Pain Cpc Kuma

Front 1

Ascending Pain Pathway: Overview

Back 1

Stimulation of nociceptors causes release of substance P and/or glutamate in the dorsal horns
This activates neurons in the ascending spinothalamic tract (AST)
The AST projects primarily to the reticular formation and periaqueductal grey (PAG; dull pain) or to the PAG to thalamus to somatosensory cortex (sharp pain)

Front 2

Pain Modulation.

Back 2

The endogenous opioid system is very important in the modulation of pain.

Front 3

The Modulation of Pain Occurs in Two Ways:

Back 3

Raising the threshold for pain perception
Increasing the tolerance for pain perception

Front 4

Raising the threshold for pain perception

Back 4

Descending pain pathway
Signals from higher brain centers intercept and modulate incoming nociceptive signals at the level dorsal horns via opioid activity (the Descending Pain Pathway)
Pain signals sent to the brain are diminished
Peripheral nerve endings
Immunocytes release opioids to modulate reactivity of nociceptors

Front 5

There are two components to the perception of pain:

Back 5

1. Sensory (nociception)
•Pain occurs via stimulation of pain receptors
•Pain sensations are transmitted via the Ascending Pain Pathway
•
Pain perception is modulated via the Descending Pain Pathway and directly at peripheral pain receptors
2. Psychological (“affective”)
•Related to a person’s state of mind
•Modulated by many intrinsic and extrinsic factors

Front 6

Increasing the pain threshold via the Descending Pain Pathway

Front 7

Increasing the pain threshold via the Descending Pain Pathway

Back 7

Front 8

Summary of the Descending Pain Pathway

Back 8

The perception of pain causes higher brain centers to stimulate the release of enkephalon in the spinal horns to diminish the activity of incoming nociceptive signals

Front 9

Nociception

Back 9

Nociception is the sensory perception of pain. It occurs through pain receptors known as “nociceptors”.
•
Nociceptors are free nerve endings

Front 10

Nociceptors fall into three main classes that correspond to:

Front 11

There are two primary neurotransmitters released from nociceptive fibers in the dorsal horn:

Back 11

1.Substance P

Front 12

The modulation of pain occurs in two ways:

Back 12

1. Pain modulation by raising the threshold for pain perception (neurochemical modulation)
•Involves the sensation of pain
•Two areas of modulation:

1. Raising the threshold for pain via modulation of the Descending pain pathway

Front 13

Pain modulation by increasing the tolerance for pain (“psychological” modulation)

Back 13

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Pain is still perceived, but the individual is less concerned by it
•
This is the affective component of pain that occurs in higher brain centers
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Pain tolerance is greatly affected by individual temperament (cognitive and emotional disposition), environmental setting, and other factors, for example, anxiety tends to intensify pain
•
Pain tolerance is modulated by higher brain centers and includes endogenous opioid activity, for example, β-endorphin modulates anxiety in the amygdala

Front 14

Increasing the pain threshold via the modulation of peripheral sensory nerves

Back 14

decreasing overall pain sensation
circulating leukocytes are attracted to injured area and cause release of opioids not Ca dependent

Front 15

Increasing the tolerance for pain perception

Back 15

Pain is still perceived, but the individual is less concerned by it
This is the affective component of pain that occurs in higher brain centers

Front 16

Affective Component of Pain Modulation: Increasing the Tolerance for Pain

Back 16

Pain tolerance is greatly affected by individual temperament (cognitive and emotional disposition), environmental setting, and other factors
For example, anxiety can intensify pain
Pain tolerance is modulated by higher brain centers and includes endogenous opioid activity
For example, B-endorphin modulates activity in the amygdala, a structure important in fear and anxiety

Front 17

Summary of the Pain System:

Back 17

Sensory component of pain
Transmission through the Ascending Pain Pathway (nociception  dorsal horns  spinothalamic tract  brain)
Modulation through opioid receptors in the Descending Pain Pathway
Raising threshold for pain
Modulation through opioid receptors on Peripheral Nociceptors
Raising threshold for pain
Affective component of pain
Modulation through opioid receptors in higher brain centers
Raising tolerance for pain

Front 18

The endogenous opioid system is the main mechanism through which pain is modulated

Back 18

Opioids modulate pain in the brain (increase pain tolerance), in the spinal cord (decrease pain perception), and at sensory nerve endings (decrease pain perception).

Front 19

OPIOID DRUGS

Back 19

Among pain relief medications, opioids are unique in that they act on both the sensory and affective components of pain. As such, opioid drugs inhibit incoming nociceptive signals at the level of the spinal cord to modulate the sensory component of pain and they also can act at higher brain centers to modulate the affective component of pain

Opioid drugs “take advantage” of the endogenous opioid system to relieve pain.

Front 20

There are three broad classes of opioid drugs:

Front 21

Systemic or local administration of opioid drugs

Back 21

inhibits incoming nociceptive signals (raising the threshold for pain).

Front 22

Systemically administered opioid drugs act at

Back 22

higher brain centers (e.g., the amygdala) to modulate the affective component of pain (increasing the tolerance for pain).

Front 23

Opioid drugs fall into two main structural groups:

Back 23

Morphine analogues
*May be agonists, partial agonists, or antagonists

Synthetic derivatives with structures unrelated to morphine
*May be agonists or partial agonists

Front 24

Opiate drugs
Pure agonists

Back 24

Morphine, codeine, oxymorphone, dextropropoxyphene, oxycodone

Methadone

Pethidine
Etorphine, bremazocine

Fentanyl, sufentanil

Front 25

Partial/mixed agonists

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Pentazocine, ketocyclazocine
Nalbuphine
Nalophine
Buprenorphine

Front 26

opioid Antagonists

Back 26

Naloxone
Naltrexene, diprenorphine

Front 27

Endogenous peptides

Back 27

β-endorphin
Leu-enkephalin
Met-enkephalin
Dynorphin

Front 28

Pharmacologic actions of opioid agonists and partial agonists

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Opioid agonists and partial agonists have a wide variety of effects, both in the central nervous system and in the periphery. The specific effects of any individual drug are due to such factors as opioid receptor binding profile, distribution, and metabolism.

Front 29

Neuronal activity
central effects of opioids

Back 29

•Reduction in neuronal firing
•Inhibition of neurotransmitter release

Front 30

Major Central Effects
analgesia

Back 30

Increase in pain tolerance
*Awareness or concern of pain is reduced
*Pain is no longer all-consuming
*Dependent on many factors (individual temperament, setting, etc.)

Increase in pain threshold
*Indirect stimulation of serotonin and norepinephrine neurons (PAG, locus coeruleus, Raphe nucleus)
*Inhibition of substance P release in axon terminals of nociceptive fibers entering the dorsal horn

decreasing pain signals getting to the brain

Front 31

Major Central Effects
respiratory depression

Back 31

•Inhibition of brain stem respiratory centers
•Depressed response to PCO2 leading to depressed respiration rate
•Slight rise in PCO2 due to decreased respiration rate (this causes cerebral vasodilation which leads to increased CSF pressure; this effect is more pronounced in the presence of head injury)
•May not be tolerated in individuals with any kind of respiratory impairment
•This effect is not separable from analgesic effects
•The effect is additive with other CNS depressants (alcohol, barbiturates, benzodiazepines)
•HIGH DOSES OF OPIOID AGONISTS, ESPECIALLY IN COMBINATION WITH OTHER CNS DEPRESSANTS MAY LEAD TO DEATH DUE TO RESPIRATORY FAILURE!

Front 32

what happens to the body's response to CO2 when taking opioids

Back 32

the bady becomes less sensitive so respiration decreases

Front 33

Major Central Effects
mood changes

Back 33

•The majority of users experience euphoria (relaxed, dreamy, floating sensation; freedom from anxiety or stress)
•A minority experience dysphoria (apprehension, anxiety, malaise)

Front 34

Major Central Effects
Sedation

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•Drowsiness, fogginess
•Sleep is frequently induced in the elderly
•Degree of sedation varies among the drugs
•Normally, the patient is easily aroused
•The effect is additive (possibly synergistic) with other CNS depressants

Front 35

central effects of opioids
excitation

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Excitation occurs in some other species (cats, horses, cows, pigs) and in some humans at low doses

Front 36

central effects of opioids miosis

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Pupil constriction
Very little tolerance develops to this effect

Front 37

central effects of opioids
N/V

Front 38

central effects of opioids
antitussive

Back 38

(prevention of cough reflex)

Front 39

central effects of opioids
endocrine

Front 40

central effects of opioids
thermoregulation

Back 40

Inhibition of hypothalamic thermoregulatory mechanisms
Ability to maintain constant temperature is impaired
Body temperature is dependent on ambient temperature

Front 41

central effects of opioids
sleep

Back 41

Disruption of Rapid Eye Movement (REM) sleep

not getting quality sleep

Front 42

peripheral effects of opioids
histamine release

Back 42

•Increased release of histamine from mast cells (this effect is unrelated to opioid receptors)
•Causes arterial and venous dilatation
•Can potentially cause hypotension, cutaneous flushing, and loss of body heat

like an allergic reaction, but not a true one just sensitive to this SE

Front 43

peripheral effects of opioids
GI effects

Back 43

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Contraction of biliary sphincter (may cause increased pain in patients with GI distress)
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Contraction of bladder sphincter (may cause painful urine retention)
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Increased tone of GI tracts, biliary tracts, ureter
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Reduced peristaltic movement causing delayed fecal passage and increased water absorption from large intestine (constipation)

Front 44

peripheral effects of opioids
cardaic affects

Back 44

Mild bradycardia (slowing of pulse)

Decrease in blood pressure due to pain relief

Front 45

PO advantages (opioids)

Back 45

Prolonged and smooth effect
Avoidance of discomfort of injection
Well absorbed from GI tract
May be easily administered by patient

Front 46

PO disadvantages (opioids)

Back 46

Potency of some drugs may be reduced due to first pass metabolism in liver; drugs with free hydroxyl group undergo conjugation with glucoronic acid, for example, morphine
Slow onset of action (up to or over 30 minutes)
GI discomfort

Front 47

Subcutaneous or intramuscular
(opioids) advantages and disadvantages

Back 47

Advantages
*Rapid onset of action (5-15 minutes)
*No reduction in potency due to first pass metabolism
Disadvantages
*Requires discomfort of injection
*May be difficult for patient to self-administer
*Increased risk of infection

Front 48

IV (opioids) advantages and disadvantages

Back 48

Advantages
Almost instant onset of action
No reduction in potency due to first pass metabolism
Disadvantages
Requires discomfort of IV catheter
May be difficult for patient to self-administer
Increased risk of infection
Very sudden onset

Front 49

Epidural/intrathecal
(opioids) advantages

Back 49

Direct injection into the spinal epidural or subarachnoid space
Mixtures of opioids/local anesthetics may be used
Advantages
Localized effect (not systemic)
Less respiratory depression and nausea

Front 50

Epidural/intrathecal
(opioids) disadvantages

Back 50

A small percentage of patients still suffer nausea and/or respiratory depression
“Low pressure” headaches can occur if the dura mater is punctured
Certain types of pain are unresponsive
Increased risk of spinal cord damage, infection

Front 51

Patient controlled analgesia (PCA) advantages for opioids

Back 51

IV, subcutaneous, epidural routes are available
Provides patient maximal control over analgesia
Pre-set “lockout” time to prevent overdose
Possibly reduced side effects
Simple to use
Patient feels more in control

Front 52

Percutaneous admin for opioids

Back 52

Transdermal patches for sustained analgesia (fentanyl; 3 days)
Should not be used immediately following surgery due to respiratory depression associated with its use
Very slow onset of action, so oral drugs may be needed initially
Works well for our four-legged friends

Front 53

nasal spray for opioids

Back 53

Rapid onset of action
Increased bioavailability (no first pass effect)
Very convenient

Front 54

Absorption of opioid drugs

Back 54

Most are well absorbed from GI tract
Serum protein binding varies from drug to drug (30-85% bound) probably contributing to half-life differences
Many of the drugs undergo first-pass metabolism decreasing bioavailability
Duration of analgesic action ranges from 1-6+ hours

Front 55

Distribution of opiod drugs

Front 56

• Metabolism of opioid drugs

Front 57

Local vs. Systemic Administration of opioids

Back 57

Local (e.g., epidural)
Requires an injection
Source of pain must be localized and known
Do not get benefit of affective effects
Avoids some side effects
Systemic (e.g., IV, oral)
Increased side effects
Does not always have to be injected
Do get benefits of affective effects

Front 58

kidney impairment and morphine

Back 58

typically 90% of the active metabolites of morphine (morphine-6-glucuronide and morphine-3-glucoronice) are renally eliminated

therefore when a patient has renal impairment the active metabolites accumulated and enter the CNS

Front 59

Tolerance to Opioid Drugs

Back 59

Tolerance: reduced effect to equivalent dose
Degree of tolerance depends on drug and response being measured
Time course:
Rapid (2-3 weeks or less): analgesia
Slow (>2-3 weeks): respiratory depression, nausea
Not at all: miosis, constipation

Front 60

Time course of tolerance in opioids

Front 61

how can tolerance be minimized with opioids

Back 61

minimized with smaller doses and longer dosing interval

Front 62

is opioid tolerance functional or metabolic

Back 62

functional: so the receptors are being altered

It is not the drug being metabolized more

Front 63

is there cross tolerace with opioids

Back 63

Cross-tolerance develops with all opioid agonists (but not antagonists)

Front 64

Physical dependence of opioids

Back 64

Prolonged use produces abstinence or withdrawal syndrome:
Sleeplessness, tremor, irritability, hallucinations, seizures
Severity is dependent on specific drug and duration of exposure
Drugs with a slow elimination produce less severe withdrawal than drugs that act quickly, intensely, and briefly (for example, methadone vs. heroin)
Typical time course: 2-3 weeks of consistent use

Front 65

Psychological dependence of opioids

Front 66

Morphine

Back 66

Agonist; high affinity for u receptor
Routes of administration: oral, IM, IV, subcutaneous, epidural, suppository
High abuse potential
Reduced oral bioavailability (because of glucaronidation)

Front 67

clinical uses of morphine

Back 67

Analgesia (moderate to severe and chronic pain)
Preoperative sedation
Myocardial infarction
Pulmonary edema
Abdominal surgical or cancer patients (epidural)

Front 68

Morphine has some adverse effects and contraindications and so should not be used in individuals with:

Front 69

morpine contraindications

Back 69

Hypersensitivity reactions
Respiratory depression
Cranium injuries, raised intracranial pressure
Compromised renal function

Front 70

codeine

Back 70

Agonist; morphine analogue
Less potent than morphine
Typically administered orally
Excellent bioavailability
Clinical uses:
Mild to moderate pain
Antitussive
Side effects:
Very sedating at analgesic doses

one less OH group makes it more bioavaiable

Front 71

Morphine has a reduced oral bioavailabilty due to _____________and an active metabolite ______________ during chronic administration.

Back 71

first pass metabolism (glucuronidation

morphine-6-glucuronide) that accumulates

Front 72

Codeine

Back 72

is a morphine analogue and agonist, but is somewhat less potent than morphine, so it is used primarily for analgesia when the pain is mild to moderate. It is also used as an antitussive. Codeine has few side effects at low antitussive doses, but at analgesic doses it can be quite sedating. It has excellent oral bioavailability and so is typically administered orally. In addition, it produces little euphoria, so the abuse potential is low. It is commonly used in combination with nonopioid analgesics, for example, acetaminophen.

Front 73

meperidine

Back 73

Agonist; phenylpiperidine
Little antitussive activity or constipative effects
Administered orally (reduced bioavailability), IM, subcutaneous
Clinical uses:
Analgesia for pulmonary patients and cancer patients
Side effects:
Tachycardia, blurred vision, dry mouth
Metabolite (normeperidine) is proconvulsant and hallucinogenic (should not be used in patients with compromised renal or liver function)

Front 74

Fentanyl

Back 74

Agonist; piperidine
Very potent analgesic (80-100 times greater than morphine)
Administered transdermally or IV
Slow onset of action
Clinical uses:
Analgesia
Adjunct to anesthesia

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se FENTANYL

Back 75

Possible teratogenic effects
High incidence of SIDS
Bradycardia, hypotension

Front 76

SE meperidine

Back 76

Tachycardia, blurred vision, dry mouth
Metabolite (normeperidine) is proconvulsant and hallucinogenic (should not be used in patients with compromised renal or liver function)

Front 77

clinical uses of meperidine

Back 77

Analgesia for pulmonary patients and cancer patients

Front 78

Levorphanol

Back 78

Agonist; morphine analogue
Potent analgesic (5-7 times greater than morphine)
Less nausea than morphine

Front 79

Levorphanol clinical uses

Back 79

Preoperative anxiolytic
Adjunct to anesthesia

Front 80

Methadone

Back 80

Agonist; unique structure
Tolerance and physical dependence slower to develop than morphine
Longer duration and better oral bioavailability than morphine

Front 81

methadone clinical uses

Back 81

Replacement therapy in treatment of opioid dependence

Front 82

drug interacations and methadone

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Tricyclic antidepressants and benzodiazepines inhibit metabolism leading to increased accumulation, prolonged half-life, intensified effects