Morphine and Other Opioids

Question 1

True or false:

Opioids are naturally-occurring compounds

Answer 1

False. The term ‘opioids’ encompasses all ligands that act at opioid receptors. These include endogenous substances, e.g. enkephalins, endorphins and dynorphins; naturally occurring exogenous substances (opiates) e.g. morphine, and synthetic drugs, e.g. fentanyl.

Question 2

True or false:

Opioids act at G-protein coupled receptors

Answer 2

True

Question 3

True or false:

Equi-analgesic doses of µ agonists cause a similar degree of respiratory depression

Answer 3

True. At equi-analgesic doses all opioids acting through the μ receptor will demonstrate similar μ receptor-related side-effects.

Question 4

True or false:

All opioid side-effects are mediated by opioid receptors

Answer 4

False. Pruritis is a common side-effect, particularly with subarachnoid or epidural administration, and is mediated by histamine release.

Question 5

True or false:

Speed of onset of analgesia after IV administration depends primarily on lipid solubility

Answer 5

True. Fentanyl and structurally related opioids have high lipid solubilities and rapid onset after an IV dose. Morphine is much less lipid soluble and the onset of analgesia is significantly slower.

Question 6

Regarding morphine and structurally related drugs (true or false):

Morphine is a naturally occurring opium alkaloid

Answer 6

True

Question 7

Regarding morphine and structurally related drugs (true or false):

The typical duration of action of a bolus dose of morphine is 2-3 h

Answer 7

True. This correlates with its elimination half-life, but is subject to great interindividual variability.

Question 8

Regarding morphine and structurally related drugs (true or false):

The principal metabolite of morphine is the 6-glucuronide

Answer 8

False. The principal metabolite is M3G, which is inactive, but M6G is of concern as it is a μ agonist.

Question 9

Regarding morphine and structurally related drugs (true or false):

Diamorphine is a pro-drug

Answer 9

True. It has no activity, but is metabolised to 6MAM and morphine.

Question 10

Regarding morphine and structurally related drugs (true or false):

When used clinically, diamorphine has twice the potency of morphine

Answer 10

True

Question 11

Is the following true or false concerning morphine?

Increases the production of antidiuretic hormone (ADH).

Answer 11

True

Question 12

Is the following true or false concerning morphine?

May cause bronchospasm.

Answer 12

True. Due to possible histamine release associated with morphine.

Question 13

Is the following true or false concerning morphine?

Has a higher affinity for the opioid receptor than diamorphine.

Answer 13

True. Diamorphine has almost no affinity for the opioid receptor and is a prodrug of morphine.

Question 14

Is the following true or false concerning morphine?

Causes direct myocardial depression.

Answer 14

False. Morphine does not cause direct myocardial depression, although it may cause a bradycardia. The hypotension associated with its use is because of a decrease in the systemic vascular resistance (SVR) which is due, in part, to histamine release.

Question 15

Is the following true or false concerning morphine?

Is a phenylpiperidine.

Answer 15

False. Phenylpiperidines include pethidine and fentanyl, whereas morphine is a phenanthrene.

Question 16

What is the relative potency of pethidine compared with morphine?

Answer 16

Pethidine has one tenth of the potency of morphine

Question 17

What is oral bioavailability of pethidine?

Answer 17

50%

Question 18

True or false:

Pethidine is more lipid soluble than morphine

Answer 18

True. Pethidine is much more lipid soluble than morphine, and crosses the blood-brain barrier faster, giving it a more rapid onset of action. It has a shorter duration of action than morphine.

Question 19

What is the important metabolite of pethidine?

Answer 19

Norpethidine. It is epileptogenic.

Question 20

What is the elimination half-life of pethidine and what is the elimination half-life of norpethidine?

Answer 20

The elimination half-life of pethidine is about four hours but that of norpethidine is much longer (14–21 h). The elimination of norpethidine is dependent on renal function so it may accumulate in patients with renal dysfunction: it is epileptogenic.

Question 21

What is the significant group of drugs to be aware of with pethidine due to a potential serious drug interaction?

Answer 21

There is a serious drug interaction between pethidine and monoamine oxidase inhibitors (MAOIs), which causes cardiovascular instability, convulsions and coma.

Question 22

What is the active metabolite of fentanyl?

Answer 22

Fentanyl has no active metabolites. It is dealkylated to norfentanyl, which is inactive.

Question 23

What is the relative potency of fentanyl compared with morphine?

Answer 23

Fentanyl is 100 times more potent than morphine

Question 24

Why does alfentanil have a more rapid onset of action than fentanyl despite being less lipid soluble?

Answer 24

Because nearly 90% of unbound drug is non-ionized (compared with 9% for fentanyl), creating a large concentration gradient across the blood-brain barrier. This is due to it’s pKa being 6.5.

Question 25

What is the elimination half-life of alfentanil?

Answer 25

Its elimination half-life is 1.6 h, mainly because its relatively low lipid solubility results in a much smaller volume of distribution than fentanyl. Alfentanil has a very short duration of action: its redistribution half-life is 11 min.

Question 26

Name three phenylpiperidines.

Answer 26

Pethidine Fentanyl Alfentanil Tramadol

Question 27

What is the principle breakdown product of remifentanil?

Answer 27

The main breakdown product is a carboxylic acid derivative, which has only 0.1% of the potency of the parent compound, and thus has clinically insignificant pharmacological effects.

Question 28

Regarding phenylpiperidines and esters (true or false): Pethidine (meperidine) is a less potent analgesic than morphine

Answer 28

True. Pethidine has one tenth the potency of morphine but, like morphine, is a μ agonist and has the same efficacy.

Question 29

Regarding phenylpiperidines and esters (true or false): Fentanyl always has a short duration of action

Answer 29

False. The duration of action of fentanyl is dose-dependent, and varies significantly between individuals.

Question 30

Regarding phenylpiperidines and esters (true or false): Alfentanil given IV has the most rapid onset of all opioids licensed in the UK

Answer 30

True

Question 31

Regarding phenylpiperidines and esters (true or false): Fentanyl and remifentanil are approximately equipotent

Answer 31

True

Question 32

Regarding phenylpiperidines and esters (true or false): Remifentanil is metabolised by plasma cholinesterase

Answer 32

False. Remifentanil is metabolised by non-specific plasma and tissue esterases. There are no abnormal variants of these enzymes, and there are insignificant interindividual differences in its pharmacokinetics.

Question 33

How is overdose of tramadol different to other opioids?

Answer 33

Seizures occur in up to 15% of cases; this is more common than with other opioids. In severe poisoning coma, seizures and hypotension can occur. Overdose can also cause serotonin syndrome which is potentially fatal. Tramadol overdose does also result in drowsiness, constricted pupils, agitation, tachycardia (as opposed to bradycardia with morphine), hypertension and nausea, vomiting and sweating.

Question 34

Regarding opioid pharmacodynamics (true or false): Anti-nociception and major side-effects of opioid drugs are mediated by the μ receptor

Answer 34

True. The drugs covered in this session are selective μ agonists. However, anti-nociception is also mediated by κ and δ receptors.

Question 35

Regarding opioid pharmacodynamics (true or false): Opioids exhibit stereo-specificity

Answer 35

Most opioids are used as single stereoisomers: their enantiomers do not conform to the opioid receptor and have little or no activity.

Question 36

Regarding opioid pharmacodynamics (true or false): In equi-analgesic doses all opioids cause serious side-effects to a similar degree

Answer 36

True. Respiratory depression, nausea, constipation, euphoria and dependence are all mediated by the μ receptor.

Question 37

Regarding opioid pharmacodynamics (true or false): Tramadol has a different mode of action from other μ agonists

Answer 37

True. Tramadol has weak μ affinity and also acts by inhibition of 5-HT and noradrenaline uptake.

Question 38

Regarding opioid pharmacodynamics (true or false): Some of the side-effects of morphine and pethidine are caused by histamine release

Answer 38

True

Question 39

Regarding opioid pharmacokinetics (true or false): Opioids generally have low oral bioavailability

Answer 39

True. Opioids are subject to first-pass metabolism. Bioavailability of some opioids is so low that they cannot effectively be administered orally. Codeine derivatives (codeine, oxycodone, tramadol) have the highest bioavailability; approximately 70%.

Question 40

Regarding opioid pharmacokinetics (true or false): The elimination half-life of morphine is approximately three hours

Answer 40

True. However, there is a very large interindividual variation in t1/2β among normal subjects.

Question 41

Regarding opioid pharmacokinetics (true or false): The elimination half-life of fentanyl is shorter than that of morphine

Answer 41

False. t1/2β is typically 3-4 h.

Question 42

Regarding opioid pharmacokinetics (true or false): Fentanyl and alfentanil have clinically active metabolites

Answer 42

False. Fentanyl and alfentanil have inactive metabolites.

Question 43

Regarding opioid pharmacokinetics (true or false): The plasma half-life of remifentanil is unaffected by hepatic or renal function or duration of infusion

Answer 43

True. Remifentanil is metabolised by plasma esterases, and its plasma half-life is predictable (about 5 min).

Question 44

Regarding the use of opioids (true or false): Opioids produce better quality of analgesia when given as part of a multi-modal analgesic regimen

Answer 44

True. NSAIDS and paracetamol decrease opioid requirements (morphine sparing effect) and improve the quality of analgesia.

Question 45

Regarding the use of opioids (true or false): Dosage requirements for morphine decrease with increasing age

Answer 45

True. This is partly due to volume of distribution of morphine decreasing with increasing age.

Question 46

Regarding the use of opioids (true or false): The dosage of opioids required to produce analgesia is predictable

Answer 46

False. Both pharmacodynamics and pharmacokinetics exhibit great interindividual variation.

Question 47

Regarding the use of opioids (true or false): Fentanyl PCA is a good option for postoperative analgesia in patients with renal dysfunction

Answer 47

True. Accumulation of active metabolites may cause problems with other opioids; fentanyl has no active metabolites.

Question 48

Regarding the use of opioids (true or false): Tramadol may be a better option than other opioids for patients in whom respiratory depression is of particular concern

Answer 48

True. Tramadol has a different mode of action, as well as weak μ agonism and, as a result, a different side-effect profile; in particular, it causes less respiratory depression.