Opioids and Analgesics

Question 1

What percentage of Canadians report they have pain and it is poorly managed?

Answer 1

40%
cost (USD): ~$7.1 billion + $61 billion in lost work productivity

Question 2

What is pain?

Answer 2

an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage

Question 3

What are the opioid receptors?

Answer 3

mu
kappa
delta
nociceptin

Question 4

What kind of receptors are opioid receptors?

Answer 4

G-coupled
-binding of an agonist decreases cAMP and inhibits inwardly rectifying K+ channels

Question 5

Where are opioid receptors found?

Answer 5

peripheral, spinal, and brain

Question 6

What is the role of opioid receptors?

Answer 6

inhibit the release of nociceptive signals peripherally and centrally

Question 7

What are examples of endogenous opioids?

Answer 7

enkephalin
dynorphin
substance P
endorphin

Question 8

Describe endogenous opioids.

Answer 8

short peptide molecules
coded on genes as “pre-pro” peptides and subject to post-translational modifications
released from synaptic vesicles

Question 9

Describe exogenous opioids.

Answer 9

aminoalkylindole compounds naturally occurring in nature and synthesized de novo
drugs and pro-drugs with variable PD and PK depending on drug and excipients

Question 10

Which opioids and their metabolites produce analgesia and all other opioid effects?

Answer 10

morphine
morphine-6-glucuronide
hydrocodone
hydromorphone
hydromorphone-6-glucuronide
oxycodone
oxymorphone
noroxycodone
fentanyl
methadone

Question 11

Describe acetaminophen.

Answer 11

CNS-selective COX inhibitor
anandamide reuptake inhibitor (boosts endocannabinoid levels)
TRPV1 agonist
hepatic metabolism via CYP2E1, 3A4, UGTs

Question 12

Describe NSAIDs.

Answer 12

absorbed in stomach and gut mucosa
undergo phase I metabolism (CYP2C9, 2D6) and are excreted in urine

Question 13

Where are CB2 receptors found?

Answer 13

glia
astrocytes
immune cells

Question 14

What happens when CB2 receptors are activated?

Answer 14

inhibition of inflammation

Question 15

What are the major effects and polymorphisms of the mu receptor?

Answer 15

major effects:
-analgesia
-euphoria
-sedation
-constipation
-respiratory depression
polymorphisms:
- > 100 found
-118AG (2-48%): lower analgesic response, greater consumption

Question 16

What are the major effects and polymorphisms of the kappa receptor?

Answer 16

major effects:
-spinal analgesia
-respiratory depression
-sedation
-dysphoria
polymorphisms:
-36 GT correlated with addictive potential and abusive liability

Question 17

What are the major effects and polymorphisms of the delta receptor?

Answer 17

major effects:
-dysphoria
-psychomimetic
polymorphisms:
-2 major SNPs, no effect

Question 18

Describe PD gene polymorphisms of NSAIDs.

Answer 18

response to analgesic effect of ibuprofen and rofecoxib is opposite and genotype related at 48h after surgery
-homozygous GG for PTGS2 SNP2 demonstrated better response to rofecoxib
-GC or CC for PTGS2 SNP2 demonstrated better response to ibuprofen
PTGS2 polymorphisms influence expression of PTGS1 and PTGS2 and consequently the analgesic effect of NSAIDs

Question 19

Describe PD gene polymorphisms of cannabinoids.

Answer 19

no known CB receptor polymorphisms that affect drug efficacy
G1359a correlated with T2DM
AATn correlated with Huntingtons

Question 20

What happens with acetaminophen in an ultra rapid metabolizer of CYP 2E1?

Answer 20

increased NAPQI = increased risk of hepatotoxicity

Question 21

What are the major themes in PK gene polymorphisms?

Answer 21

if drugs are pro-drugs or metabolism produces an active metabolite, then polymorphisms that increase metabolism will increase efficacy and ADRs
-reduced safety
polymorphisms that reduce metabolism may lead to high drug conc
-reduced safety
polymorphisms that enhance drug metabolism will reduce drug safety and may be misconstrued as drug-seeking behavior

Question 22

Which analgesics show actionable clinical PG implementation?

Answer 22

codeine and 2D6
tramadol and 2D6

Question 23

Which analgesics show moderately actionable clinical implementation?

Answer 23

morphine and OPRM1

Question 24

Which analgesics have no guidelines for PG implementation?

Answer 24

oxycodone and CYP 2D6
hydrocodone and CYP 2D6
fentanyl and OPRM1
methadone

Question 25

What is the PD effect of opioids and cannabinoids when overlapped?

Answer 25

synergism

Question 26

What is the goal of PG as a clinical tool in opioid therapy?

Answer 26

optimize pain relief and prevent AE
when PG is coupled with clinical factors such as age, weight, renal, and hepatic function, concomitant medications, personalized pain management can be actualized
however, to date, the evidence is not compelling enough for widespread adoption