Ep.28 – Remifentanil and the Minto Model

Remifentanil: Core Knowledge for the FRCA Primary

Classification Of Remifentanil  

• Synthetic opioid analgesic
• Phenylpiperidine derivative
• Potent µ-opioid receptor agonist

Presentation Of Remifentanil 

• Supplied as a lyophilised white powder (remifentanil hydrochloride in glycine buffer)
• Vials typically in 1 mg, 2 mg, or 5 mg formulations
• Glycine buffer means dont put it in the CNS space, and its offset means it is a pointless drug to bolus near the spinal cord anyway.

Mechanism of Action Of Remifentanil  

• µ-opioid receptor agonism:
  • GPCR (Gi subunit) → ↓ adenyl cyclase → ↑ K⁺ efflux → ↓ Ca²⁺ influx
  • Net result: neuronal hyperpolarisation and inhibition of nociceptive transmission
• Dense opioid receptor activity in:
  • Rexed lamina II (substantia gelatinosa, dorsal horn)
  • Periaqueductal grey (PAG)

Pharmacokinetics Of Remifentanil  

• Absorption: IV only
• Distribution:
  • 70% protein bound (mostly α1-acid glycoprotein)
  • Vd (initial bolus): ~0.1 L/kg; steady state ~0.25–0.5 L/kg
  • Crosses placenta; 68% unionised at physiological pH
• Metabolism:
  • Rapid ester hydrolysis via non-specific tissue and RBC esterases
  • Produces remifentanil acid, which is 4600x less potent
• Elimination:
  • Context-sensitive half-time ~3.2 minutes (unchanged by infusion duration)
  • Clearance: 4.2–5 L/min
  • Independent of renal or hepatic function

Pharmacodynamics Of Remifentanil  

• Onset: 1–3 min
• Offset: 5–10 min
• Effect-site peak:
  • Young adult: ~1 min
  • Elderly: ~2.5 min

Clinical Uses Of Remifentanil 

• Analgesia and sedation during:
  • Laparotomies
  • Cardiac surgery (effect-site targets up to 12 ng/mL)
  • Obstetric pain relief with a PCA (if your hospital does this [seems to work nicely])
• Facilitates  non-paralysed intubation

Dosing Of Remifentanil

The quoted mcg.kg.min range is 0 – 1 mcg/kg/min ( I don’t advocate mls/hour )

Boluses to render a patient apnoea and practically atonic for sans paralysis intubation – 4mcg.kg (not for the faint of heart, i’m not recommending this) As it is not common practice.

Effect Site Targets Of Remifentanil

• 4-6 ng/ml for adequate analgesia during laryngoscopy and tracheal intubation.
• 1-4 ng/ml for that period where the surgeons are washing their hands and nothing is occurring.
• 6-8 ng/ml are usually necessary during painful operations such as laparotomy.
• 10-12 ng/mlare potentially required during some cardiac surgery. (sternotomies sting)

Contraindications & Precautions Of Remifentanil 

• Caution in elderly, obese,
• Always ensure appropriate postoperative analgesia cover

Side Effects Of Remifentanil

By system:  

• CVS: ↓ MAP, bradycardia (~20%), ↓ CO
• Respiratory: profound depression; risk of chest wall rigidity
• CNS: sedation, miosis, opioid-induced hyperalgesia
• GI: nausea, vomiting, ↓ GI motility
• Others: Flush-line hazard—unflushed octopus ports can cause apnoea

Drug Interactions  

• Potentiation with other sedatives and hypnotics  ‘propofol sparing’
• Rapid offset will unmask underlying pain if not covered by longer-acting opioids

Clinical Relevance / Key FRCA Points  

• Unique ultrashort context-sensitive half-time independent of infusion duration
• Not renally/hepatically metabolised, obviating the concern for intra operative opiates causing later issues
• Key exam trigger words: ester hydrolysis, µ-agonist, chest rigidity, hyperalgesia, context-sensitive half-time

Remifentanil and the Minto Model Target-Controlled Infusion Model

Why Use TCI?  

• Manual infusion risks: non–age-adjusted, risk of over/underdosing, slow to reach steady state
• Minto model uses age, sex, and weight → calculates lean body mass
• Provides effect-site targeting for consistent anaesthesia depth

Developmental Summary  

• Derived from data on 65 adults (20–85 years) receiving 1–8 mcg/kg/min infusions
• Key findings:
  • Older patients need ~50% less drug for equivalent EEG suppression
  • Sex is not a direct covariate, but is used in lean body mass calculations
• Volume/compartment modelling:
  • V1 & V2 scale with lean body mass
  • V3 fixed (5.42 L)
  • Clearance from plasma is esterase-dependent and scales with age & LBW

Clinical Pearls  

• Elderly: smaller central compartments → higher plasma concentrations
• But, → longer time to peak onset. The differences in VOD against accessing effect site smooths this out
• Obese patients: LBW may underdose → use adjusted body weight 40 (per Sober app)
• Infusion adaptation: once stable, convert TCI rate to mcg/kg/min in case of pump failure

Key Takeaways

• Remifentanil is a potent, ultra-short acting opioid with unique metabolism via plasma and tissue esterases
• Its context-sensitive half-time does not alter, making it ideal for prolonged and short procedures,
• Half life means a rapid  titration to effect, dial it up for intubation, wind it back until the surgeons has a knife in hand.
• Minto model enables simplicity to achieve effect site concentrations, without forgetting that mic/kg/min dose rate for 15 mins you set to achieve intubating conditions early
• Watch out for opioid-induced hyperalgesia, recovery flushed remnant drug apnoea, and rigid chest phenomena

References & Further Reading

Soba app https://www.sobauk.co.uk/app-1

Depth of Anaesthesia Podcast (David How MD) – 38: Does remifentanil cause opioid-induced hyperalgesia?

Egan TD, Minto CF, Schnider TW. Steady‑state trumps accuracy: target‑controlled infusion as a gain switch. Br J Anaesth. 2024 Oct;133(4):726–729. doi: 10.1016/j.bja.2024.07.014.

Target-controlled-infusion models for remifentanil dosing consistent with approved recommendations. Eleveld, Douglas J. et al. British Journal of Anaesthesia, Volume 125, Issue 4, 483 – 491

Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ, Gambus PL, Billard V, Hoke JF, Moore KH, Hermann DJ, Muir KT, Mandema JW, Shafer SL. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology. 1997 Jan;86(1):10-23. doi: 10.1097/00000542-199701000-00004. PMID: 9009935.

Egan TD. Remifentanil pharmacokinetics and pharmacodynamics. A preliminary appraisal. Clin Pharmacokinet. 1995 Aug;29(2):80-94. doi: 10.2165/00003088-199529020-00003. PMID: 7586903.

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Podcast Information

Transcript Remifentanil: The Ultra-Short-Acting Opioid – ULTIVA yeaaaa!

Introduction and Overview

[00:00-00:50]

Please listen carefully. And let’s get on with the show.

Hello, everyone. This is James and I, GasGasGas. Today, we sink ever deeper into our soporific, dozy, dreamlike, opiate-induced coma. And we are probably in the deepest, yet safest coma to induce in a patient right now. We’re covering remifentanil.

This episode is going to be a bit longer because we’re doing two things. We’re going to make sure that we pick out all the important elements to know about the drug, but also we’re going to talk about actually administering the drug, particularly going through its most commonly used pharmacokinetic model, i.e. Minto.

Key learning objectives:

• Understanding remifentanil’s unique pharmacological properties
• Mastering the Minto pharmacokinetic model for safe administration
• Recognising clinical applications and potential pitfalls

Chemical Properties and Presentation

[01:20-02:03]

So naturally, if someone asks you about remifentanil in an exam, you’re going to start by telling them that it is a highly potent synthetic opioid, and it is derived from fentanyl, i.e. a phenylpiperidine derivative. It is presented as a white lyophilised powder containing remifentanil hydrochloride in a glycine buffer and you will classically find it in one, two and five milligram vials for reconstitution. You could also tell them the molecular weight is 412 but they’re probably not going to be desperate for that information.

Essential facts:

• Highly potent synthetic opioid
• Phenylpiperidine derivative (fentanyl family)
• White lyophilised powder in glycine buffer
• Available in 1mg, 2mg, and 5mg vials
• Molecular weight: 412 Da

Mechanism of Action

[02:04-03:32]

Now I have ranted on about how opiates work and we’re just going to hit it home again because you just need to be able to reel this off in the exam, smooth as butter and move on.

So it agonises opioid receptors. These opioid receptors are G protein coupled receptors with a Gi subunit, i.e. they have inhibitory effects on the cell where you will find them in the membrane. It works to hyperpolarise that cell membrane, inhibiting conductance across synaptic clefts. It does so by increasing potassium conductance, decreasing calcium conductance, and inhibiting adenylyl cyclase.

Where is the chief effect of opioids? In the substantia gelatinosa of the dorsal horn of your spinal cord, in Rexed lamina 2, if you’re going in that level of detail. You will also find a highly dense area of them in the periaqueductal grey matter of the midbrain.

What are its actions? You guessed it, rip-roaring analgesia, sedation, and it stops your coughing. So you can breathe on that tube until the cows come home. And you can be awake and be very disinterested in breathing and quite happily you can say, hey, you, take a breath. And they go, oh, yeah, I should breathe. And then you have to say it again. Take a breath. Well done, patient. Good. Excellent. Keep doing that. It’s just hilariously great stuff.

Mechanism summary:

• Μu-opioid receptor agonist
• G protein-coupled receptors (Gi subunit)
• Hyperpolarises cell membranes via K+ and Ca2+ channel modulation
• Primary sites: substantia gelatinosa (Rexed lamina 2) and periaqueductal grey
• Effects: profound analgesia, sedation, cough suppression

Dosing and Administration

[03:35-06:27]

Anyway, before I get terribly distracted, that lyophilised powder is readily soluble in water. How might you go about dosing remifentanil? So classically, it is dosed as an infusion.

Now, I think when remifentanil first came on the scene, people were just bolusing it to facilitate intubation and just smashing it in. And then we were getting people with rigid chests and perhaps some cardiac instability. So people have sort of wound their neck in a tad on that.

I’ve seen doses of four micrograms per kilogram given to facilitate intubation without relaxant to not terribly much ill effect. It would probably be smoother with slightly less of a peak if you were to just TCI the patient. We’re going to go over this in a minute and turn that up instead.

And if someone were to ask you, oh yes, but you know, you’re in the middle of nowhere and all you’ve got is a syringe driver as opposed to a pharmacokinetically enabled pump, what dose rate are you going to give in micrograms per kilogram per minute? And the quoted range I’ve got is zero to one microgram per kilogram per minute.

So if you imagine if you’ve got a standard 75 kilogram patient, you might be giving 75 micrograms per minute. If you were going at 75 micrograms per minute, that five milligram ampoule of remifentanil would last you about an hour.

Dosing guidelines:

• Standard infusion: 0-1 μg/kg/min
• TCI effect site targets:
  • Intubation/laryngoscopy: 4-6 ng/ml
  • Laparotomy: 6-8 ng/ml
  • Cardiac surgery: 10-12 ng/ml
• Peak effect: 1-3 minutes
• Offset: 5-10 minutes

Cardiovascular and Respiratory Effects

[06:27-08:14]

So we’ve thought about what the drug does to that person in terms of the beneficial effects but what about the less beneficial effects of remifentanil? So remember now we are going to split these side effects down by system because we want to look slick in the exam.

Cardiovascular effects: it decreases your mean arterial pressure and drops your heart rate by about 20%. Therefore you may expect to see a drop in cardiac output. Sounds reasonable doesn’t it?

Respiratory systems wise it is a significantly potent respiratory depressant. It literally just renders someone unwilling to breathe. They’re going to take smaller breaths, they’re going to take fewer breaths, or they’re just not going to breathe. Like all other opioids, it desensitises people to CO₂, but also interestingly, alongside all the other opioids, although it’s harder to give a big dose of, say, morphine to achieve this, you can get a wooden chest phenomenon. This is where someone gets really stiff, and therefore it’s quite challenging to ventilate them.

System-specific effects:

• Cardiovascular: MAP ↓20%, HR ↓20%, cardiac output reduction
• Respiratory: potent respiratory depression, CO₂ desensitisation
• Wooden chest phenomenon possible (treat with paralysis)
• Vagally mediated bradycardia

Central Nervous System Effects and Hyperalgesia

[08:18-10:34]

What does it do to your central nervous system? Well, that bradycardia we mentioned from a cardiovascular perspective is vagally mediated. It causes moderate sedation and it’s going to cause miosis, as all opioids do, due to its fiddling around with the Edinger-Westphal nucleus.

There is another important CNS effect of remifentanil that we see perhaps more than we do with other opioids, again probably because we can just give so much more remifentanil and get away with it, is a situation whereby a patient is sensitised to pain stimuli following the withdrawal of remifentanil. We call it opioid-induced hyperalgesia.

There’s been a few studies on it, and actually I was recently listening to a podcast, i.e. yesterday, which explored this in further detail. This is called the Depth of Anaesthesia podcast from David Howe. The crux of it is that remifentanil hyperalgesia exists, although it seems to ease within the first hour or so of a patient being post-op.

In the UK it’s standard practice to load a patient up with a non-remifentanil opioid before waking them up i.e. give them some fentanyl, give them some morphine, make sure it’s working as they’re waking up instead of just turning off the remifentanil and crossing your fingers.

CNS effects summary:

• Moderate sedation
• Miosis (pupillary constriction)
• Opioid-induced hyperalgesia (OIH)
• Prevention: administer alternative opioid before emergence

Pharmacokinetics: Metabolism and Clearance

[11:26-14:29]

How is it absorbed? Well it’s an intravenous drug. How is it distributed once you’ve given someone an injection of remifentanil? Well, it is 70% protein bound. Approximately two thirds of that to our dear friend alpha-1 acid glycoprotein. It has a really low measured volume of distribution, 0.1 litres per kilogram, and it also will sneak across the placenta. It is 68% unionised at physiological pH. It has a pKa of 7.1.

So this is now where we’re really interested is the metabolism of remifentanil. I probably all know that it’s rapidly cleared and it is cleared by ester hydrolysis and these are by esterase enzymes. It’s broken down chiefly by tissue esterases and also red blood cell esterases. And the important thing that makes this such a beautiful drug is that that ester linkage is involved in the drug being an effective opioid receptor agonist. So when it undergoes ester hydrolysis, the opioid binding bit of the molecule is rendered dysfunctional, which is super clever, isn’t it?

Now, it does break it down into a carboxylic acid derivative called remifentanil acid and this has activity. However it is 4,600 times less potent.

Pharmacokinetic profile:

• 70% protein bound (mainly α₁-acid glycoprotein)
• Vd: 0.1 L/kg (single dose), 0.25-0.5 L/kg (steady state)
• Metabolism: non-specific tissue and RBC esterases
• Context-sensitive half-time: 3.2 minutes (independent of infusion duration)
• Clearance: 4.2-5 L/min (hepatic and renal independent)
• Elimination half-life: 5-14 minutes

Clinical Pitfalls and Safety Considerations

[14:37-16:59]

So we’ve got ourselves a drug that is really potent, has a rapid offset and sounds great. So what are the pitfalls? So I think the first one that really jumps to my mind is this opioid-induced hyperalgesia. So don’t just titrate someone, they’ve had some local in the wound and just think, ah, it’ll be fine. You know, it’s probably reasonable to give them some extra pain relief there.

But also we’ve got a really potent drug that if you accidentally leave in a cannula, you know, in one of those octopus things or whatever, and then someone dutifully flushes that octopus thing later down the line, you might have a patient who stops breathing. The trouble is that if you stop breathing you’re going to accumulate CO₂. If you’re already in a semi-obtunded state because you’re recovering from anaesthesia where your sensitivity to CO₂ might be a bit diminished already you quite rapidly just become terribly disinterested in breathing.

Now this is transient because it’s going to wear off but you might find yourself for five minutes with a patient who isn’t going to breathe. And if you don’t recognise that and do something about it, it’s important. It’s much like leaving paralysing agents in these octopus connectors because you forgot to flush it at the end of the case. Remifentanil carries quite a high risk of that. So be super careful and vigilant when you’re taking off your T-pieces. Make sure things are flushed.

Safety priorities:

• Prevent opioid-induced hyperalgesia with alternative opioids
• Flush all lines thoroughly to prevent inadvertent boluses
• Maintain vigilance for respiratory depression in recovery
• Double-check drug concentrations when preparing infusions

The Minto Model: Pharmacokinetic Principles

[17:00-19:02]

So now we need to talk about how we actually go about putting remifentanil into people. So you’re probably just thinking, why did they even bother with a target control infusion model? Why don’t you just give a microgram per kilogram per minute dose and just call it there?

Well, for a number of reasons. One, this drug is rapidly metabolised. So if you’re not giving enough, you’re not really going to achieve an effect. Two, a microgram per kilogram per minute dose isn’t age adjusted. And there’s a fair wad of evidence to suggest that the susceptibility of a young person to remifentanil is very much less than the susceptibility of an older person to remifentanil.

Furthermore, we all understand a few bits and pieces about pharmacology, and we know that it takes four and a half half-lives to achieve steady state. And as the half-life is three to five minutes, we’re looking at 15 minutes to achieve steady state.

Advantages of TCI over manual infusion:

• Age-adjusted dosing (EC₅₀ drops 50% from age 20 to 85)
• Rapid achievement of target concentrations
• Accounts for lean body mass differences
• Avoids under/overdosing in extremes of age

Minto Model: Technical Details

[19:02-22:56]

So our dear fellow Minto comes along and thinks, you know what, remifentanil, that’s right for making a name for myself and a name for himself he has. As with every pharmacokinetic model, it takes variables into account. The variables chiefly used by the Minto model are age, weight and sex. It then works out lean body mass to guide its dosing.

So the original paper describing the development of the model utilised 65 adults, 20 to 85 years of age, having constant infusions of between one and eight micrograms per kilogram per minute. They had arterial lines in. They took loads of samples and continued to take samples for four hours after the cessation of infusion. They took these blood samples and then immediately tipped in something called acetonitrile into the sample to inhibit the esterase activity.

They also found that the EC₅₀ dropped by 50% across the age range from a 20 year old to an 85 year old. So an 85 year old required half the amount of drug to achieve the same amount of suppression of brain.

Model parameters:

• Variables: age, weight, sex (to calculate lean body mass)
• V1 and V2: vary with lean body mass
• V3: fixed at 5.42 litres
• Peak effect time: 1 minute (age 20) vs 2.5 minutes (age 80)
• Clearances adjusted for age and lean body mass

Clinical Application and Individual Variation

[23:02-25:59]

What about in some clinical uses and extremes? So if we had a really, really obese patient and we plumbed their numbers into our lean body mass calculator, it may actually end up underdosing the patient because we all know that really heavy people do have more plasma and it doesn’t scale in a linear manner. The Sober app recommends using the adjusted body weight 40 for remifentanil TCI to try and balance this problem out.

It’s important quickly here to digress about this magical machine that does dosing for us and the rigidity to which we might hold ourselves to a certain concentration and deem that, oh yes, when I do laparotomies, I go for an effect site of 6 nanograms per mil. Now every patient is different and actually if you look at the second paper from the Minto folks looking at some simulations of the actual true range it’s quite tremendously divergent.

So it is a tool that allows you to reach convenient steady states that bear out in pharmacokinetic reality more or less. So some patients need more, some patients need less. Don’t be rigid.

Clinical pearls:

• Use adjusted body weight for BMI >40
• Individual variation is significant – titrate to effect
• Monitor μg/kg/min display for pump failure contingency
• Remember: TCI is a tool, not a rigid protocol

Conclusion and Future Directions

[25:59-27:25]

Anyway, thanks for listening, guys. That’s a little bit of an intro to Minto. We covered remifentanil in reasonable detail. It’s a really cool drug. I think it’s going to be used more and more and more to avoid having to paralyse people because you can get them deep on remifentanil and they do very much relax. And you can sneak that tube in without having to paralyse them, which means you avoid all the problems of having to reverse them at the end and post-op pulmonary complications of microaspiration, etc, etc, that don’t crop up for a week once the patient’s at home and then they get a chest infection.

Always worth having some paralysis to hand, though, just in case they go very rigid, those pesky patients.

Take-home messages:

• Remifentanil offers unique pharmacokinetic advantages
• TCI optimises dosing but requires clinical judgement
• Always plan for transition analgesia before emergence
• Keep muscle relaxant available for rigid chest syndrome