNotes 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. OR dose 3mg/kg followed by 0.25mg boluses; for
pruritus dose 5-10 mg every 3 hours 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.
Slide 71
How Do Pain Treatments Work What do we use???
Slide 72
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 usenon-opioid analgesics, COX-2 inhibitors, nerve blocks,
etc.
Slide 73
Pain intensity & management Pain IntensityPain
managementSurgery examples Mild COX-2 inhibitors (pre and postop)
Local anesthesia infiltration Single injection blocks Oxycodone,
hydrocondone PRN Carpal tunnel release Hardware removal Moderate to
severe 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
Slide 74
Pain intensity & management Pain IntensityPain management
Surgery examples Severe 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 Thoracic, open heart
surgery, open abdominal surgery
Slide 75
Pain IntensityPain management Severe 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
Slide 76
Coxibs=cyclooxygenase inhibitors. NE=norepinephrine.
NSAIDs=non-steroidal anti-inflammatory drugs. Peripheral
nociceptors Descending modulation Ascending input via spinothalamic
tract Peripheral nerve Dorsal horn Opioids 1 Alpha-2 agonists 1
Acetaminophen 1 Anti-inflammatory agents 1 Ketamine 2 Opioids 1
Alpha-2 agonists 1 Acetaminophen 1 Anti-inflammatory agents 1
Ketamine 2 Local anesthetics (peripheral nerve block) 1 Local
anesthetics (peripheral nerve block) 1 Pain Local anesthetics
(epidural) 1 Opioids 1,3 Alpha-2 agonists 3 NMDA antagonists 3
Local anesthetics (epidural) 1 Opioids 1,3 Alpha-2 agonists 3 NMDA
antagonists 3 Local anesthetics (field block) 1 NSAIDs, coxibs 1
Local anesthetics (field block) 1 NSAIDs, coxibs 1 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: Reduce pain Minimize opioid use and related side effects
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: Reduce pain Minimize opioid use and
related side effects A Multimodal Approach
Slide 77
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-2 Inhibitors Celecoxib (Celebrex) Valdecoxib (Bextra) and
Rofecoxib (Vioxx)- taken off market
Slide 80
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.
Slide 81
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)
Slide 82
Where COX inhibitors work Block the cyclooxygenase pathway but
arachidonic acid already formed
Slide 83
Steroids Inhibits inflammatory response. Steroidal anti-
inflammatory effects are more profound than COX inhibitors.
Corticosteroids - block Phospholipase A2
Slide 84
Opiates Opiates are drugs built on same structures as MSO4. The
synthetic opioids are not structurally related to Morphine. i.e.:
Fentanyl, Meperidine
Slide 85
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.
Slide 86
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.
Delta Enkephalins Butorphanol Pentazocine Analgesia (spinal
& supraspinal), Antidepressant effects Depression of
ventilation, some constipation, Urinary retention Physical
dependence Naloxone
Slide 91
Sigma Pentazocine Action unknown Dysphoria, delirium,
mydriansis, hallucinations, tachycardia, hypertension Little is
know about These receptors, not an Opioid receptor. Effects of
sigma Receptor stimulation include: hypertonia (increased muscle
tension) tachycardia tachypnea mydriasis (pupil dilation) Euphoria
or dysphoria anti-depressant effect
Slide 92
Epsilon Endorphin Decrease Stress response do not appear to be
related to analgesia; exact role unknown
Slide 93
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
Slide 94
Pharmacologic adjuvants NMDA receptor: Dextromethorphan and
Ketamine Miscellaneous: Baclofen and Calcitonin Muscle relaxants:
Cyclobenzaprine, carisoprodol, and methocarbamol
Slide 95
Consequences of inadequate pain relief The issue of
postoperative pain is the most distressing factor for most patients
going for surgery.