Session 7 - Opioids

Question 1

Give three endogenous opioids and pre-cursors

Answer 1

o	Enkephalins
	Precursor – Proenkephalin
o	Endorphins
	Precursor – Pro-opiomelanocortin (POMC)
o	Dynorphins
	Precursor – Prodynorphin

Question 2

What are the three main opioid receptors and where do they have an effect?

Answer 2

o Mu (μ) (MOP)
 Evidence for supraspinal analgesia in the CNS – most painkilling effects.
o Kappa (κ) (KOP)
 Evidence for analgesia in the spinal cord
o Delta (δ) (DOP)
 Enkephalins. Widely distributed.

Question 3

Where do opioids have an effect?

Answer 3

Pre-synaptically

Question 4

How do opioids interact with synapses and prevent release of things like substance P?

Answer 4

Binding to μ or δ receptors causes hyperpolarisation of the neuron by opening potassium channels, decreasing excitability.
Δ decreases cAMP and also reduced calcium influx.
They also inhibit voltage gated calcium channels and subsequently the release of Substance P.
Binding to κ receptors inhibits voltage gated calcium channels and subsequently the release of Substance P.

Question 5

What is a full opioid agonist?

Answer 5

o Higher affinity for μ receptor
o Codeine, Methadone, Morphine
 Codeine and Methadone are relatively weak agonists compared to Morphine and lack dependence

Question 6

What is a partial opioid agonist?

Answer 6

o Developed to have mixed effects at all three receptors
o Can provide excellent analgesia without euphoria
o Nalbuphine
 Mixed agonist/antagonist effects at μ
 Partial agonist at κ
 Weak against δ

Question 7

Name a full opioid antagonist

Answer 7

o Bind predominantly to μ receptors and used to reverse potentially fatal agonist effects (Respiratory Depression)
o Naloxone
Agonist/Antagonist
- Nalbuphaine
o Full antagonist for Mu, Full agonist for kappa.

Question 8

What is the route of admin for opiates?

Answer 8

o Oral
 70% removed by first pass metabolism, necessitating larger doses
o Rectal
o Intravenous
 Most rapid response, avoids first pass metabolism
 Often used for severe pain, with patient controlling the level of analgesia
o Intramuscular
o Intrathecally

Question 9

What is the half life of morphine?

Answer 9

Dose adjustment necessary for Oral preparations. Normally the t½ of Morphine is about 2 hours. However, one of its metabolites Morphine-6-Glucoronide is at least pharmacologically equivalent to Morphine with a t½ of 4-5 hours. This extends the period of effective analgesia.

Question 10

What is the oral bioavailability of methadone?

Answer 10

Methadone has an oral bioavailability of ~90%. It also has a t½ of about 24 hours, making it more suitable for treating chronic pain.

Question 11

What are the pharmacokinetics of codeine?

Answer 11

Codeine is an important opiate, which is given orally. It needs to be metabolised by CYP2D6 into Morphine to become pharmacologically active.

CYP2D6 is subject to Genetic Polymorphism, so that 10% of the Caucasian population cannot effectively convert Codeine to Morphine.
Another polymorphism seen in Chinese people means codeine is less effectively converted to Morphine and dose may need to be adjusted upwards in this ethnic group.

Question 12

Give six uses of strong opioids

Answer 12

o	Visceral
o	Postoperative
o	Cancer-related
o	Myocardial infarction
o	Pulmonary Oedema
o	Peri-operative analgesia

Question 13

What are weak opioids used for?

Answer 13

Mild to moderate pain relief and as an anti-diarrhoeal

Question 14

How do opiates cause respiratory depression?

Answer 14

The most serious opioid ADR is Respiratory Depression, and is the single greatest cause of death following opiate overdose. This is due to a μ receptor mediated action of opiates on CO2 sensitivity.
Normally therapeutic levels do not cause excessive depression, but when combined with sleep, pulmonary deficit or other depressant drugs such as anaesthetics, alcohol or sedatives the risk of death can be much greater.

Question 15

Give an opiate ADR

Answer 15

Other Opiate ADRs
o	Miosis (Important overdose sign)
o	Euphoria
o	Confusion
o	Psychosis
o	Coma
o	Tolerance and dependence
o	GI disturbances (nausea, vomiting, constipation) (Codeine especially)
o	Rarely anaphylactic responses, due to non-opiate receptor effects on mast cells, causing the release of histamine, leading to bronchoconstriction & hypotension

Question 16

What do you give in opiate overdose?

Answer 16

Treat with Naloxone, which is an antagonist of the μ receptor, rapidly reversing adverse agonistic effects, such as respiratory depression.
Naloxone has a short t ½ (1 hour) therefore repeated doses may be needed.

Question 17

What are the two acts of parliament governing drug prescrio]ption?

Answer 17

o Some opioid analgesics are controlled drugs
o Misuse of Drugs Act 1971
o Misuse of Drugs Regulations 2001

Question 18

Give four schedule 2 drugs?

Answer 18

o Diamorphine (heroin)
o Morphine
o Remifentanil
o Pethidine

Question 19

What is the metabolisation of morphine?

Answer 19

-> Morphine -6- glucuronide + Morphine – 3 - Glucoronide

Question 20

Why is diamorphine twice as potent?

Answer 20

 Diamorphine is twice as potent as Morphine, as it has greater penetration of the Blood-Brain Barrier. It is metabolised to 6-Acetylmorphine and therefore morphine in the body. Two acetyl groups give it greater lipid solubility.
 Diamorphine (Pseudocholinesterase) -> Monoacetyl morphine -> Morphine

Question 21

What is pethidine?

Answer 21

 Pethidine is more lipid soluble than morphine, and it has rapid onset and short duration of action, making it useful in labour.

Question 22

What is buprenorphine?

Answer 22

 Buprenorphine has both agonist and antagonist actions at opioid receptors. May precipitate withdrawal symptoms in patients dependent on other opioids.

Question 23

What does codeine do?

Answer 23

 Codeine has about one twelfth the analgesic potency of Morphine. It needs to be metabolised by CYP2D6 into Morphine to become pharmacologically active (10% of people lack this enzyme).

Question 24

Outline some new endogenous opioid peptides

Answer 24

New peptides involved in pain relief include endogenous opioid, nociception and its antagonist nocistatin. They bind to ORL1, along with endomorphin-1 and endomorphin-2