Opioids

Question 1

What is the path of the sense of pain?

Answer 1

Nociceptor (type A or C) is activated
Travels to dorsal root of spinal cord
Interneurones from substantia gelatinosa stop pain getting through from mechanoreceptors
Travels to thalamus and primary sensory cortex (they can also inhibit pain)

Question 2

What are the different endogenous opioids, their precursors and different types in each category?

Answer 2

Proenkephaplin -> enkephalins

• > metenkephalin
• > leu-enkephalin

POMC -> endorphins
->β-endorphin

Prodynorphin -> dynorphins

Question 3

Which type one of type A and C pain fibres is myelinated?

Answer 3

Type A

Question 4

What are the different classes of opioid receptors?

Answer 4

μ - mu - MOP
δ - delta - DOP
κ - kappa - KOP

Question 5

What type of receptor are opioid receptors?

Answer 5

GPCRs

Question 6

Which receptor appears to mediate the majority of therapeutic effects of exogenous opioids?

Answer 6

Mu/MOP

Question 7

What is the signalling pathway begun when an opioid binds to receptor?

Answer 7

They are all Gi GPCRs
Inhibition of adenylyl cyclase and reduction in cAMP levels
Activates K+ channels allowing K+ efflux
Causes hyperpolarisation of membrane so less excitable
Decreased influx of Ca
Reduced release of glutamate and substance P from vesicles (requires Ca)

Question 8

What are the different types of opiates?

Answer 8

Agonists eg morphine
Partial agonists eg buprenorphine
Agonists/antagonists eg nalbuphine
Antagonists eg naloxone

Question 9

Morphine

• half life?
• oral bioavailability?
• lipid soluble?

Answer 9

Half life: 1.3-6.7 hours
Oral bioavailability: 25% (low)
Not lipid soluble

Question 10

What is the metabolite of morphine? Half life?

Answer 10

Morphine-6-glucuronide

4-5 hours

Question 11

What are slow release preparations of morphine used for?

Answer 11

Chronic pain control

Question 12

Half life of diamophine?

Answer 12

0.08 hours

Question 13

Methadone

• half life?
• oral bioavailability?
• protein binding?

Answer 13

Half life: 15-30 hours
Oral bioavailability: 90%
90% of oral bioavailability is bound to protein, reducing direct availability for receptor binding

Question 14

Codeine

• half-life?
• bioavailability?

Answer 14

Half life: 1.9-3.9 hours (quite short)

Bioavailability: 90%

Question 15

Benefits of administering opiates IV?

Answer 15

Most rapid response
Avoids hepatic first pass metabolism
Good for severe pain
Patient can control the level of analgesia directly

Question 16

What is a risk factor for ADRs/overdose with opiates?

Answer 16

Hepatic and renal failure

• can increase half-life by up to 50 hours
• careful with palliative care patients who could be suffering from terminal organ failure

Question 17

Uses of morphine?

Answer 17

Analgesic

Diarrhoea

Question 18

Metabolism of morphine?

Answer 18

Conjugated with glucuronide to produce morphine-6-glucuronide and morphine-3-glucuronide
Metabolites can be measured in the urine for screening

Question 19

Metabolism of diapmorphine?

Answer 19

Prodrug - metabolised to morphine

Can cross blood brain barrier

Question 20

What is diamorphine used for?

Answer 20

Analgesic in terminal illness

Question 21

Use if methadone?

Answer 21

Maintenance in dependence

Question 22

Uses of tramadol?

Answer 22

Analgesic

Also has serotonin and NA effects

Question 23

Effects of tapentadol?

Answer 23

Analgesic

• specific μ agonist
• NA re-uptake inhibitor

Question 24

Why does codeine not have an effect in some people?

Answer 24

Metabolised to morphine by CYP2D6
Some people do not express this enzyme
(Chinese and Caucasians)

Question 25

Which opiates are used in anaesthetics? Why are they suitable for this?

Answer 25

Fentanyl - 100 times more potent than morphine
Alfentanil - 1000 times more potent than morphine
Remifentanil

Rapid onset and short half-life

Question 26

ADR of alfentanil and remifentanil?

Answer 26

Can cause histamine release

Question 27

Problem with pethidine?

Answer 27

Its metabolite, norpethidine, can build up with frequent repeated doses - dangerous so don’t give lots of doses

Question 28

Name some opioid agonists-antagonists

Answer 28

Pentazoxine
Nalbuphine
Butorphanol
Buprenorphine 
Meptazinol

Question 29

Why can agonists-antagonists be better than full agonists?

Answer 29

Full agonists have a higher affinity for μ receptors
Partial opioid agonists-antagonists have mixed effects at the three sites
E.g. Nalbuphine
-antagonises μ
-partial agonist at κ
-weak agonist at δ
Good analgesia without euphoria

Question 30

What are the uses of opioid antagonists? Name some and their half-lives

Answer 30

Opioid toxicity
Reverse respiratory depression
Treatment of dependence

Naloxone - 1-1.5 hours
Naltrexone - 4 hours

Question 31

What are ADRs of agonising μ and κ receptors?

Answer 31

μ: nausea, vomiting, constipation, drowsiness, miosis, respiratory depression, hypotension

κ: dysphoria

Question 32

What increases the risk of respiratory depression with opiates?

Answer 32

When combined with a pulmonary deficit

When combined with other depressant drugs eg anaesthetics, alcohol or sedatives

Question 33

How do opiates cause respiratory depression?

Answer 33

Via μ receptor - action of CO2 sensitivity

Question 34

What are other general ADRs of opiates?

Answer 34

Neurological effects such as euphoria, confusion, miosis, psychosis and coma
Constipation
Immunosuppresion with long term use (rare)
Anaphylaxis - non-opiate receptor effects on mast cells causing release of histamine

Question 35

How does naloxone manage an opiate overdose?

Answer 35

It is an antagonist
Highly competitive with opiates
Rapidly reverses respiratory depression
-short half-life so need continued dosing over time