Session 8 Opioids

Question 1

What is nociception?

Answer 1

non-conscious neural traffic due to trauma or potential trauma to tissue

Question 2

What is pain?

Answer 2

complex, unpleasant awareness of sensation modified by experience, expectation, immediate context and culture

Question 3

Describe the pain reflex (ending with post central gyrus)

Answer 3

1. Cell damage / death
2. Nociceptors stimulated
3. Release of substance P and Glutamate
4. Afferent nerve stimulated - 1st order neuron
5. First order neurone synapses with 2nd order neurone in dorsal horn
6. 2nd order neurone decussates
7. Action potential ascends
8. 2nd order neurone synapses with 3rd order neurone in thalamus
9. 3rd order neurone projects to post central gyrus

Question 4

We modulate pain through modulators. Where are these found a) peripherally and b) centrally?

Answer 4

a) substantia gelatinosa

b) periaqueductal grey

Question 5

How do we modulate pain peripherally? (i.e. the pathway)

Answer 5

1. tissue damage occurs
2. project with alpha-delta and c fibres towards the dorsal horn
3. this transmits to the thalamus and makes our body realise that we are experiencing pain

when tissue damage occurs, we also send inhibitory signals to the substantia gelatinosa (main modulator)

‘rubbing it better’ stimulates the substantia gelatinosa which then inhibits lamina 1 and lamina 5 and reduces the pain that’s projecting towards the thalamus

Question 6

How do we modulate pain centrally?

Answer 6

1. tissue damage occurs
2. project with alpha-delta and c fibres to the dorsal horn
3. this projects to the thalamus then the cortex

When the thalamus and cortex detect pain, the thalamus sends stimulatory signals towards the periaqueductal grey matter which then sends inhibitory signals to the dorsal horn - they do this by releasing endogenous opioids e.g. 5-HT and enkephalins

these endogenous opioids work on our endogenous opioid receptors which causes a reduction in pain

Question 7

How do opioid GPCR work?

Answer 7

action = decrease cAMP –> hyperpolarisation and decreased substance P release + increased dopamine release

Question 8

u (MOP) GPCR

location =
endogenous opioids =
effects =

Answer 8

location = supraspinal / GI tract
endogenous opioids = enkephalins and b-endorphins
effects = analgesia, depression, euphoria, dependence, respiratory sedation

Question 9

delta (DOP) GPCR

location =
endogenous opioids =
effects =

Answer 9

location = widely distributed
endogenous opioids = enkephalins
effects = analgesia, inhibit dopamine, modulate u

Question 10

k (KOP) GPCRs

location =
endogenous opioids =
effects =

Answer 10

location = spinal cord, brain and periphery
endogenous opioids = dynorphins
effects = analgesia, diuresis, dysphoria

Question 11

Describe the WHO analgesic ladder

Answer 11

simple analgesia e.g. paracetamol and NSAIDS
weak opioid e.g. codeine
strong opioid e.g. morphine, fentanyl

Question 12

What are the four general principles of Opioids (as a class)

Answer 12

1. Exploit natural opioid receptors (either agonise or antagonise)
2. Main therapeutic effects are via u-receptors
3. Aim to modulate pain
4. Also indicated in cough, diarrhoea and palliation

Question 13

Which opioid’s are strong agonists?

Answer 13

Morphine

Fentanyl

Question 14

Which opioid’s are moderate agonists?

Answer 14

Codeine

Question 15

Which opioid is a mixed agonist/antagonist (partial agonist)?

Answer 15

Buprenorphine

Question 16

Which opioid is an antagonist?

Answer 16

Naloxone

Question 17

Morphine

Absorption =
Distribution =
Metabolism =
Elimination =

Answer 17

Absorption = PO (long term pain relief), IV, IM, SC, PR

• IV and SC - in acute pain relief
• significant first pass effect - 40% bioavailability

Distribution = rapidly enters all tissues but struggles to cross BBB

Metabolism = morphine + glucuronic acid –> M6G (main analgesic effect) + M3G (neuroexcitatory/euphoria side effect)

Elimination = renal

Question 18

What receptor does morphine have a strong affinity for?

Answer 18

u receptors (minimal for k and d)

NB: complete activation of u

Question 19

main actions of morphine?

Answer 19

analgesia and euphoria

Question 20

side effects of morphine?

Answer 20

respiratory depression - medullary respiratory centre becomes less responsive to Co2
vomiting - as chemoreceptors are stimulated
GI tract - as morphine decreases motility (constipation), increases sphincter tone
miosis -constriction of pupils
histamine release - caution in asthmatics

Question 21

Fentanyl

Absorption =
Distribution =
Metabolism =
Elimination =

Answer 21

Absorption = IV, epidural, intrathecal, nasal
* 80-100% bioavailability
Distribution = highly lipophilic, highly protein bound, high level of CNS crossing
Metabolism = hepatic (via CYP3A4)
Elimination = renal (very short half life)

Question 22

Fentanyl compared to morphine? (receptors etc)

Answer 22

100 x more potent
higher affinity for u receptor

less histamine release, sedation and constipation

Question 23

main actions of fentanyl?

Answer 23

analgesia

anaesthetic

Question 24

side effects of fentanyl?

Answer 24

respiratory depression
constipation
vomiting

Question 25

Codeine Absorption = Metabolism = Elimination =

Answer 25

Absorption = PO, SC Metabolism = codeine converted to morphine via CYP2D6 (CYP2D6 is inhibited by fluoxetine) Elimination = renal! glucoronidation of morphine

Question 26

Codeine vs morphine potency

Answer 26

codeine is only 1/10th of the potency of morphine (less potent)

Question 27

main actions of codeine?

Answer 27

mild to moderate analgesia | cough depressant

Question 28

side effects of codeine?

Answer 28

constipation | respiratory depression - worse in children so don't give if aged under 12!

Question 29

Buprenorphine Absorption = Distribution = Metabolism = Elimination =

Answer 29

Absorption = transdermal, buccal and sublingual Distribution = very lipophilic Metabolism = hepatic (via CYP3A4) then glucoronidation (prior to biliary excretion) Elimination = biliary (safe in renal impairment) * half life = 37 hours

Question 30

Buprenorphine vs morphine

Answer 30

very high affinity for u receptor - low Kd long duration of action not easily displaced lower Emax as its a partial agonist so lower efficacy antagonist at k receptors

Question 31

main actions of buprenorphine?

Answer 31

moderate to severe pain (chronic pain) | opioid addiction treatment

Question 32

side effects of buprenorphine?

Answer 32

respiratory depression low BP nausea dizziness NB: side effects aren't as bad as buprenorphine is a partial agonist

Question 33

Naloxone Absorption = Distribution = Metabolism = Elimination =

Answer 33

``` Absorption = IV, IM, intranasal and PO * very LOW oral bioavailability as extensive first pass effect (i.e. very well absorbed in the gut) Distribution = rapid as very lipophilic Metabolism = hepatic * converted to naloxone-3-glucuronide Elimination = renal * duration of action is 30-60 minutes ```

Question 34

Naloxone vs morphine in terms of affinity?

Answer 34

u>d>k greater affinity than morphine but less than buprenorphine

Question 35

main action of naloxone?

Answer 35

competitive antagonism of opioid

Question 36

side effects of naloxone?

Answer 36

short half life so someone could go back into overdose quickly so need to give as a slow infusion so that the overdosed drug (morphine or heroin) can be metabolised

Question 37

How do we build up a tolerance to opioids? (i.e. what are the mechanisms?)

Answer 37

1. Phosphorylation and uncoupling | 2. cAMP production

Question 38

How does the phosphorylation and uncoupling mechanism lead to opioid tolerance?

Answer 38

without tolerance: - u receptor coupled to G Protein * give opioid which leads to decreased cAMP and therefore decreased pain BUT on repeated exposure to opioid ---> 1. sensitivity of u receptor to the opioid is reduced * so opioid wont bind as readily OR 2. Arrestin (a protein) binds to u receptor which means that G proteins become uncoupled and can no longer bind to the u receptor * downstream process can't occur - no decrease in cAMP and therefore no decrease in pain felt

Question 39

How does the process of cAMP production lead to opioid tolerance?

Answer 39

Normally, opioid will decrease cAMP and decrease pain BUT when opioid is removed, you can get a rebound effect within that cell: cell becomes flooded with cAMP --> neuronal excitability occuring --> multisystemic withdrawal symptoms this means that you need greater doses to minimise that period of time where your cells aren't exposed to opioid to minimise the effect

Question 40

What is a leading cause of opioid addiction / overdose?

Answer 40

Iatrogenic causes