Ep 25 – Oxycodone for the FRCA Primary

Don't miss out on all the other opiate episodes from GasGasGas

Fentanyl : Morphine : Methadone : Alfentanil : Tramadol : Oxycodone : Remifentanil : Diamorphine

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Classification

• Major class: Opioid analgesic (strong)
• Sub‑class: Phenanthrene derivatives (morphine analogues)
• Legal class (UK): Controlled Drug, Schedule 2 (Misuse of Drugs Act).

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Presentation

Form	Concentration / Strength	Route
Immediate‑release tablets/capsules	5, 10 mg	PO
Modified‑release tablets ("OxyContin®")	5–160 mg	PO
Oral liquid	1 mg mL⁻¹	PO
Solution for injection	10 mg mL⁻¹ (1 mL amp)	IV, SC, IM
†availability country‑specific.

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Mechanism of Action

Full agonist at μ‑opioid receptors (dominant), with weaker δ and κ activity. μ‑receptor activation couples to Gi/o proteins → ↓adenylyl‑cyclase → ↑K⁺ efflux & ↓Ca²⁺ influx → neuronal hyper‑polarisation and reduced nociceptive neurotransmitter release in the dorsal horn and periaqueductal grey (PAG) matter.

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Pharmacokinetics

	Key data	Clinical implication
Absorption	Oral bio‑availability 60–87 % (cf. morphine ≈ 30 %)	Reliable oral effect
Distribution	Vd 2.6 L kg⁻¹; 45 % protein‑bound; crosses placenta & breast milk	Caution as always in babs
Metabolism	Hepatic: CYP3A4 → nor‑oxycodone (minimally active metabolite); CYP2D6 → oxymorphone (Active, ×10–45 potency) (N-Demethylation reactions)	2D6 polymorphisms alter efficacy % potential toxicity
Excretion	19 % unchanged in urine; remainder as conjugates; CL ≈ 0.8 L min⁻¹	Accumulates in ESRF, consider dose reduction
Half‑life	IR 3–5 h; MR ≈ 12 h	Steady‑state ≈ 24 h

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Pharmacodynamics

• Potency: ≈ 1.5 × morphine (parenteral), ≈ 2 × morphine (oral).
• Onset: IV 1–3 min (peak 5 min); oral IR 30 min.
• Duration: IV 3–4 h; oral MR 8–12 h.
• Ceiling effect: None (full agonist) but limited by adverse effects.
• Dose–response modifiers: Age, renal/hepatic impairment, 3A4 inhibitors/inducers, 2D6 genotype.

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Clinical Uses / Indications

Indication	Typical adult dosing
Post‑operative IV PCA	Demand 1 mg, lockout 5–8 min, no background (institution‑specific) Sometimes a morphine PCA takes a while to get to a therapeutic level unless boluses are used
IV bolus for acute pain	1–2 mg slow IV q5 min (max 0.1 mg kg⁻¹)
Oral IR step‑up	5 mg PO q4–6 h (titrate)

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Contraindications and Precautions

• Absolute: Hypersensitivity;
• Relative / caution: Renal or hepatic failure, head injury (↑CO₂ drive), pregnancy & lactation, elderly/frail, concurrent CNS depressants, obstructive sleep apnoea.

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Side Effects / Complications

System	Common	Serious / rare
CNS	Sedation, euphoria, dizziness	Seizures, myoclonus
Respiratory	Dose‑dependent depression	Arrest in overdose
GI	Nausea, vomiting, constipation	Ileus, biliary spasm
CVS	Mild vasodilation → hypotension	Bradycardia (high doses)
Derm	Pruritus, flushing
Endocrine	Hypogonadism (chronic/abuse)

Management of overdose: Naloxone 0.1-0.4 mg IV, repeat if many repeats may need infusion

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Drug Interactions

• CYP3A4 inhibitors (clarithromycin, azoles, ritonavir) ↑ levels → toxicity.
• CYP3A4 inducers (rifampicin, carbamazepine) ↓ efficacy.
• CYP2D6 ultra‑rapid metabolisers → ↑oxymorphone → toxicity.
• CNS depressants (benzodiazepines, alcohol) ↑ respiratory depression.
• Serotonergic drugs (SSRIs, MAOIs, linezolid) → serotonin syndrome (rare++).

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Clinical Relevance / Key FRCA Points

1. Oral bio‑availability is twice that of morphine, use lower equianalgesic doses.
2. Metabolism split: 3A4 makes it weak; 2D6 makes it potent, genetic and drug interactions deserve attention.
3. Modified‑release oxycodone is no longer licensed for post‑op pain in the UK (MHRA, 12 Mar 2025).
4. Equipotent conversion: 10 mg PO oxycodone ≈ 20 mg PO morphine; 1 mg IV oxycodone ≈ 2 mg PO oxycodone.
5. In renal failure, active metabolites accumulate, choose alternatives (e.g., fentanyl, buprenorphine) or reduce dose.

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References

1. MHRA. Drug Safety Update: Prolonged‑release oxycodone removal of post‑operative indication. 12 Mar 2025.
2. NICE. NG193: Chronic pain (primary and secondary) in over 16s. 2021.
3. ONS. Drug‑poisoning deaths in England & Wales, registrations 2023. Office for National Statistics; 2024.
4. Kinnunen, M., Piirainen, P., Kokki, H. et al. Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone. Clin Pharmacokinet 58, 705–725(2019). https://doi.org/10.1007/s40262-018-00731-3
5. Riley, J., Eisenberg, E., Müller-Schwefe, G., Drewes, A. M., & Arendt-Nielsen, L. (2007). Oxycodone: a review of its use in the management of pain. Current Medical Research and Opinion, 24(1), 175–192.

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Podcast Information

Transcript GasGasGas Episode 24: Oxycodone Pharmacology

Introduction and Historical Context

00:30-01:57

And let's get on with the show. Hello everyone, this is James at Gas, Gas, Gas. This episode is going to smash the doors down on oxycodone.

Now, when I actually first started anaesthesia, I definitely had not prescribed very much oxycodone. It was always morphine and codeine, and Oramorph on the wards, wasn't it? It's certainly crept in amongst the corners in the shadows over the last few years. It was always the drug we sort of went for when the patient had dodgy kidneys and needed pain relief.

I always was under the impression that it was actually quite a new morphine-like drug. Turns out in 1916 in Germany - Germany seems to be a busy place for synthesising opioids - they developed oxycodone, calling it Eukodal. Now apparently this was a drug that was quite heavily utilised during World War II and maybe Hitler had a penchant, or at least his physicians had a penchant, for administering Eukodal.

But bringing it up to the 21st century, 12th of March 2025, in the UK, oxycodone loses its licence for post-op pain control in its prolonged release version alongside prolonged release morphine. So you can only administer short-acting morphines now. Unless of course you go off licence, which we don't not do anyway.

So I mentioned oxycodone and Germany in 1916. The company was Freund and Speyer and they were fiddling about as it seems quite a few pharmacists or chemists at the time used to, and from thebaine they derived oxycodone.

Chemical Classification and Modern Development

01:57-03:58

Summary: Oxycodone's classification as a semi-synthetic opioid and the controversial role of Purdue Pharma.

We could describe oxycodone as a semi-synthetic opium alkaloid derivative derived from thebaine. T-H-E-B-A-I-N-E. Thebaine.

So why on earth did I think that oxycodone was actually quite a modern opioid? Well it's probably courtesy of Purdue Pharma. I'm sure you've probably heard of these guys. They developed an extended release version of oxycodone and called it OxyContin, and this was approved by the FDA in the United States in 1995.

But what also came along with this FDA approval was a prolific, planned and pernicious advertising campaign that framed OxyContin as a drug that is safer than morphine with lower addiction rates, less tolerance and is less likely to be abused. And they thoughtfully targeted physicians. You know, everyone had a lovely time and probably had lots of dinners out eating steak. But that led to the massive uptick in prescribing of oxycodone.

Now, actually, oxycodone possibly is a bit more addictive than morphine on paper. And it is more potent than morphine as we know. But I think the real nail in the proverbial coffin, if you forgive the slightly negative pun there, is that Purdue Pharma, owned by the Sackler family, is now bankrupt and having to invest heavily in programmes to treat opioid addiction. And they had got hit by a six billion dollar fine.

So it's there in black and white. Well, they did bad, but the drug may be quite good. I had the misconception that actually took a while to work, wasn't very good because, you know, morphine takes a while to work, isn't very good. If you give someone IV oxycodone, the onset time seems spectacularly fast and they feel much better. I was stunned having administered an IV to an awake patient in ITU in acute pain once. I was like, "wow, gosh, shock horror. Pain controlled." And it lasts for quite a long time.

But, you know, we all know that opioids are habit forming. So we need to be thoughtful and manage how we go about giving these and have plans for winding people back down and getting them off it when they don't require it anymore.

Clinical Considerations and Harm Reduction

03:58-06:27

Summary: Discussion of prescription monitoring, safety measures, and basic pharmacology.

Anyway, lots of waffling. You all know about prescription drug monitoring programmes in the community, potentially co-prescribing naloxone on the wards, and I think that's now happening in the community as well in order to try and mitigate the number of deaths. We're going to talk about the number of deaths later. We need to get into the bulk of the show. You're here to study for the FRCA, and I'm getting carried away, and it's minute six.

Basic Pharmacology

So oxycodone is an opioid. That means it's synthetic. It is available in immediate and modified release preparations, and the routes can be intravenous, oral, subcutaneous, or PR, if that suits your needs.

As we all know, it is a mu and delta agonist, although again it seems to prefer mu somewhat, and we all know that opioid receptors are G-protein coupled receptors that ultimately lead to reduced synaptic transmission and those pain signals aren't getting very far up the spinal cord courtesy of its effects. But do remember that it's not just in the spinal cord that we find these receptors but also in your brain. Its effects are sedating, anxiolytic, it's an antitussive as are all opioids generally, and it causes some sedation and euphoria as well.

Oh, this all sounds great. How do you dose it, you ask?

Dosing Guidelines

Well, it is about 1.5 to 2 times the strength of morphine. So generally speaking, if you've got a fit, healthy young adult who you would have given 10 milligrams of IV morphine to without really thinking twice, maybe give them 5 milligrams or 7.5 milligrams of oxycodone. Orally, it generally comes in at about 5 milligrams to start with QDS. So that's great.

Side Effect Profile

06:27-06:58

Summary: Comprehensive overview of oxycodone's adverse effects across organ systems.

Now we know how to dose it, but what are the patients going to complain about when they have oxycodone?

Well, they can get orthostatic hypotension apparently, but generally speaking, like with all opioids, it's a very cardiovascularly stable agent.

It will cause respiratory depression. And remember, respiratory depression isn't just a diminished respiratory rate, but it might be worth thinking about it broadly as, well, if they're not coughing as much, they're less likely to clear secretions, they're more likely to get pneumonia. They might be breathing eight times per minute, but actually they're not taking terribly deep breaths and they're getting basal atelectasis, another predisposition to getting infections and bugs. So not just a singular respiratory depression effect.

From a nervous system perspective we're going to see drowsy people. Maybe they feel a bit good. If they have too much they might start hallucinating or if they're particularly sensitive they might hallucinate, and you're more likely to predispose your patient to delirium if they're having lots of opioids. But these are all general opioid problems, not specific to oxycodone.

As with all the other opioids it makes you feel sick a bit. It can cause you to have constipation and reduce GI motility. It might put some people into urinary retention.

And generally, it's an opioid. That's all fun and games. And you could pretty much spout that off for any opioid in the exam. And, you know, they would respect that as a reasonable answer.

Pharmacokinetics

06:58-09:56

Summary: Detailed breakdown of absorption, distribution, metabolism, and elimination.

However, kinetics, you know, pharmacokinetics, they are particular to individual drugs, which is, you know, deeply frustrating for all involved. So we like to compare and contrast.

Absorption and Distribution

Oxycodone, absorption: 60 to 87% oral bioavailability. That's really quite good. Morphine has a bioavailability of like 30%. That's why your 10 milligrams of Oramorph is equivalent to 3 milligrams of IV morphine.

With immediate release oxycodone preparations, the peak plasma concentration occurs in about 1-1.5 hours.

How is it distributed throughout the body? Well, it is about 45% protein bound, chiefly to albumin. Its volume of distribution at steady state, which is a bit of a weird thing to suggest a volume of distribution as, is 2.6 litres per kilogram. This is, I think, after a 4-hour infusion. It's quoted in one of those papers I've had the delight of reading to prepare.

It also crosses the placenta and it is also found in breast milk.

Metabolism and Active Metabolites

Now, something a bit more interesting is how is it metabolised? And I bet you can guess it is chiefly metabolised in the liver. Ta-da! Much like almost all those other opioids except for, you guessed it, remifentanil, which your plasma handles itself.

So we all know of CYP450 3A4 and CYP450 2D6 and those delightful little enzymes are busy with oxycodone as well.

45% of oxycodone is cleared by 3A4 into noroxycodone, which is weak, feckless, and doesn't really do very much. A non-problem.

Whereas our dear colleague CYP450 2D6, which is a busy little enzyme, as we all remember now, converts about 19% of oxycodone into oxymorphone. This is a super duper potent active metabolite, 10 to 45 times more potent than oxycodone and really does like those opioid receptors.

Now generally speaking if you took a cross-section of the whole population and then said "oh is that oxymorphone metabolite a bother?" you would say on average no it ain't. However in our unfortunate cohort of patients who are endowed with an exceedingly busy CYP450 2D6 - an ultra-metaboliser - then you're going to get quite a spike of that there oxymorphone and you might actually have complications from it.

Although it's very hard to tease this out of literature, isn't it? Because you've got to figure out who the ultra-metabolisers are and that's not very easy.

You may also have another cohort within this group who has the opposing CYP2D6 polymorphism bother where about 5-10% of Caucasians have no activity, in which case they might get less pain relief from oxycodone. Unlike with codeine whereby they get no effect because codeine on itself ain't really very busy, but once it gets converted to morphine by the liver, hey presto, you've got some pain relief.

There is one more step in this whole pathway and that is that both of these metabolites, noroxycodone and oxymorphone, can be converted into noroxymorphone. This is potent but can't get across the blood-brain barrier.

Elimination and Clinical Considerations

09:56-11:26

Summary: Renal elimination and considerations in organ failure.

So now we've done loads of metabolising and mixing and making in the liver, but how do we get rid of these things? Well, you've guessed it, it is the kidneys. So all these metabolites are kicked out into the urine.

About 19% of the free drug is eliminated in the urine. 50% is conjugated oxycodone and then they say about 14% is oxymorphone. Remembering there are other bits and pieces and metabolites and things that we're not going to talk about that also cleared in the urine.

With the immediate release preparation the elimination half-life is about three hours and clearance is 800 millilitres per minute.

Organ Failure Considerations

Important things to note is that if a patient has liver failure they're going to accumulate oxycodone, they're going to get encephalopathy. And patients with end-stage renal failure, they're going to accumulate drug aren't they?

The reason why I think we're a bit happier with oxycodone in renal failure than morphine in renal failure is the metabolites are less potent. Although if you are really deeply, superbly concerned, buprenorphine is something that is cleared almost entirely by the liver and therefore really does dodge the renal problem.

Clinical Uses

So how do we use oxycodone in the hospital? Well you know it's approved for moderate to severe pain, chiefly acute pain, but also it's used in cancer pain and palliative care, and it's one of those drugs that you might rotate a patient onto to rotate them off something else if you're managing chronic pain.

We need to be aware that giving it to someone for chronic pain probably doesn't help them very much and the role of some of these pain clinics is actually to try and eventually reduce the opioid dependence in these cohorts.

Public Health Perspective

11:26-12:56

Summary: Statistics on drug-related deaths and the broader opioid crisis.

Now what about abuse of this drug? So in the UK in 2023, 5400 and something drug poisoning deaths, 47% of these involved an opioid and mortality has doubled since 2012 - and that's off the Office for National Statistics.

The trends in the US, I think they've got a little bit more data in some ways, is 80% of overdose deaths are now fentanyl related in the United States and that's probably because it's easier to transport, get across the borders, it's easily concentrated and therefore, you know, a kilogram bag of fentanyl goes much further than a kilogram bag of heroin.

Summary and Conclusion

12:56-End

So overall, oxycodone: interesting history in that it was perhaps an excellent test case for proving how pharmaceutical companies really do need to be actually kept a bit of an eye on when they're getting up to mischief like advertising drugs that are great when really they're secretly not. Which does seem to happen a worryingly large amount of the time. Especially when they refuse to compare their drugs against the competitors and only compare their drugs against previous drugs that they've already invented.

But anyway, oxycodone: synthetic opioid, stronger than morphine, more bioavailable than morphine so easier to give orally, perhaps more addiction forming, has the potential for some potent active metabolites although on average we can manage that. And again, you just have to know about CYP2D6 and these patients. If codeine ain't working for them, then oxycodone is probably actually quite a safe choice, although they won't get as much of an effect as perhaps the average patient.

So thanks for listening. I've tried not to ramble along too much on that. Like you, I'm excited to finish covering all the opioids because whilst you need to learn them, and I'm glad that you're paying attention and learning about all these opioids, I'm excited to do something else.

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