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Palliative Medicine (SB) > 7.6 (9.4) Opioid therapy: optimizing outcomes > Flashcards

7.6 (9.4) Opioid therapy: optimizing outcomes Flashcards

1
Q

What are three major categories of analgesics used to manage pain?

A

opioid analgesics

non opioid analgesics

adjuvant analgesics - primary action not pain relief (ie. TCA)

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2
Q

Opioids have complex pharmacology (i.e. inter-individual variability in response).

Name 4 systems, the interplay of which may explain pain as a complex neuropsychophysical problem.*

A
  1. pain pathways
  2. endogenous and exogenous opioid systems
  3. inherent neuroplasticity
  4. individual susceptibility to adverse effects
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3
Q

Explain the difference between the terms opiate, opioid, and narcotic

A
  1. Opiate: drugs extracted from opium poppy (i.e. morphine, heroin, codeine)
  2. Opioid: natural/semi-/synthetic drugs, all of which bind to opioid receptors (can be angonists/antagonists)
  3. Narcotic: imprecise term to describe morphine like drugs. Avoid using as relation to drug use implies prejorative intent
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4
Q

What are the 4 main opioid receptors and their endogenous ligands?

A

Mu (OP3) - beta endorphin, leu and met encephalin, endomorphins

Delta (OP2) - beta endorphin, encephalins

Kappa (OP1) - dynorphins

Orphan (Nociceptin orphanin FQ receptor - ORL-1) - Nociceptin

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5
Q

Once activated, opioid receptors inhibit which 3 excitatory NTs that play are role in pain perception/feelings of well being?

A
  1. Substance P
  2. serotonin
  3. catecholamine (eg dopamine, noradrenaline, adrenaline)
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6
Q

A) Name 2 chemical methods by which opioid receptors inhibit pain pathways

B) What happens to these pathways with opioid abstinence?

A

A) 1. Inhibition of a common enzyme: adenylate cyclase

  1. Activation of cellular potassium pump

B) Excessive rebound activity

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7
Q

List 5 central areas where mu opioid receptors (MORs) are located.

In the dorsal horn, where are most MORs located?

What are peripheral MORs important in the response to?

A

Central areas - pre- and post synpatic neurons in the spinal cord, periaqueductal grey (midbrain), nucleus raphe magnus (medulla), thalamus , cortex

70% MORs expressed on primary afferent terminations (presynaptic) modulating afferent transmission

Response to inflammation

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8
Q

Name 3 recognized opioid receptors and their:
a) molecular classification
b) subtypes*
c) endogenous ligands
d) site of action

Note: considerable overlap between the 3 and all mediate analgesia

A
  1. MOR (mu opioid receptor):
    a) OP3
    b) u1, u2
    c) beta-endorphine, leu- and met- enkephalin, endomorphins
    d) peripheral inflammation, pre- & postsynaptic neurons in spinal cord, periaqueductal grey, nucleus raphe magnus, thalamus, cortex
  2. DOR (delta opioid receptor):
    a) OP2
    b) δ1, δ2
    c) beta-endorphin, enkephalins
    d) olfactory centres, motor integration areas in cortex, some in nociception areas
  3. KOR (kappa opioid receptor):
    a) OP1
    b) k1, k2, k3
    c) dynorphins
    d) spinal cord, supraspinal, hypothalamus
  4. Orphan (not a true opioid receptor):
    a) ORL-1 (opioid like receptor)
    b) ?none that i could find
    c) nociceptin
    d) spinal cord
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9
Q
  1. Which is the main type of opioid receptor responsible for inhibition of nociceptive pain pathways?
  2. Name 6 other opioid effects mediated through this receptor
  3. What happens if this receptor is stimulated in absence of pain?
A
  1. MOR family
  2. Psychoactive, respiratory depression, constipation, nausea/vomiting, sedation, reward/euphoria, and dependence/withdrawal
  3. Feelings of euphoria/serenity (due to MOR’s cross reaction with dopamine and GABA n.t. systems)
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10
Q

Describe how cross-affinity for opioid receptors differs between endogenous and exogenous opioid ligands.

A
  1. Endogenous ligands for MOR (beta-endorphin), DOR (methionine-enkephalin) and KOR (dynorphin) have significant cross affinity for the other receptors
  2. Morphine and morphine-like exogenous opioids have greatest affinity for MOR. Can bind to other receptors to lesser degree
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11
Q

Name 1 mechanism (other than suppression of neuronal activity) by which opioids mediate analgesia

A
  1. Activate descending neural circuits which modulate nociception - (demonstrated in functional MRI studies)**
  2. Activation of immune cell opioid receptors leading to secretion of endogenous opioid peptides –> activate neuronal opioid receptors –> alleviate pain
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12
Q
  1. Define pain.
  2. What area of the brain plays an important role in nociception and pain perception ?
A
  1. International Association for the study of pain defines it as:
    An unpleasant sensory or emotional experience associated with actual or potential tissue damage
  2. Insular cortex
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13
Q

Which regions of the brain play a role in the “affective” aspect of pain?*

How do activations in these areas respond to opioids?*

A
  1. Amygdala
    Anterior insula
    Cingulate cortices
  2. Per fMRI, they are maximally suppressed at lowest opioid doses, (i.e. directly influencing emotional responses at low doses that do not alter sensory aspects of pain)

.

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14
Q

List 2 phenomena each, mediated by MOR, DOR, and KOR in opioid related reward pathways*

A
  1. MOR:
    - reinforcement & reward (potential for addiction)
    - physical dependence
    - abstinence phenomena
  2. DOR:
    - convulsions
    - rewarding effects of other drugs of abuse
  3. KOR:
    - aversion and dysphoria
    - sedation
    - diuresis
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15
Q

Respiratory depression:

  • Which opioid receptor family
  • which 4 areas of the brain are involved
  • how
A

Activation of MORs in the cortex, thalamus, amygdala and brain stem (medulla and pons)

via inhibition of neurons in brainstem respiratory center

(peripherally, also in the carotid body to lesser extent)

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16
Q

List 2 opioid receptors and 1 area of the brain involved in opioid mediated sedation

A

MOR and KOR
activation in
hypothalamus + locus coeruleus

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17
Q

List the main opioid receptor and 2 nervous system mechanisms for opioid related constipation*

A
  1. Mostly mediated by MORs via:

i) Peripheral sensory neurons in the GI tract (acetylcholine and substance P blockade)

ii) spinal/supra-spinal receptors

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18
Q
  1. Which opioid receptor mediates nausea and vomiting?
  2. Name 4 locations where this takes place
A
  1. MORs
  2. medulla
    cortex
    vestibular apparatus
    (partially)GI tract 2/2 constipation
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19
Q
  1. Where are peripheral opioid receptors found?
  2. What is 1 advantage of targeting these receptors?
  3. What are 3 mechanisms that enhance analgesia mediated by peripheral opioid receptors?*
A
  1. On nociceptor peripheral terminals innervating peripheral tissues (skin, joint, viscera)
  2. They mediate analgesia but are not involved in side effects
  3. Inflammation at peripheral tissues results in:
    - more opioid receptor synthesis
    - perineural disruption (receptor access)
    - more immune cells with opioid pepties
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20
Q

Name 4 clinical phenomena that may involve opioid-induced neuroplasticity as an underlying mechanism

A
  1. Chronic pain
  2. Tolerance
  3. Hyperalgesia
  4. Addiction
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21
Q

List 1-2 possible changes to the brain’s response to opioids in CHRONIC PAIN

A
  1. Decreased opioid-receptor-binding over time
  2. Changes in reward circuitry
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22
Q

What are 1-2 broad mechanisms underlying the development of analgesic tolerance?

A
  1. altered molecular signalling pathways
  2. downregulation of opioid receptors
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23
Q

List 3 ways in which opioid induced hyperalgesia (OIH) is clinically distinguished from tolerance as both are associated with increased pain

A
  1. Distribution (generalized) and quality of pain differs from baseline pain
  2. Pain worsens with increased opioid doses
  3. Improvement following opioid dose reduction
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24
Q

Opioid induced hyperalgesia may be related to the excitatory effects of opioids. List 1 proposed mechanism (out of 5)

A
  1. NMDA receptor activation*
  2. spinal dynorphins stimulating KORs
  3. decreased inhibitory descending modulation of central pathways
  4. genetic variation in COMT
  5. activation of glial cells
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25
Q

What is the impact of DOR on analgesia?

Impact in DOR agonists when used with MOR agonist?

What opioid has prominent activity on DOR?

A

Linked to analgesic response and to Mu receptor activation (Potency of Mu agonists can be increased by administration of a delta agonist)

Involved in opioid tolerance at the receptor

methadone

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26
Q

What is the superfamily of receptors that opioid receptors belong to?

What type of chemical impact do they typically have on the post synaptic cell?

A

G-protein-coupled receptors (GPCRs)

increase opening of potassium channels -> hyperpolarization of post synapatic cell -> overall INHIBITORY effect

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27
Q

List 3 structure classes of opioids used clinically

(review with group: is this relevant?)

A
  1. phenanthrenes (i.e. morphine)
  2. phenylpiperidines (i.e. fentanyl)
  3. diphenylpropylamines (i.e. methadone) - phenylheptane
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28
Q

All opioids are weak bases and the ionized fraction (active) depends on its pka and plasma pH.

List 3 factors that influence amount of opioid diffusing to the site of action

A

lipid solubility / Vd/ half life

concentration gradient

degree of protein binding (diffusible fraction)

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29
Q

Opioids tend to have large Vd due to high lipid solubility.

  1. Define “context sensitive t1/2”
  2. How does it differ for opioids delivered as bolus dose vs. continuous infusion
A

1.Context sensitive t1/2 is the time taken for the plasma concentration to fall by 50% after an infusion has stopped

2.This is increased for most opioids after prolonged infusion (vs. bolus dose) due to sequestration in fat stores for highly lipid-soluble opioids

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30
Q
  1. Opioid receptor effectiveness depends on pharmacokinetics (ADME) of the administered drug as well as what four intrinsic elements of the receptor?*

(ADME = absorption, distribution, metabolism, excretion)

  1. Name 4 other factors that may influence opioid effectiveness*
A
  1. Transport proteins
    metabolizing enzymes
    opioid receptors
    second messenger molecules
    WP: MOST
  2. neurobiology of pain
    characteristics of pain networks
    plasticity of pain networks
    genomic differences of all above factors
    WP: Ch-Ne Pla-Gen ? God save our souls
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31
Q

What are 1-2 reasons pharmacological tolerance be difficult to clinically diagnose?

A
  1. Disease progression could be cause of declining analgesic effects
  2. Worsening pain can lead to reduction of side effects due to activating effects of pain itself (i.e. respiratory depression after nerve block)
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32
Q

List three processes that may contribute to tolerance to opioids at the cellular and molecular level*

A

cellular processes that occur in response to chronic ligand binding to mu receptors include:
- Diminution of spare opioid receptors
- decreased receptor density
- altered coupling
- activation and phosphorylation of G proteins
- altered downstream pathways
- induction and up-regulation of pro excitatory peptides (calcitonin-gene-related peptide, substance P, protein kinase c)

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33
Q

Describe how the majority of opioids are metabolized.

What is the major determinant of plasma clearance.

A

Most opioid metabolism happens in the liver via Phase 1 (cyp450) and Phase II reactions

hepatic function / blood flow is major determinant of plasma clearance (clears and metabolizes opioids )

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34
Q

List 2 endogenous opioid ligands with anti opioid actions

A

neuropeptide FF
cholecystokinin
nociceptin*
dynorphin*

WP: DyNo Cho FF :O

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35
Q

There is high variability in the response to opioids and side effects. In part this is likely genetically mediated as there are polymorphisms in drug metabolizing enzymes, drug transporters, opioid receptors or in the structures involved in the perception and processing of nociceptive information.

What are 2 possible candidates where genetic alterations may impact the response to opioids?

A

OPRM1 (mu opioid receptor)*
Morphine
M6G

CYP2D6 (cytochrome P450 2D6)*
Codeine
Tramadol

COMT (catechol-O-methyl transferase)
Morphine

MC1R (melanocortin-1 receptor)
Morphine
M6G
Pentazocine

P-glycoprotein
Morphine

ABCB1 (adenosine triphosphate-binding cassette subfamily B member 1)
Morphine

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36
Q

How does lipid solubility of an opioid impact its action

A

One of three things that impacts diffusible fraction (along with concentration gradient and degree of protein binding) which is the amount of opioid diffusing to the site of action

impacts volume of distribution

impacts context specific half time

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37
Q

List 3 opioids that are metabolized by glucuronidation (phase 2 metabolism)

A

morphine
hydromorphone
buprenorphine

(Less drug drug interaction compared opioids that undergo phase 1 metabolism involving CYP450 - tramadol, oxy, methadone, codeine, fentanyl)

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38
Q

List 3 opioids that are metabolized by N-dealkylation (phase 1 - CYP 3A4)

A

Buprenorphine
morphine
methadone
fentanyl

FS: TOM-F (tramadol, oxy, methadone, fentanyl)

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39
Q

List where an opioid is excreted (urine vs feces), how much of it, and in what time frame for the following:

morphine
codeine,
buprenorphine,
meperidine
methadone
fentanyl

which opioids excreted in stool? Especially which opioid?

A
  1. Morphine: 90% in 24 hours via urine
  2. Codeine: 86% in 24 hours via urine
  3. Meperidine: 70% in 24 hours via urine
  4. Methadone: 60% in 24 hours via urine, 30% via feces**
  5. Fentanyl: 70% in 4 days via urine, 9% via feces
  6. Buprenorphine: 2-13% in 7 days via urine. 70% unchanged via feces***

FS:
- buprenorphine excreted via feces mainly

  • morphine, codeine, meperidine majority metabolized in 24 hours (short half lives)
  • methadone 50%~ in 24 hours (assuming half life = 24h)
  • fentanyl and buprenorphine excretion takes much longer

methadone t1/2 = on average 24 hrs (range 13 to >100 hrs)

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40
Q

List the following opioids based on their degree of protein binding from least to most (codeine, morphine, oxycodone, fentanyl, methadone)

Ie most acidic/least protein binding/highest fraction -> most basic/highest protein binding/lowest fraction

A

codeine
morphine
oxycodone
fentanyl, methadone

(Table 7.6.4)

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41
Q
  1. What is an agonist?
  2. Define efficacy vs potency
A
  1. An agonist has affinity for and binds to a specific receptor.

Agonist opioids have no clinically relevant ceiling effect to analgesia (i.e. with dose increase, analgesia increases in log-linear function until analgesia or dose limiting side effects)

  1. Efficacy is MAX drug response induced by active agent in an ideal environment
  2. Potency is drug response relative to dose (dose response relationship)
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42
Q

Figure 7.6.4:

Does drug A or B have a greater efficacy? Does drug A or B have a greater potency? What two factors influence the potency of a drug

A

Drug A and B have the same efficacy (defined by maximum response)

Drug A is more potent than B because it achieves a maximal clinical response at a lower dose

Potency is influenced by pharmacokinetic factors (ie. how much drug enters the body’s circulation and then reaches receptors) and by affinity for drug receptors - FS: absorption and distribution

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43
Q

Pure antagonists have no intrinsic action but interfere with action of agonist.

What is the difference between a competitive and a non-competitive antagonist?

What are two opioid antagonists and two PAMORAs?

how do they impact the 3 opioid receptors?

How are they used in PC?

A

Competitive antagonists bind to the same receptor and compete for receptor sites

Non-competitive antagonists block the effects of the agonist in other ways

Naloxone (short acting)
naltrexone (long acting)

Methylnaltrexone (pamora - SC relistor)
Naloxegol (pamora - oral movantik)

block mu, delta, kappa receptors equally

generally only used to treat resp depression as they will reverse analgesia and tx of opioid induced constipation (PAMORAs)

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44
Q

A. What are the properties of buphrenorphine?

B. A patient is on regular moderate dose morphine. They are switched to buprenorphine. What is the risk of this? Why does this happen?

C. What is the risk if patient switched from buprenorphine to morphine?

A

A.
Partial agonist at MOR
+ antagonist at KOR/DOR

Note: Partial agonist has low intrinsic activity (efficacy) at this receptor (i.e. buprenorphine at MOR –> dose response curve has ceiling effect as less than max effect from full agonist) See Fig 7.6.5

B. They can precipitate withdrawal in patients who are physically dependent on morphine like drugs - as buprenorphine has more MOR affinity yet less efficacious than morphine

C. Analgesic of morphine could be blunted in patient switched from buprenorphine -> morphine as buprenorphine has longer half life and more MOR affinity

FS: buprenorphine has lower efficacy yet higher affinity and longer half life compared to morphine

45
Q

List 2 reasons the use of buprenorphine may be limited in management of pain in cancer?

What is its ceiling dose?

How can transdermal formulations expand its role in chronic pain?

A
  1. partial agonist at MOR (low efficacy) + may displace other mu agonists with higher efficacy but less affinity (eg morphine)
  2. Reported ceiling of > 8-16 mg in 24 hours
  3. Less risk of respiratory depression as partial MOR agonist

?Multiple patches can be used without approaching ceiling dose (below this act as full mu agonist, in linear part of dose response curve) Review with group. pg. 382

46
Q
  1. Name 2 mixed mechanism pain meds
  2. What is their evidence in managing cancer pain?
  3. Name one major (although rare) side effect of these drugs
A
  1. Tramadol and tapentadol - both are centrally acting mu agonists + monoamine (serotonin and NE) reuptake inhibitors
  2. No evidence they are superior to pure mu agonists for cancer pain
  3. Serotonin syndrome at high doses or with other monoaminergic drugs
47
Q

What is “relative potency” of opioids?

Conventionally what is it based on?

A
  1. Relative potency is the RATIO of two opioid DOSES required to produce the same analgesic effect
  2. Based on comparison to 10 mg of PO morphine
48
Q

List four factors that contribute to the variable efficacy of a drug in an individual patient

A

intensity of pain*
prior opioid exposure* in terms of dose, duration, drug
age*
route of administration
LOC
metabolic abnormalities
genetic polymorphism in experssion of relevant enzymes, receptor

FS: ADME *

49
Q

List the major active metabolities of the following opioids:
- morphine
- oxycodone
- hydromorphone
- methadone
- fentanyl

A 
morphine - M6G, M3G (major)
hydromorphone - H6G, H3G (major)
oxycodone - oxymorphone 
methadone - none
fentanyl - none

FS: M3G and H3G thought to cause OIN

50
Q

Which of the following opioids have lowest oral bioavailabilty: (name 3)

  • codeine
  • morphine
  • oxycodone
  • hydromorphone
  • methadone
  • fentanyl
A 
morphine 20-30%
hydromorphone 35-80%
oxycodone 60-90%
methadone 60-90%
fentanyl 25% (buccal) <2% (oral), 90% (transdermal)

FS: fentanyl, morphine and codeine have low bioavailability

51
Q

List the approximate half-lives (h) of the following opioid formulations:
1. sc morphine?
2. IR morphine?
3. SR morphine (BID dosing)?
4. SR morphine (once daily dosing)?
5. sc HM
6. IR HM
7. IR oxycodone
8. SR oxycodone
9. methadone?
10. codeine
11. sc/buccal fentanyl infusion?
12. fentanyl patch?

FS - summary slide - name time to peak, half life and duration of following opioids

IR PO
IR SC

SR BID
SR OD

Methadone

Fentanyl IV
Fentanyl patch

A

Half life in hours (Table 7.6.6) :
1. sc morphine: 2-3 hours
2. IR morphine: 2-3
3. SR morphine (BID dosing): 2-3
4. SR morphine (OD dosing): 2-3
5. sc HM: 2-3
6. IR HM: 2-3
7. IR oxycodone: 2-3
8. SR oxycodone: 2-3
9. methadone: 12 to >150
10. codeine: 2-3
11. sc/IV fentanyl infusion: 3-12
12. fentanyl patch: 13-22

FS - uptodate

IR PO opioids:
- time to peak - 1 hour
- half life - 2-4 hours
- duration - 3-5 hours

IR SC opioids:
- time to peak - 0.5- 1 hour
- half life - 2-4 hours
- duration - 3-5 hours

SR BID opioid:
- time to peak - 3-4 H
- half life - 8-15 H***
- duration - around 12 H

SR OD opioid:
- time to peak - 10 hour***
- half life - 11-13 hours
- duration - 24 hours

Methadone:
- time to peak - 1-2 hours
- half life - 8-60 hours
- duration - around 8 hours

Fentanyl IV:
- time to peak - 15 min
- half life - 2-4 hours***
- duration - 0.5-1 hour

Fentanyl patch:
- time to peak - 20-72 hours
- half life - around 24 hours
- duration - 72-96 hours

3 half lives -> increase dose
SA and IV F - up 3x per 24 hour (8h apart)
LA - up every 1.5 day (36h apart)
Patch F - up 72 hours apart

52
Q

List the approximate time to peak effect (h) of the following opioid formulations:
1. sc morphine?
2. IR morphine?
3. SR morphine (BID dosing)?
4. SR morphine (once daily dosing)?
5. sc HM
6. IR HM
7. IR oxycodone
8. SR oxycodone
9. methadone?
10. codeine
11. sc/buccal fentanyl
12. fentanyl patch

A

Peak effect in hours (Table 7.6.6):
1. sc morphine: 0.5-1 hours
2. IR morphine: 1.5-2
3. SR morphine (BID dosing): 3-4
4. SR morphine (OD dosing): 4-6
5. sc HM: 0.5-1
6. IR HM: 1-2
7. IR oxycodone: 1
8. SR oxycodone: 3-4
9. methadone: 0.5-1.5
10. codeine: 1.5-2
11. sc/IV fentanyl infusion: blank in table
(10-30 mins for SC as per UpToDate)
12. fentanyl patch: blank in table
(20-72 hrs as per UpToDate)

53
Q

List the approximate duration of analgesic effect (h) of the following opioid formulations:
1. sc morphine?
2. IR morphine
3. SR morphine (BID dosing)?
4. SR morphine (once daily dosing)?
5. sc HM
6. IR HM
7. IR oxycodone
8. SR oxycodone
9. methadone?
10. codeine
11. sc/IV fentanyl infusion
12. fentanyl patch?

A

Duration in hours (Table 7.6.6):
1. sc morphine: 3-6 hours
2. IR morphine: 4-7
3. SR morphine (BID dosing): 8-12
4. SR morphine (OD dosing): 24
5. sc HM: 3-4
6. IR HM: 3-4
7. IR oxycodone: 3-6
8. SR oxycodone: 8-12
9. methadone: 4-8
10. codeine: 3-6
11. sc/IV fentanyl infusion: -
12. fentanyl patch: 48-72

54
Q

Codeine is only minimally active at MOR receptor.

How does codeine act as an opioid?

What enzyme is responsible for this?

What are the genetic issues with this?

A

Codeine acts as an opioid by biotransformation to morphine (ie prodrug for morphine)

is metabolized to morphine by CYP2D6 (ie codeine is a substrate of CYP2D6)

Genetic polymorphisms of CYP2D6 exist - 7% of caucasians lack CYP2D6 activity due to inheritance of two non functional alleles - diminished analgesic activity

55
Q

List 3 reasons codeine is not preferred for the management of acute or chronic pain

(Side notes about codeine:
- aka methylmorphine
- naturally occuring opium alkaloid
- usual dose 30-60 mg
- duration 4-6 hours
- main metabolite codeine-6-G but clinically important one is morphine**

A
  1. lack of efficacy (miniminally effective at MOR) or due to genetic polymorphism in CYP2D6
  2. risk of toxicity in hypermetabolizers (greater than expected potency)
  3. variation in bioavailability (12-84%) –> uncertainty in dosing
56
Q

Why is tramadol described as a mixed action opioid agonist

A

posses opioid agonist properties (modest affinity for MOR and weak affinity for KOR, DOR), also inhibits reuptake of noradrenaline and serotonin which causes monoaminergic spinal inhibition of pain

57
Q

List 3 broad principles of the WHO analgesic ladder (as endorsed by 2019 evidence-based guidelines)

  • how to pick analgesics
  • how to pick adjuvants
  • non drugs
A
  1. INTENSITY of pain rather than stage of disease should determine analgesic selection
  2. Underlying ETIOLOGY and pain mechanism may direct to appropriate adjuvant drugs
  3. Any analgesic strategy should be integrated with NON-PHARM measures of cancer pain control (rads, chemo, surgery, hormone therapy, anesthesia, PT, psych/cog)
58
Q

Describe the 3 steps of the WHO ladder

A
  1. Mild pain - treat with non-opioid (+ adjuvant if specific indication exists)
  2. Moderate pain (or mild pain unresponsive to step 1) - treat with “opioids conventionally used for moderate pain” +/- adjuvant:
    -combination product
    - codeine/dihydrocodeine
    -low dose pure opioid agonist
    -partial agonist (buprenorphine)
    -mixed mechanism (tramadol)
  3. Severe pain or milder but not responsive to step 2:
    - treat with opioids “conventionally used for severe pain”
59
Q

**ask group if this card relevant
Discussed: IGNORE THIS CARD

  1. What is dihydrocodeine?
  2. List 3 indications for its use.
  3. How does it differ from codeine in its analgesic effect?
  4. How does it compare to codeine in potency via the oral route? parenteral route?
  5. What is the usual starting dose, frequency, and range of effective dosing.
  6. Name 1 uncommon but notable side effect.
A
  1. semi-synthetic analogue of codeine
  2. analgesic, antitussive, antidiarrhoeal
  3. It is not dependent on CYP2D6 activity:
    - has intrinsic analgesic effect
    - little role of dihydromorphine in analgesic effects
  4. PO route: equianalgesic to codeine
    poor oral bioavail- hepatic pre-systemicmetabolism

Parenteral: approx 2x as potent as codeine

  1. starting dose: 30 mg PO q4-6h
    May inc to 60 mg, but higher s/e at this dose (compared to codeine)
  2. Priaprism in patients also on alpha-1 blocker, trazadone, PDE-5 inhibitors etc.
60
Q
  1. What is the composition of morphine?
  2. List 2 compounds it is available as.*
  3. List 4 types of routes of administration.
A
  1. It is the main naturally-occuring alkaloid of opium (from poppy Papaver somniferum)

2.
SULPHATE
HYDROCHLORIDE
TARTATE (more soluble, so higher liquid conc. formulation possible)

  1. oral, rectal, parenteral, intraspinal
61
Q
  1. Where is morphine predominantly absorbed?
  2. What is the oral bioavailability of morphine? Why is this variable?
  3. What is the rectal bioavailabilty in comparison?
  4. Why is morphine an ideal opioid for epidural or intrathecal administration?
  5. What is the plasma half life of morphine with normal renal function?
  6. What are the pharmacokinetics of morphine with repetitive administration?
A
  1. in the upper small bowel
  2. 20-30% but highly variable due to extensive pre-systemic elimination in the liver
  3. Rectal bioavailability = to oral
  4. Relatively hydrophilic so not rapidly absorbed into systemic circulation - so long t 1/2 in CSF, ++ rostral redistribution
  5. plasma t 1/2 of 2-3 hours (somewhat shorter than duration of analgesia 4-6 h)
  6. linear (no autoinduction of biotransformation even following large chronic doses)
62
Q
  1. List the 2 major metabolites of morphine.
  2. List 3 minor metabolites (NB: ?is this important)
  3. What is the predominant site of metabolism? What are 2 other postulated sites of metabolism in animal models?
  4. What is the role of M3G in the pharmacodynamics of morphine?
  5. List 2 known effects of M6G
  6. How is M6G excretion related to renal function?
A
  1. 90% of morphine is converted into the 2 clinically important glucoronide conjugates M3G and M6G.
    (M3G>M6G)
  2. codeine
    normorphine
    morphine ethereal sulphate
  3. Mainly in liver
    - small bowel and proximal renal tubule
  4. No significant role of M3G. No evidence of:
    - functional antagonism of morphine by M3G
    - but can it mediate adverse effects (OIN) ***
  5. M6G binds to opioid receptors and produces potent opioid effects:
    - analgesia
    - toxicity (resp depression)
  6. M6G excretion by kidney is directly related to creatinine clearance.
    t 1/2 is 2-3 hours in normal renal function
    -progressively longer with deteriorating renal fxn
63
Q

A patient with renal insufficiency is placed on morphine. 7 days later they are admitted to the hospital with myoclonus and resp depression. What metabolite is the cause of each of these symptoms?

A

Morphine is metabolized into morphine-6-glucuronide (M6G) (active) and M3G (non-active). In patients with renal dysfunction M6G may accumulate in blood and CSF and high concentrations are associated with toxicity (myoclonus), resp depression (accumulation)

some evidence in animal models that M3G can cause excitatory effects such as myoclonus (not in 6th edition)

M3G - myoclonus / OIN
M6G - resp depression

64
Q
  1. What is chemical composition of heroin -available for legal medicinal use in the UK (and Canada?)
  2. What is its potency relative to morphine: i) orally ii) parenterally
A
  1. It is a semi-synthetic analogue of morphine
  2. i) oral heroin rapidly metabolized to morphine with no difference in potency

ii) parenterally heroine is more soluble and lipophilic therefore: faster onset and 2x as potent

65
Q

Why is meperidine not routinely used for the management of chronic cancer pain?

Why is the use of naloxone potentially dangerous when using meperdine?

A

meperidine is n-demethylated to norpethidine which is twice as potent as a convulsent and half as potent as an analgesic. accumulation of norpethidine can result in CNS excitability characterized by subtle mood effects, tremors, multifocal myoclonus, and seizures

when naloxone is given it does not reverse seizures and it could block the depressant action of meperidine allowing convulsent activity to manifest.

FS:
Basically meperidine is less potent and high risk of OIN

Naloxone can worsen OIN

66
Q

A patient is taking moclebemide (MAOi) and is given a dose of an opioid but cannot remember which. The patient suddenly develops a fever, becomes rigid and starts having a seizure. What opioid for moderate to severe pain might they have received?

A

meperidine/tramadol and MAOI are contraindicated as high risk of serotonin syndrome

67
Q
  1. What is the composition of oxycodone?
  2. What is its oral bioavailability?
  3. What is its analgesic potency relative to morphine?
  4. What is its active metabolite? How prevalent is this? What role does it play in oxycodone’s effects?
  5. List 2 combination products of oxycodone
A
  1. Semi-synthetic congener of morphine
  2. High oral bioavailability of 60-90%
  3. Analgesic potency 30-50% greater than morphine
  4. Oxymorphone
    10% of oxycodone’s metabolites
    Does not contribute significantly to pharm. effects
    (?what about toxicity - not mentioned in 6th edition)
  5. oxycodone with paracetamol or aspirin

oxycodone with naloxone (2:1) to reduce constipation

68
Q
  1. What is the composition of hydromorphone?
  2. What is its potency relative to morphine?
  3. List 4 available routes
  4. What is its oral bioavailability?
  5. What is its half-life?
  6. How is hydromorphone largely excreted?
A
  1. Semi-synthetic opioid derived from morphine
  2. About 5 times more potent than morphine
  3. Oral, rectal, parenteral, intraspinal
  4. Varies from 35%-80%
  5. T 1/2 = 1.5-3 hours
  6. Largely excreted unchanged by the kidneys
    but
    partically metabolized in liver to 3-glucoronide
    which is excreted by kidneys
    (what about H6G? - oxford says no active metabolites??)
69
Q

A patient is started on a fentanyl patch. They ask whether the location of the patch influences the uptake of the drug. What do you tell them?

What is the impact of age on absorption? What is the impact of temperature?

A

Neither age nor patch location appears to affect absorption from the transdermal system

Temperature-dependent increases in fentanyl absorption can occur, increased skin permeability with febrile patients, suggest monitoring

Fentanyl:
- semi-synthetic
- highly selective mu agonist
- 80x potent as parenteral morphine

70
Q

What is the major limitation for the use of mixed agonist-antagonist drugs in setting of chronic cancer pain?

A

ceiling effect

Can precipitate withdrawal in patients who are already on morphine like drugs.

71
Q
  1. How can methadone cause QTC prolongation
  2. List 3 risk factors that increase the chance of QTC prolongation in a patient on methadone
  3. List 3 drugs to exercise caution if co-prescribing methadone
A
  1. Through interaction with voltage-gated K+ channels on myocardium
  2. pre-existing heart failure
    hypomagenesemia
    co-admin of other QTC prolonging drugs
  3. haloperidol, olanzapine, ondansetron, tricyclic antidepressants, and citalopram.
72
Q
  1. How does advanced liver disease (Child Pugh C) impact methadone metabolism. How can you adjust for this?
  2. List 3 patient conditions/scenarios in which methadone therapy may NOT be appropriate
A
  1. Impairs methadone metabolism –> increased free drug.
    May need to lower doses or wait longer between uptitration (longer to achieve steady-state).
  2. Pre-existing QTC prolongation (esp if heart failure)

Severe, acute hepatic impairment

Central/obstructive sleep apnea

Pt’s needing concurrent benzo therapy (unless benefit»risk) due to risk of sleep apnea

Unexplained hypoglycemia (methadone may be a cause)

Patient’s living alone or with cognitive impairment

73
Q

A patient is unable to swallow and does not want to have a PEG tube or NG tube placed. List four options for delivering opioids

A 
rectal
IM
subcut 
IV 
transdermal patch
epidural, intrathecal, intraventricular
buccal 
sublingual 
topical
74
Q

When deciding on a route of administration for opioids what are three major considerations?

A

least invasive

Effective - route capable of providing adequate analgesia

Safe

75
Q

List three situations where the use of oral opioids is inappropriate

A

impaired swallowing
impaired GI absorption
patients who require rapid onset of analgesia
for patients who require very high doses

76
Q

A patient is on regular q4h hydromorphone subcutaneously. 30 minutes after receiving a dose the patient falls asleep and 30 minutes before the next dose is due the patient calls for a breakthrough.

What is the problem here (what is the term)?

How can it be mitigated?

A

Bolus effect - toxicity at the peak concentration and pain breakthrough at the trough.

Consider switching to a continuous parenteral infusion

77
Q

A patient is on a continuous subcut infusion of opioids.

How long can the subcut butterfly remain in place?

What is the maximum volume of fluid that can be delivered through the butterfly to maintain patient comfort?

A

Butterfly can remain in the skin for up to a week

Maximum volume delievered is 5mL/hr (local pharmacist says 2ml/hour)

78
Q

Intraspinal infusions - name 2 benefits

How does fat solubility of a drug impact its behaviour in an intraspinal infusion?

What is the role of local anesthetic in an intraspinal infusion?

Other than opioid, what other drug is commonly added?

A

intraspinal infusions provide LONGER duration anesthesia at doses LOWER than required by systemic administration

hydrophilic drugs such as hydromorphone, morphine have prolonged t1/2 in the CSF and significant rostral redistribution. Lipophilic opioids such as fentanyl and sufentanil have less rostral redistribution (uptake by spinal cord) and therefore fewer prolonged adverse effects if these become a problem.

The addition of a local anesthetic (ie. bupivicaine) to epidural or intrathecal has been demonstrated to improve analgesia without increasing toxicity

clonidine (alpha 2 adrenergic agonist) is normally added as well

79
Q

List 1 situation in which the intraventricular administration of opioid should be considered

A

upper body or head pain

severe diffuse pain

80
Q

The analgesic response of an opioid increases linearly to logarithmic increases in dose. What does this mean for the size of a dose increase that is required for an opioid?

A

As overall opioid dose increases, larger dose adjustments are needed to improve analgesia significantly.

In general dose increases of less than 30-50% are not likely to improve analgesia significantly

81
Q

What is the conversion ratio for subcut morphine to epidural and then from epidural to intrathecal

A

100:10:1
SC morphine: epidural: intrathecal

82
Q

A patient is on morphine long acting 60mg PO q12h and has been stable for 4 weeks. They start to notice their pain increasing. What two processes are more likely than tolerance to the morphine

A

disease progression

psychological distress

83
Q

List five CNS effects of opioids

A 
drowsiness*
cognitive impairment*
hallucinations
delirium*

resp depression*

myoclonus*
Hyperalgesia*
seizure disorder*
84
Q

List two side effects of opioids from each of the following body systems: GI, autonomic, cutaneous, endocrine

A

GI - Nausea/vomiting, constipation

Autonomic - xerostomia, postural hypotension, urinary retention

cutaneous - itch, sweating

Endocrine - hypogonadism, adrenal insufficiency, obesity, DM

85
Q

List four patient factors that impact the risk of developing side effects from opioids

A

genetic predisposition (ie. family history)

Age (decreased volume of distribution and clearance)

impaired renal function

coadministration of drugs which may have cumulative toxicity especially sedation

other concurrent comoribidity (ie. sepsis) that may mimic opioid induced adverse effects

FS:
Age (A, D)
Kidney (E)
Liver (M)
Other drugs that interact (M)

(ADME)

86
Q

List the following types of opioid induced adverse effects in order of strength of the dose response curve, from most prominent to least: GI side effects, constipation, CNS effects

A

CNS
GI
constipation

87
Q

List 4 CNS pathologies that may mimic the CNS side effects of opioids in patient with advanced cancer

A

cerebal mets
leptomeningeal mets

cerebrovascular event
extradural hemorrhage

88
Q

List four pathologies that may mimic the GI side effects of opioids in a patient with advanced cancer

A 
leptomenigeal mets
cerebral mets
hypercalcemia 
renal failure
liver failure 
sepsis/infection 
bowel obstruction

FS: ddx of constipation and NV

89
Q

What are the four approaches to treating opioid side effects? (Eg constipation)

A

specific therapy to reduce adverse effect

Dose reduction of systemic opioid

Route switching

opioid switching

90
Q

A patient develops side effects to an opioid and the dose cannot be reduced due to inadequately controlled pain.

What are four approaches to take that may improve analgesia such that the opioid can be reduced

A

The addition of

  • non-opioid co-analgesic
  • adjuvant analgesic
  • regional anesthetic or neuroablative intervention
  • therapy targeting the cause of the pain (eg radiation or surgery)
91
Q

A patient presents with opioid induced NV.

What part of the brain does the opioid activate to cause this side effect?

What are the first two antiemetics you are likely to use?

A

medullary chemoreceptor trigger zone

metoclopramide or haldol

92
Q

List 2 medication that can be used to manage opioid induced sedation

A

amphetamines-dextroampehtamine (adderal)

Methylphenidate (Ritalin)

amphetamine like agents (donepezil, modafinil)

93
Q

A patient presents with opioid induced delirium. What are five steps you will take to manage this patient?

A

Box 9.4.3

  1. DC non essential centrally acting meds
  2. If analgesia is satisfactory reduce opioid by 25%
  3. Exclude sepsis or metabolic derangement
  4. Exclude CNS involvement by tumor
  5. If delirium persists:
    - trial or neuroleptic (haldol)
    - change to alternative opioid drug
    - change in opioid route to the intraspinal route (+/- local anesthetic)
    - a trial of other anesthetic or neurosx options

FS:
- treat delirium - cause (DIMS) and symptoms (haldol)
- manage like opioid induced neurotoxicity (IVF, reduce dose, rotate opioid)

94
Q

A patient on hydromorphone LA presents to the ED in respiratory distress after a recent dose increase with tachypnea (increased RR) and anxiety. The R1 in emergency wants to give the patient naloxone.

What is the role of naloxone in this situation? Why?

A

Respiratory compromise accompanied by anxiety and tachypnea is never a primary opioid event

presence of tachpynea excludes opioids

Naloxone is not indicated. When patients are on chronic opioids administration of naloxone generally improves ventilation even if the cause of the respiratory event was not the opioids. It should not be taken as proof that they opioid was the cause and investigations into other causes should ensue

95
Q

A patient on the PCU has a 50% dose increase on their hydromorphone. They are found to have a resp rate of 6 breaths per minute and an oxygen saturation of 96% and ROUSES to stimulation. Their next dose of HM is due in two hours.

How would you manage this patient?

When would you give naloxone?

A

If the patient is bradypneic but arousable and the peak plasma level of the previous dose reached then the opioid should be held and patient monitored until improved

Give naloxone if bradypneic and not rousable or severe hypoventilation

naloxone diluted 1:10

96
Q

A patient develops multifocal myoclonus after the uptitration of their oxycodone. The patient’s preference is to remain on oxycodone at the current dose given the analgesic effect.

How can you symptomatically manage the myoclonus (3 meds from different classes)?

A

Lorazepam (benzo)

gabapentin (anticonvulsant)

dantrolene (skeletal muscle relaxant)

97
Q

How do opioids cause hypogonadism?

List four ways this can manifest

What is the treatment?

A

opioids have inhibitory action on the hypothalamic pituitary adrenal axis -> hypogonadism

fatigue
muscle wasting
erectile dysfunction*
reduced libido*
vaginal dryness*
menstrual abnormalities
hot flashes*
anxiety 
rare: changes in pubic hair and breast size

treatment - hormone replacement

98
Q

opioid induced hyperalgesia - list two pathological mechanisms to explain this

A
  • central sensitization involving glutaminergic system
  • changes in pain processing
  • activation of glial cells via opioid binding to toll-like receptors inducing a central neuroinflammatory response
  • alterations in the balance between antinociceptive and facilitatory descending systems

FS:
Other explanation from MD Anderson
- Clear pathology unclear
- Accumulation of excitatory non-analgesic opioid metabolites*
- Accumulation of the parent opioid
- NMDA activation*

99
Q

While there are no evidence based algorithms for the management of OIH; list 5 principles for the management of this syndrome

A

Hydration

Gradual reduction in opioid dose and assessing analgesic effect

Opioid rotation

use of NMDA receptor antagonist (ketamine, alpha 2 agonists)

Use non opioid co analgesics /spinal opioids

100
Q

A patient is started on morphine and asks if they can still drive. What do you tell them?

A

Do not drive or operate heavy machinery when first starting opioid and after dose increase.

However when the initial sedative effects have resolved and pt and physician confident that cognitive and psychomotor performance is not longer impaired driving may restart

101
Q

List four behaviours that are seen when somebody is addicted to opioids

A

continued use despite harm
impaired control over drug use
compulsive use
craving

(4Cs - con con comp crave)

102
Q

Your patient with advanced cancer tells you that he has been unable to reduce his dose of long acting hydromorphone (the dose has been stable for five months and no refills have been required for breakthrough pain for the past three months) without feeling a recurrence of pain as well as nausea and agitation. He tells you he is worried he is now addicted to opioids. What phenomenon is he describing? Is he addicted or will he become addicted to opioids?

A

physical tolerance

Risk of developing addictive behaviours or substance abuse as a consequence of medical use of opioids is low

103
Q

List five withdrawal symptoms from the abrupt cessation of opioids in a patient with chronic cancer pain.

What two factors influence the severity of withdrawal?

A

Dose and duration of use

anxiety*
nervousness
irritability 
alternating chills and hot flashes
rhinorrhea* (nose)
gooseflesh
diarrhea* (butt)
N/V
salivation * (mouth)
lacrimation* (eyes) 
sneezing 
sweating* (skin)
abdo cramps
insomnia
multifocial myoclonus (rare)
104
Q

A patient receives 100mg of morphine on monday. What is the minimum dose of morphine they should receive tuesday to prevent withdrawal

A

75mg

75%

105
Q

List two tools that can be used to screen for risk of opioid misuse in patients

A

Screener and Opioid Assessment for Pain Patients (SOAPP)*

Current Opioid Misuse Measure (COMM)

*best validated tool

106
Q

What are four impacts of age on opioid pharmacokinetics

A
  • decreases metabolism
  • decreased volume of distribution for hydrophilic drugs and increased Vd for lipophilic drugs
  • Hepatic blood flow decreases with age -> reduced clearance of opioids
  • increased CNS sensitivity to opioids

FS: think ADME

107
Q

Where does most opioid metabolism happen

A

liver

108
Q

What opioid side effects does one develop tolerance to? What side effects does one rarely develop tolerance to?

A

Tolerance to nausea, resp depression and sedation occurs rapidly.

Tolerance to constipation happens slowly if at all.

Palliative Medicine (SB) (145 decks)

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