Individual characteristics of opioid drugs

In this step, Dr Thomas Reed, Core Anaesthesia Trainee at Kings College Hospital London, and Dr Dermot McGuckin, Specialty Registrar in Anaesthesia and Pain Medicine at UCLH, discuss how the pharmacokinetics of individual opioids affect how we use them clinically.

As you have learned in previous steps, a characteristic shared by all exogenous opioids is their interaction with the MOP receptor. However, their differing chemical structures give each opioid distinct physicochemical and pharmacokinetic properties.

You will now look at the specific characteristics of some frequently used opioids more closely, with a specific focus on how they influence how we use them clinically.

Please note that the specific drugs available in common clinical practice in different countries will depend on local licensing by regulatory agencies. This is also not an exhaustive list.

Supplementary reading is available to download at the end of this step. Dr Luke Mordecai discusses the pharmacokinetics of opioid infusions and how this influences our choice of opioid for infusion.

Alfentanil

Alfentanil is a synthetic opioid, derived from phenylpiperidine. It has a similar chemical structure to fentanyl, but with some key differences. Alfentanil is less lipophilic, and therefore less potent than fentanyl, yet it has a faster onset of action (1-2 minutes). Two mechanisms are responsible for this: firstly, alfentanil is much more un-ionised (up to 90%) at the body’s pH. It is therefore able to cross effect site cell membranes more readily. In comparison, only 9% of fentanyl exists in un-ionised form at the physiological pH of 7.4. Secondly, being less lipophilic, it is less readily absorbed by other tissues (it has a smaller volume of distribution), meaning a greater concentration gradient between plasma and the effect site of the drug resulting in faster diffusion at the effect site.

This smaller volume of distribution also means alfentanil is eliminated faster than fentanyl, despite having a smaller clearance value (duration of action approximately 10 minutes).

Alfentanil is also exclusively metabolised in the liver via CYP3A3/4, as is midazolam; therefore, concurrent use of one will increase the half-life of the other.

Buprenorphine

Buprenorphine is an atypical opioid with several mechanisms of action. Although it acts as a partial MOP receptor agonist in vitro, more recent evidence suggests it behaves as a full agonist at clinically relevant doses used in pain management in vivo. It is a partial agonist at NOP receptors, and an antagonist at KOP receptors. Relative to morphine, it has a slower onset but longer duration of action of up to 10 hours owing to its high affinity (it dissociates very slowly from the MOP receptor site).

Up to two-thirds of mainly unchanged buprenorphine is excreted via faeces and the remainder undergoes metabolism via the liver and gut wall to form largely inactive metabolites, making it safer for use in renal impairment.

Buprenorphine’s high lipid solubility makes it suitable for delivery via transdermal patch as well as sublingually. Transdermal buprenorphine demonstrates a ceiling effect of respiratory depression (i.e. increasing the dose doesn’t increase the risk of opioid-induced ventilatory impairment [OIVI]), although this is lost when combined with another CNS depressant drug and deaths associated with its use have been reported.

Codeine

Codeine is a methylated morphine derivative. It has a slightly higher oral bioavailability (50%) than morphine, but is ten times less potent. Codeine itself is a low-affinity MOP-receptor agonist, its analgesic effect comes from the 10% that is converted to morphine via the CYP2D6 cytochrome P450 isoenzyme. Significant genetic variation exists in CYP2D6 activity, as described in Step 2.10.

Dihydrocodeine

Dihydrocodeine is a semisynthetic low-affinity opioid agonist. Derived from codeine, it is structurally similar but twice as potent when given orally. It is less dependent on CYP2D6 metabolism to bring about its analgesic effect. It therefore exhibits less inter-individual variability, although it is in part metabolised by this enzyme to form dihydromorphine which has a much higher affinity at the MOP-receptor than dihydrocodeine.

Diamorphine

Diamorphine is a synthetic diacetylated derivative of morphine which acts as a prodrug—rapid hydrolysis produces morphine and monoacteylmorphine (MAM) as metabolites, which exert their analgesic properties (diamorphine itself has no affinity for opioid receptors).

Owing to extensive first pass metabolism, diamorphine’s oral bioavailability is low, limiting its use orally. Its high lipid solubility, on the other hand, makes it suitable for use via both subcutaneous and neuraxial routes – MAM is able to cross the blood-brain barrier more readily than morphine, resulting in a faster onset of action and reduced risk of delayed respiratory depression relative to morphine when given via epidural or intrathecal routes. Here, its duration of action can extend to up to 18-24 hours.

It is metabolised rapidly in the liver, plasma and CNS, resulting in a plasma half-life of approximately 5 minutes, although the duration of analgesia is longer than this as the half-lives of its active metabolites are longer. It is excreted predominantly via the urine.

Fentanyl

Fentanyl is a synthetic opioid derived from phenylpiperidine, like alfentanil, and it is a full agonist at the MOP receptor. Fentanyl is extremely lipid soluble (approximately 600 times more than morphine), which has several important implications.

Firstly, it is significantly more potent than morphine as a result – reflected by a dramatic dose reduction in comparison.

Secondly, it has a faster onset of action (<5 minutes) relative to morphine. In discrete doses of 1-2micrograms/kg, fentanyl has a shorter duration of action (approximately 30 minutes) due to redistribution; this becomes significantly prolonged when it is given as an infusion as tissues become saturated and its context-sensitive half-life (the half-life depending on the duration of the infusion) increases.

Finally, its lipophilicity makes fentanyl suitable for use transdermally as a patch as it is well absorbed via the skin, as well as sublingually. In the UK, sublingual administration is only licensed for use in cancer pain.

Fentanyl undergoes elimination almost exclusively via the liver to inactive metabolites, therefore making fentanyl more suitable than morphine or oxycodone in patients with renal impairment, although a dose reduction may still be required (as up to 10% of fentanyl is excreted unchanged via the kidneys).

Hydromorphone

Hydromorphone is another morphine derivative, also a full agonist at the MOP-receptor site and is 5 times as potent. When administered orally, it has a bioavailability of approximately 30% and a similar onset of action as morphine. Hydromorphone-3- glucuronide (H3G) is the major metabolite, which may accumulate in renal impairment and precipitate neurotoxic effects.

Methadone

Methadone is a synthetic opioid predominantly used as opioid-substitution therapy in opioid use disorder as well as (less frequently) in chronic pain. It is composed of a racemic mixture (ie it contains equal proportions of two enantiomers, or molecules that form a ’mirror-image’ of each other: the R- and L- enantiomers). The R-enantiomer is significantly more potent, conferring most of methadone’s MOP receptor-induced analgesia. Methadone also acts as a weak NMDA-receptor antagonist and monoamine reuptake inhibitor, however, there is limited evidence to suggest it is effective in neuropathic pain.

Methadone has unusual pharmacokinetic activity – it has good oral bioavailability (up to 80%) but is highly bound to plasma proteins and tissue proteins (lipoproteins in the lungs, liver and kidney), with slow transfer between these, contributing to its long duration of action.

Metabolised predominantly by the P450 system, genetic variation and concurrent medication use will also affect its elimination. The inter-individual variation in peak plasma concentration and its unpredictable half-life (4-190h, mean 22h) mean methadone is not used in the treatment of acute pain owing to the risk of accumulation, and needs to be titrated slowly.

Morphine

Morphine is a naturally occurring opioid (hence, an opiate), acting at the MOP-receptor. It forms the standard against which other opioids are compared. Morphine is a weak base so, when given orally, it relies on absorption from the small bowel as it becomes un-ionised in the relatively alkaline contents here.

It undergoes extensive first pass metabolism resulting in an oral bioavailability of approximately 20-30%. When given intravenously/intramuscularly, its peak effect is seen between 10-30 minutes, with a duration of action between 3-4 hours.

Morphine’s low lipid solubility makes its use via epidural and intrathecal routes less desirable as its concentration in the CNS falls slowly, thereby increasing the risk of delayed respiratory depression.

It is predominantly metabolised in the liver and has two main metabolites: morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G is an MOP receptor agonist and is up to 13 times more potent than morphine, contributing significantly to its analgesic effect (as well as OIVI), whilst M3G has little to no analgesic properties owing to its low affinity for opioid receptors. Both metabolites are excreted via the urine and therefore accumulate in renal failure, requiring a dose adjustment or alternate opioid choice in these patients.

Oxycodone

Oxycodone is a semisynthetic opioid. Often considered as the main alternative to morphine in many settings, it has a faster onset and slightly longer duration of action (4-6 hours). It has greater oral bioavailability (up to 80%) in comparison to morphine (30%), and therefore requires a dose reduction of approximately half that of oral morphine, whilst intravenously it is equally potent to morphine.

It is metabolised in the liver via CYP3A4 and CYP2D6 to noroxycodone and oxymorphone (a potent MOP receptor agonist which may have analgesic properties). As a result, both genetic polymorphisms and concurrent medication use can influence a patient’s response to oxycodone, as previously discussed.

These metabolites, alongside up to 10% of unchanged oxycodone, are excreted via the kidney. Therefore, both hepatic and renal dysfunction result in delayed elimination, requiring a dose reduction here (oral bioavailability is increased by 90% and 60% in hepatic and renal dysfunction, respectively).

Pethidine

Pethidine is a synthetic phenylpiperidine derivative which acts on both MOP and KOP receptors. It is more lipid-soluble than morphine so has a faster onset of action and has a higher bioavailability (although is typically given intravenously or intramuscularly). This increased lipophilicity means it is able to cross the placenta easily and may accumulate in the foetus owing to reduced clearance – this is relevant as it used to be widely used in obstetric practice in the UK.

Pethidine is metabolised to pethidinic acid (inactive) and norpethidine, an active metabolite which is half as strong. Norpethidine accumulates in renal impairment, provoking neuroexcitatory symptoms including seizures and is not reversed by naloxone – as a result, it has become less favourable in comparison to other opioids.

Remifentanil

Remifentanil is a synthetic opioid and a pure MOP receptor agonist. It is only given intravenously, typically as a continuous infusion. In comparison to fentanyl and alfentanil, remifentanil’s duration of action is dependent wholly on metabolism rather than distribution. Rapid hydrolysis by non-specific plasma and tissue esterases means it has a duration of action of 3-10 minutes from the end of the infusion. The abundance of these esterases in the body means they cannot be saturated, thus the increasing duration of infusion has no effect on the duration of action – it has a ‘context-insensitive half-life’. This also means hepatic and renal impairment do not influence its elimination.

Tramadol

Tramadol is an atypical opioid acting both as an opioid agonist (with high affinity at the MOP receptor in particular) and as a serotonin-/noradrenaline-reuptake inhibitor (SNRI). Tramadol is a racemic mixture. The (+) enantiomer is more potent at inhibiting serotonin reuptake, and the (-) enantiomer more potent at inhibiting noradrenaline reuptake.

Additionally, it also stimulates pre-synaptic serotonin release modulating descending inhibitory pathways in the spinal cord, further contributing to analgesia. It has a high oral bioavailability greater than 70% and is approximately 1/5th to 1/10th the potency of morphine.

It undergoes hepatic metabolism, including via CYP2D6 and CYP3A4, and therefore its effect is subject to genetic polymorphisms in enzyme activity and concurrent medication use. Of note, selective serotonin reuptake inhibitors (SSRIs) often inhibit CYP2D6, increasing tramadol concentration, which in turn may lead to serotonin syndrome.

Chemical structures from Reaxys

References

_{Schug SA, Palmer GM, Scott DA, et al. Acute Pain Management: Scientific Evidence (5th edition). APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine, Melbourne (2020).}

_{Joint Formulary Committee. British National Formulary London: BMJ and Pharmaceutical Press.}