7.6 (9.4) Opioid therapy: optimizing outcomes

Question 1

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

Answer 1

opioid analgesics

non opioid analgesics

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

Question 2

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.*

Answer 2

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

Question 3

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

Answer 3

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

Question 4

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

Answer 4

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

Question 5

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

Answer 5

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

Question 6

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

B) What happens to these pathways with opioid abstinence?

Answer 6

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

2. Activation of cellular potassium pump

B) Excessive rebound activity

Question 7

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?

Answer 7

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

Question 8

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

Answer 8

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

Question 9

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?

Answer 9

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)

Question 10

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

Answer 10

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

Question 11

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

Answer 11

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

Question 12

1. Define pain.
2. What area of the brain plays an important role in nociception and pain perception ?

Answer 12

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

Question 13

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

How do activations in these areas respond to opioids?*

Answer 13

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)

.

Question 14

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

Answer 14

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

Question 15

Respiratory depression:

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

Answer 15

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)

Question 16

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

Answer 16

MOR and KOR
activation in
hypothalamus + locus coeruleus

Question 17

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

Answer 17

1. Mostly mediated by MORs via:

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

ii) spinal/supra-spinal receptors

Question 18

1. Which opioid receptor mediates nausea and vomiting?
2. Name 4 locations where this takes place

Answer 18

1. MORs
2. medulla
   cortex
   vestibular apparatus
   (partially)GI tract 2/2 constipation

Question 19

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?*

Answer 19

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

Question 20

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

Answer 20

1. Chronic pain
2. Tolerance
3. Hyperalgesia
4. Addiction

Question 21

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

Answer 21

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

Question 22

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

Answer 22

1. altered molecular signalling pathways
2. downregulation of opioid receptors

Question 23

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

Answer 23

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

Question 24

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

Answer 24

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

Question 25

What is the impact of DOR on analgesia? Impact in DOR agonists when used with MOR agonist? What opioid has prominent activity on DOR?

Answer 25

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

Question 26

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?

Answer 26

G-protein-coupled receptors (GPCRs) increase opening of potassium channels -> hyperpolarization of post synapatic cell -> overall INHIBITORY effect

Question 27

List 3 structure classes of opioids used clinically (review with group: is this relevant?)

Answer 27

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

Question 28

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

Answer 28

lipid solubility / Vd/ half life concentration gradient degree of protein binding (diffusible fraction)

Question 29

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

Answer 29

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

Question 30

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) 2. Name 4 other factors that may influence opioid effectiveness*

Answer 30

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

Question 31

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

Answer 31

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)

Question 32

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

Answer 32

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)

Question 33

Describe how the majority of opioids are metabolized. What is the major determinant of plasma clearance.

Answer 33

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 )

Question 34

List 2 endogenous opioid ligands with anti opioid actions

Answer 34

neuropeptide FF cholecystokinin nociceptin* dynorphin* WP: DyNo Cho FF :O

Question 35

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?

Answer 35

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

Question 36

How does lipid solubility of an opioid impact its action

Answer 36

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

Question 37

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

Answer 37

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

Question 38

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

Answer 38

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

Question 39

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?*

Answer 39

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

Question 40

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

Answer 40

codeine morphine oxycodone fentanyl, methadone (Table 7.6.4)

Question 41

1. What is an agonist? 2. Define efficacy vs potency

Answer 41

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) 2. Efficacy is MAX drug response induced by active agent in an ideal environment 3. Potency is drug response relative to dose (dose response relationship)

Question 42

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

Answer 42

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

Question 43

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?

Answer 43

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)

Question 44

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?

Answer 44

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

Question 45

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?

Answer 45

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

Question 46

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

Answer 46

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

Question 47

What is “relative potency” of opioids? Conventionally what is it based on?

Answer 47

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

Question 48

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

Answer 48

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 *

Question 49

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

Answer 49

``` morphine - M6G, M3G (major) hydromorphone - H6G, H3G (major) oxycodone - oxymorphone methadone - none fentanyl - none ``` FS: M3G and H3G thought to cause OIN

Question 50

Which of the following opioids have lowest oral bioavailabilty: (name 3) - codeine - morphine - oxycodone - hydromorphone - methadone - fentanyl

Answer 50

``` 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

Question 51

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

Answer 51

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

Question 52

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

Answer 52

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)

Question 53

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?

Answer 53

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

Question 54

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?

Answer 54

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

Question 55

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****

Answer 55

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

Question 56

Why is tramadol described as a mixed action opioid agonist

Answer 56

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

Question 57

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

Answer 57

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)

Question 58

Describe the 3 steps of the WHO ladder

Answer 58

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"

Question 59

**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.

Answer 59

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 5. starting dose: 30 mg PO q4-6h May inc to 60 mg, but higher s/e at this dose (compared to codeine) 6. Priaprism in patients also on alpha-1 blocker, trazadone, PDE-5 inhibitors etc.

Question 60

1. What is the composition of morphine? 2. List 2 compounds it is available as.* 3. List 4 types of routes of administration.

Answer 60

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) 3. oral, rectal, parenteral, intraspinal

Question 61

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?

Answer 61

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)

Question 62

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?

Answer 62

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

Question 63

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?

Answer 63

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

Question 64

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

Answer 64

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

Question 65

Why is meperidine not routinely used for the management of chronic cancer pain? Why is the use of naloxone potentially dangerous when using meperdine?

Answer 65

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

Question 66

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?

Answer 66

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

Question 67

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

Answer 67

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

Question 68

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?

Answer 68

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??)

Question 69

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?

Answer 69

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

Question 70

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

Answer 70

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

Question 71

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

Answer 71

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.

Question 72

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

Answer 72

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

Question 73

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

Answer 73

``` rectal IM subcut IV transdermal patch epidural, intrathecal, intraventricular buccal sublingual topical ```

Question 74

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

Answer 74

least invasive Effective - route capable of providing adequate analgesia Safe

Question 75

List three situations where the use of oral opioids is inappropriate

Answer 75

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

Question 76

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?

Answer 76

Bolus effect - toxicity at the peak concentration and pain breakthrough at the trough. Consider switching to a continuous parenteral infusion

Question 77

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?

Answer 77

Butterfly can remain in the skin for up to a week Maximum volume delievered is 5mL/hr (local pharmacist says 2ml/hour)

Question 78

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?

Answer 78

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

Question 79

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

Answer 79

upper body or head pain | severe diffuse pain

Question 80

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?

Answer 80

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

Question 81

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

Answer 81

100:10:1 SC morphine: epidural: intrathecal

Question 82

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

Answer 82

disease progression | psychological distress

Question 83

List five CNS effects of opioids

Answer 83

``` drowsiness* cognitive impairment* hallucinations delirium* resp depression* myoclonus* Hyperalgesia* seizure disorder* ```

Question 84

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

Answer 84

GI - Nausea/vomiting, constipation Autonomic - xerostomia, postural hypotension, urinary retention cutaneous - itch, sweating Endocrine - hypogonadism*, adrenal insufficiency, obesity, DM*

Question 85

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

Answer 85

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)

Question 86

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

Answer 86

CNS GI constipation

Question 87

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

Answer 87

cerebal mets leptomeningeal mets cerebrovascular event extradural hemorrhage

Question 88

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

Answer 88

``` leptomenigeal mets cerebral mets hypercalcemia renal failure liver failure sepsis/infection bowel obstruction ``` FS: ddx of constipation and NV

Question 89

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

Answer 89

specific therapy to reduce adverse effect Dose reduction of systemic opioid Route switching opioid switching

Question 90

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

Answer 90

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)

Question 91

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?

Answer 91

medullary chemoreceptor trigger zone metoclopramide or haldol

Question 92

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

Answer 92

amphetamines-dextroampehtamine (adderal) Methylphenidate (Ritalin) | amphetamine like agents (donepezil, modafinil)

Question 93

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

Answer 93

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)

Question 94

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?

Answer 94

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

Question 95

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?

Answer 95

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

Question 96

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)?

Answer 96

Lorazepam (benzo) gabapentin (anticonvulsant) dantrolene (skeletal muscle relaxant)

Question 97

How do opioids cause hypogonadism? List four ways this can manifest What is the treatment?

Answer 97

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

Question 98

opioid induced hyperalgesia - list two pathological mechanisms to explain this

Answer 98

- 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*

Question 99

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

Answer 99

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

Question 100

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

Answer 100

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

Question 101

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

Answer 101

continued use despite harm impaired control over drug use compulsive use craving (4Cs - con con comp crave)

Question 102

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?

Answer 102

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

Question 103

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?

Answer 103

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) ```

Question 104

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

Answer 104

75mg | 75%

Question 105

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

Answer 105

Screener and Opioid Assessment for Pain Patients (SOAPP)* Current Opioid Misuse Measure (COMM) | *best validated tool

Question 106

What are four impacts of age on opioid pharmacokinetics

Answer 106

- 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

Question 107

Where does most opioid metabolism happen

Answer 107

liver

Question 108

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

Answer 108

Tolerance to nausea, resp depression and sedation occurs rapidly. Tolerance to constipation happens slowly if at all.