Ep 24 – Methadone for the FRCA Primary

Pharmacology Data for Methadone

• Class: Synthetic opioid analgesic
• Chemical Class: Diphenylheptane derivative (piperidine-based)
• Schedule: Controlled Drug (Class A, Schedule 2 in the UK)

Presentation

• Intravenous: Clear, colourless liquid
• Oral: Typically green-coloured liquid in the UK (for identification/deterrence purposes)
• Other routes: Subcutaneous, intramuscular, rectal

Clinical Use

• Opioid substitution therapy (e.g., heroin addiction)
• Chronic cancer-related pain, particularly in palliative care
• Neuropathic pain or opioid-resistant pain (due to NMDA antagonism)
• Postoperative pain, e.g., scoliosis surgery in paediatrics

Pharmacodynamics of Methadone

Mechanism of Action

Methadone primarily acts as:

• µ-opioid receptor agonist – classical opioid effects
• NMDA receptor antagonist – contributes to its role in neuropathic pain and opioid tolerance modulation
• 5-HT2A receptor agonist – serotonergic activity

This multimodal action gives methadone unique utility in both pain and addiction contexts, but also introduces risk for serotonin syndrome when combined with other serotonergic agents.

Dose for Methadone

1mg methadone approximate equivalence to 10mg morphine

IV Dosing : 0.1-0.2mg/kg 6-8 hourly

Cancer pain in the opiate naive
Oral 2.5mg TDS/BD , every 5-7 days can edge up.

Stark cessation naturally leads to opiate withdrawal if they’ve had a prolonged course.
Cessation requires a de-escalating course in ideal circumstances – if dosing is greater than 15mg or so a day.

Onset – 30 mins – 4-6 hour effect

Pharmacokinetics of Methadone

• Absorption: Oral bioavailability 70–80%
• Distribution:
  • Highly lipid-soluble
  • Large volume of distribution: 1–8 L/kg
  • 60–90% protein-bound (mostly α1-acid glycoprotein)
• Metabolism:
  • Hepatic, mainly via CYP3A4 and CYP2D6
  • CYP2D6 polymorphisms can prolong action (10% are poor metabolizers)
• Elimination:
  • Renal and faecal routes
  • Half-life: 15–55 hours (potentially up to 65 hours in chronic users)

Contraindications and Precautions

• Prolonged QT interval or history of arrhythmia
• Concomitant serotonergic agents
• Hepatic impairment
• CYP2D6 poor metabolizers
• Elderly/frail patients

Drug Interactions

• CYP3A4 and CYP2D6 inhibitors (many!)
• Other serotonergic drugs (many many many on the BNF….)
• Other QT-prolonging agents

Clinical Relevance / Key FRCA Points

• Methadone’s multiple receptor activity makes it unique among opioids.
• High oral bioavailability and long half-life differentiate it from morphine/fentanyl.
• Familiarity with CYP metabolism and pharmacogenetics is key.
• Recognising serotonin syndrome and QT prolongation are critical for FRCA viva and MCQ content.
• Likely to feature in comparative questions with morphine, fentanyl, buprenorphine.

Methadone Clinical Data Table

Name	Methadone
Class	Opioids
Stem	Synthetic piperidine derivative
Colour/Appearance	Enantiomeric mix – L-Methadone and R-Methadone (R is the active molecule) Routes : Oral, SC / IM or IV / rectal In the Uk a Green liquid oral preparation no idea why but perhaps so its obvious its been consumed
Molecular weight	309g/mol
Mechanism of action	Mu and Kappa GPCR Receptor Agonist Opiate Receptors are Gi Protein coupled GPCRs Hyperpolarization of pre-synaptic neuronal cell membranes by: * Increased K Conductance (Closure of K Channels) * Adenyl Cyclase Inhibition = <cAMP * Decreased Ca Conductance (Closure of Ca Channels) NMDA Antagonist Neuromodulatory effect on neurones  Serotonin Activity Binds to 5HT2a
Actions	Uses: Chiefly – Opiate withdrawal /addiction management Pain control (Spinal Surgery in kiddies as one example) Cancer related pain
PkA	PKA 9.2 1% unionised
Volume of distribution	1 – 8 L / kg
Half life	15-55 hours / 2-65 hours…. (very fat souble, so can have sighnificant tissue store of agent in prolonged use)
Dose	1mg methadone approximate equivalence to 10mg morphine  IV Dosing : 0.1-0.2mg/kg 6-8 hourly Cancer pain in the opiate naive  Oral 2.5mg TDS/BD , every 5-7 days can edge up. Stark cessation naturally leads to opiate withdrawal if they’ve had a prolonged course.  Cessation requires a de-escalating course in ideal circumstances – if dosing is greater than 15mg or so a day. Onset – 30 mins – 4-6 hour effect
Side Effects	CVS: Orthostatic Hypotension QT Prolongation (especially at 150mg+ a day Resp: Depressant Anti-Tussive CNS Potent analgaesic agent – Drowsiness, euphoria, hallucination, delirium Miosis from Edinger-Westphal nucleus stimulation Itching… GI Dry mouth Nausea Vomiting Constipation. Rarely – hypoglycaemia (Cancer patients / rapid uptitration) Renal Urinary retention Meta Diaphoreis, pruritis (not histamine mediated) Adrenal insufficiency
Kinetics:
Absorption	Excellent oral absorption as very fat soluble, peak onset varies muchly 1-5 hours.  Oral bioavailabiliy 70-80%
Distribution	Highly protein bound (60-90%) – to alpha1 glycoprotein mostly.
Metabolism	With extended use has a high half time (15-55 hours) – given it soaks into the patients tissue stores.  CYP 3A4 and 2D6 metabolism 10% of people on the 2D6 side dont do a good job of breaking down methadone – and have an extended effect.
Elimination	Faecal and urinary clearance
OTHER:	Reversed with naloxone

References & Further Reading

1. Davis MP, Walsh D. “Methadone for relief of cancer pain.” J Clin Oncol. 2001;19(23):4091–4097.
2. NICE. Overview | Methadone and buprenorphine for the management of opioid dependence | Guidance | NICE
3. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy. 2003 Jun;23(6):802-5. doi: 10.1592/phco.23.6.802.32186. PMID: 12820821.
4. [U.S. Food and Drug Administration. METHADOSE™ (methadone hydrochloride oral concentrate USP) prescribing information. NDA 017116, S-032. 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017116s032lbl.pdf
5. Moryl N, Pope J, Obbens E. Hypoglycemia during rapid methadone dose escalation. J Opioid Manag. 2013 Jan-Feb;9(1):29-34. doi: 10.5055/jom.2013.0144. PMID: 23709301.
6. Pharmacology of opioids – https://derangedphysiology.com/main/cicm-primary-exam/nervous-system/Chapter-334/pharmacology-opioids
7. Methadone in Pain Management: A Systematic Review, Hanna, Verina et al. The Journal of Pain, Volume 22, Issue 3, 233 – 245

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Podcast Information

Transcript GasGasGas Episode: Methadone Pharmacology

Introduction and Episode Overview

00:30-00:57

And let’s get on with the show. Hello everyone, this is James at Gas Gas Gas. Welcome to another episode of the Primary FRCA podcast. We’re going to smash through methadone today. I hope you’re finding this podcast useful and it is fitting into your day. If you reckon I need to improve things, change things, just drop a comment or send me an email. I’m super game to receive it. Anyway, getting on with the show.

Basic Properties and Formulation

00:57-01:27

Summary: Introduction to methadone’s chemical classification and available formulations.

Methadone. Methadone is a synthetic opioid – i.e. we’ve invented it as humans on planet Earth. It’s a derivative of piperidine, much like fentanyl, alfentanil, etc. It comes as a clear colourless liquid if it’s IV, or in the UK as an oral preparation with colouring, classically green, but I think it used to be brown as well. Now as to why it’s coloured, don’t really know, but I’m guessing it’s obvious if a bright green liquid has been drunk, as opposed to maybe being squirrelled away for later. Not that I’m jumping to any conclusions about anything in particular there.

It can be given orally, subcutaneously, intramuscularly, intravenously or rectally depending on your inclinations, and it’s important to note that it is an enantiomeric mixture, so you’ve got L-methadone and R-methadone, and it’s the R-methadone that is the active molecule.

Mechanism of Action: Opioid Receptors

01:27-02:57

Summary: Comprehensive review of opioid receptor mechanisms and methadone’s broader receptor activity.

Before we dip into all the pharmacokinetics, I’m yet again reminding you how opioids work because that’s a likely question to come up in a multitude of manners and clearly is something we should just know.

Standard Opioid Receptor Mechanisms

So opioid receptors are G-protein coupled receptors. There’s mu, delta, and kappa, and a load of other ones probably, but mu, delta, and kappa are important, and they are coupled to a Gi – i.e. an inhibitory subunit – that you will find on the other side of your cell membrane. Remembering that a G-protein coupled receptor is a serpentine transmembrane protein with seven transmembrane domains and a bunch of secondary messenger molecules on the internal side that are released on agonism, where they go and potter off and trigger intracellular pathways that yield changes in things. Things being, you know, vascular endothelium, bronchodilation, etc.

What happens when an opioid receptor is agonised? You trigger potassium channel opening – i.e. more potassium is getting outside your neuron. You cause closure of calcium channels – i.e. less calcium is getting inside your neuron. Calcium triggers the release of synaptic vesicles, and you inhibit adenylyl cyclase, which leads to less cyclic AMP, which also influences the activity of the neuron.

Methadone’s Additional Receptor Activity

But thinking about methadone, as with tramadol, it doesn’t just mess with mu, kappa, etc. receptors. Methadone potters along and binds to other receptors as well. So it is an NMDA receptor antagonist, so it influences the activity of neurons much like ketamine does. Methadone also has serotonin activity, binding to 5-HT2A, remembering that there’s loads of serotonin receptors.

Serotonin Syndrome Risk

03:27-04:32

Summary: Important clinical consideration regarding serotonin syndrome when using methadone with other agents.

Why is it important to know that methadone doesn’t just work on those things? Well, lots of medicines actually probably have a little bit of covert serotonin activity, and a number of anaesthetic agents we use also have some serotonin activity, or we perhaps may neglect to remember that fentanyl, for example, and alfentanil, and sometimes a bit of morphine, all can influence your serotonin activity. The summative effects of this could end up being serotonin syndrome if you were unforeseen.

And let’s just all recall that in serotonin syndrome you would find yourself with a classically agitated, fairly flushed, red, tremulous patient. You might have a tachycardia and a hypertension. They will go on to get more and more agitated, develop hyperreflexia. You can get ankle myoclonus that can be quite prominent. They can be bouncing around in the bed and if they’re really unfortunate, opsoclonus – i.e. myoclonic eyeballs where they’re bouncing around all over the place. You’re going to see it classically with combinations of serotonergic agents. Anyway, brief sojourn to intensive care medicine there.

Clinical Uses

04:32-05:32

Summary: Primary clinical applications of methadone across different medical settings.

Let’s just come back to methadone. So what do we use methadone for?

Addiction Management

So in the UK particularly, and I imagine in other places around the world, it is used to manage opioid addiction – i.e. those people who have been unfortunate enough to develop addictions to either, you know, heroin, either injected or smoked, or those who’ve managed to become addicted to prescription opioids where they’ve managed to get their hands on bottles of Oramorph or oxycodone through indirect routes and actually they found themselves accidentally addicted to opioids.

Perioperative and Cancer Pain

It’s used sometimes in pain control in the perioperative setting. It might have a bigger role in this than it currently does in the future. It has been used for example in children having spinal surgery for like a correction of scoliosis, kyphosis and it is growing in its use in managing cancer-related pain, sort of palliative hospice-type settings.

Dosing Guidelines

05:32-06:50

Summary: Detailed dosing recommendations for different clinical scenarios.

How would you go about dosing methadone? Well, there are two subject areas here, or maybe three subject areas in fact.

Addiction Treatment Dosing

Dosing methadone for those who are trying to get off heroin is an entirely separate topic and not one I’m going to cover, but sounds quite tricky in some regards and needs to be titrated in the community by drug and alcohol specialists.

Cancer Pain Dosing

For cancer-related pain, one paper provided guidance saying 2.5mg twice or three times a day. You can increase the dose every five to seven days. You could consider starting on 5 milligrams a day if they are already using opioids.

IV Dosing

IV dosing for methadone: 0.1 to 0.2mg per kilogram, six to eight hourly.

Morphine Equivalence

And it’s important to think about morphine equivalents, and 1 milligram of methadone is approximately equivalent to 10mg of morphine. Now, why do I say approximately? Well, nothing is hard and fast. And actually, if you are on frequent methadone, the level of activity is altered. And that is because you alter the amount you can absorb – i.e. the oral bioavailability.

Pharmacokinetic Properties

06:50-07:41

Summary: Key pharmacokinetic parameters including pKa, distribution, and duration of action.

pKa and Ionisation

What’s the pKa of methadone, you so astutely ask? 9.2, in fact. It’s 1% unionised. And you say, “well, 1% unionised. I was under the impression that things need to be, you know, fairly unionised for it to be of any use.” And methadone is very fat soluble.

Volume of Distribution and Half-life

In fact, it’s got a volume of distribution of 1-8 litres per kilogram and the quoted half-life is 2-65 hours. But in prolonged use, you’re going to fill up that person’s fat stores and actually you probably have a reasonably prolonged effect of methadone.

Onset and Duration

Onset time is about 30 minutes and it lasts for about 4-6 hours. We’re talking about this acute dosing as opposed to someone who’s on it all day every day because actually they take methadone once a day.

Side Effect Profile

07:41-08:30

Summary: Comprehensive overview of methadone’s adverse effects across organ systems.

What’s the side effect profile of methadone?

Cardiovascular Effects

It can cause orthostatic hypotension from a cardiovascular perspective.

Respiratory Effects

Naturally you’re going to have the opioid respiratory side effects of it being an antitussive and a respiratory depressant.

CNS Effects

CNS-wise you’re going to expect opioid effects so it can cause drowsiness, euphoria, hallucination. If you were to give it to an elderly population you’re probably going to trigger more delirium and you get small pupils from Edinger-Westphal nucleus alterations.

GI Effects

GI effects, again opioid: dry mouth, nausea, vomiting, constipation. But interestingly with methadone it can also cause hypoglycaemia. This is more prominent in situations with a cancer patient and those who are having a rapid up-titration of methadone in the community. Although it is pretty rare.

Other Effects

It can cause urinary retention as can most opioids and it’s also been noted to potentially cause some adrenal insufficiency in some patients as well.

So it’s not without its complications.

Alternative Options

08:30-09:46

Summary: Discussion of alternative treatments and detailed pharmacokinetics.

It would be important just to touch base here. We’re all thinking “oh it sounds like it’s got quite a rough side effect profile when we’re considering using it as a way to wean people off opioids.” It’s not the only option. You can also use buprenorphine patches which have perhaps a different side effect profile, which we’ll find out at a later date when we cover buprenorphine.

Pharmacokinetics: What the Body Does to the Drug

Those are the pharmacodynamics of methadone. Now what about the pharmacokinetics of methadone – i.e. what the body does to the drug?

Absorption and Distribution

So we’re going to say we’re going to give some oral methadone. It’s got an oral bioavailability of about 70 to 80 percent. It is highly protein bound to chiefly alpha-1 acid glycoprotein, 60 to 90 percent protein binding.

Metabolism

Now with extended use from a metabolism perspective, you’ll creep up into those higher half-times of 55 hours. The range is 15 to 55 hours. It is metabolised by our dear friends CYP3A4 and CYP2D6. Remembering that CYP2D6 – 10% of the population don’t do a terribly good job of having functional CYP2D6. They’re hyporesponders, under-responders, whatever you want to call them. They will have an extended effect of methadone.

Elimination and Reversal

It is cleared renally and faecally and you can reverse its opioid effects with naloxone.

Conclusion and Future Considerations

09:46-10:14

So that’s pretty much it for methadone guys. There’s not much more that anyone could really possibly want to know from you and if you’re finding yourself talking about methadone in the FRCA, hopefully it’s because they’re asking you to compare it and contrast it with other drugs and they’re just trying to catch you out or something awful like that, although they’re not meant to do that anymore.

But I’ve put it in here for interest also because perhaps in 20 years’ time we might be reaching for a lot more methadone. Who knows?

Anywho, thanks for listening. Have a nice weekend. Cheerio and goodbye.

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