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Opioid metabolism

How are opioids metabolised and does this affect prescribing? This article explains the theory of opioid metabolism.
© Newcastle University
Opioids are metabolised by the liver, primarily so that they can be converted from lipophilic to hydrophilic molecules which are then excreted in urine. Some “parent” opioid molecules have little or no analgesic effect and must be converted to active metabolites by the liver. Opioid metabolism varies between individuals, which is one reason why patients must be closely monitored when these drugs are initiated or the dose increases.
There are two main types of opioid metabolism: modification reactions and conjugation reactions.

Conjugation reactions

Some opioids undergo a conjugation reaction called glucuronidation, through which they are joined to hydrophilic molecules. This metabolic pathway is less susceptible to drug-drug interactions than modification reactions. The following opioids are metabolised in this way.

Morphine

The are two main metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M3G has low affinity for opioid receptors and therefore has little analgesic effect. However, it is neuro-excitatory and may decrease the seizure threshold. M6G is both a potent analgesic and neuro-excitatory agent.

Diamorphine

Diamorphine is metabolised to morphine and subsequently behaves in a similar way to morphine.

Hydromorphone

Hydromorphone is metabolised to Hydromorphone-3-glucuronide (H3G). This structurally resembles M3G and has similar neurological effects.

Modification reactions

These oxidation-reduction reactions are catalysed by cytochrome P450 (CYP) enzymes. Many drugs are metabolised in these pathways, meaning drug-drug interactions can occur. Oxycodone, fentanyl, alfentanil and methadone are primarily metabolised in this way.

Oxycodone

The analgesic effect of oxycodone largely comes from the parent drug. The two principal metabolites of oxycodone are noroxycodone (inactive) and oxymorphone (active). Despite being ten times more potent than oxycodone, the amount of oxymorphone produced is so small that its clinical effect in humans is negligible. Oxymorphone is further metabolised by glucuronidation.

Fentanyl

Fentanyl is mostly metabolised to norfentanyl. None of fentanyl’s metabolites have clinically significant effects in humans.

Alfentanil

Like fentanyl, all the metabolites of alfentanil are inactive in humans. However, alfentanil metabolism is more unpredictable than that of fentanyl due to variations in individual enzyme expression.

Methadone

The metabolites of methadone are inactive and are excreted into the GI tract.

Codeine

Codeine is inactive in terms of analgesia until it is metabolised by CYP pathways to morphine. Some of the drug is also conjugated to codeine-6-glucuronide, which is itself pharmacologically active. Codeine should not be prescribed in the presence of hepatic impairment because its analgesic effect is unpredictable or absent.

Opioids and hepatic impairment

Liver function must be considered when prescribing opioids. Hepatic impairment may result in accumulation of the parent drug. This is particularly important for drugs, such as oxycodone, where the parent is the principal effector of opioid effects. Similarly the effects of opioids which produce active metabolites must be closely monitored.

The half lives of opioids tend to increase in the presence of hepatic impairment

In most instances of hepatic impairment, opioids should used with caution: consider prescribing at lower doses, with longer intervals between doses and using immediate release preparations. Patients must be monitored closely.
In the next step we will examine opioid elimination.
© Newcastle University
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