Opioids

Question 1

Describe the gate control theory of pain

Answer 1

C and Ad nociceptive fibres enter the dorsal root to synapse with the 2nd order neurone. This neurone is usually inhibited by descending inhibition and by inhibitory neurones from the substantia gelatinosa, which itself is stimulated by descending inhibition and mechanical stimulation. The nociceptive fibres stimulate the 2nd order neurone (to thalamus and samatosensory cortex) and inhibit neurones from the substantia gelatinosa reducing the inhibition.

Question 2

What are the endogenous opioids and what are they made from?

Answer 2

Enkephalins - proenkephalin

Endorphins - POMC

Dymorphins - prodynorphin

Question 3

What are the opioid receptors and where are they found in the CNS?

Answer 3

u (MOP) - supraspinal

k (KOP) - spinal cord

d (DOP) - widely distributed

Question 4

Which receptor is responsible for most therapeutic effects?

Answer 4

u

Question 5

Outline the mechanism of exogenous opiates

Answer 5

Predominantly act on u receptors which are GPCRs. These are Gi which reduces cAMP, increases K+ efflux (makes more -ve) and decreases Ca2+ entry making the cell less excitable and reduces neurotransmitter release

Question 6

Name 3 full agonists

Answer 6

Morphine, codeine, methadone

Question 7

Name an agonist-antagonist and state how it acts at each receptor

Answer 7

Nalbutine - antagonist at u, partial agonist at k, weak agonist at d

Question 8

Name an antagonist, it’s half life and when it is used

Answer 8

Naloxone - 1-1.5 hours (shorter than morphine so requires repeat dosing), used to treat opioid overdose, opioid toxicity and respiratory depression

Question 9

What are some indications for opiates?

Answer 9

Moderate to severe pain (morphine), palliative care (morphine), cancer pain, anaesthesia, stopping addiction (methadone)

Question 10

What factors can increase the ADR risk?

Answer 10

Hepatic impairment, impaired respiratory function, elderly

Question 11

Describe the pharmacokinetics for morphine

Answer 11

25% bioavailability, half life of 2 hours, metabolised to morphine-6-glucoronide which has a half life of 4-5 hours. Hepatic and renal failure can increase the half life. This means that care should be taken when managing palliative patients who may have terminal organ failure

Question 12

Why is diamorphine used when it on,y has a half life of 5 minutes?

Answer 12

Diamorphine is more soluble and crosses the BBB quickly. It is then hydrolysed to morphine which has a longer half life but has quickly gotten to the brain

Question 13

Outline the pharmacokinetics of methadone

Answer 13

Bioavailability of 90% and is 90% protein bound with a half life of 24 hours making it more suitable to treat chronic pain

Question 14

Outline the pharmacokinetics of coedine

Answer 14

Given orally and has a bioavailability of 50%, metabolised by CYP2D6 into morphine but this is subject to polymorphism with 10% of Caucasians unable to effectively convert codeine

Question 15

What are the ADRs of opiates?

Answer 15

Respiratory depression (u receptor affects CO2 sensitivity)

Neurological effects - euphoria, confusion, miosis, psychosis, coma

GI effects - nausea, constipation

Hypersensitivity - can effect mast cells which can release histamine to result in bronchoconstriction, hypotension and a rash

Tolerance

Dependence

Question 16

Describe the new endogenous opioid peptides and receptor. Other peptides include nocistatin (blocks effects of nociceptin), endomorphin-1 and endomorphin-2

Answer 16

Opioid-receptor-like 1 binds the endogenous opioid nociceptin.