Ep.29 – Comparing Opioids For the FRCA Primary

Each opiate has distinct pharmacokinetic and pharmacodynamic properties that make it a better (or worse) choice for individual scenarios. This episode focuses on making sensible comparisons between morphine, fentanyl, alfentanil, and remifentanil – when and where to choose each one.

Quick Reference Comparison to Compare Opioids

Drug	Onset Time	Peak Effect	Duration	Context-Sensitive Half-Time
Morphine	15-30 min	20 min	3-5 hours	Long, progressive increase
Fentanyl	1-3 min	3-5 min	30-60 min	Very long, steep increase
Alfentanil	90 seconds	90 seconds	15-30 min	Short, minimal increase
Remifentanil	60-90 seconds	90 seconds	3-10 min	Context-insensitive (~9 min)

Key Pharmacological Properties

Drug	pKa	% Unionised	Protein Binding	Lipid Solubility	Relative Potency
Morphine	8.0	23%	30%	1 (reference)	1
Fentanyl	8.4	9%	85%	580×	80-100×
Alfentanil	6.5	89%	90%	90×	10-20×
Remifentanil	7.1	60%	70%	18×	150-300×

Clinical Decision Making

RSI and Difficult Airway Management

Scenario: 75-year-old for laparotomy, large bowel obstruction, no respiratory distress.

Key Consideration: how fast does it work!

Drug Selection:

• Alfentanil/Remifentanil: 90-second onset vs fentanyl’s 3-5 minutes
• Alfentanil: Very effective but short duration – may need repeat dosing if prolonged instrumentation
• Remifentanil TCI: Consistent analgesia level, easily titratable (effect site target 4-5 ng/ml)
• Fentanyl: Slower onset but longer duration may facilitate non-hypertensive intubation if difficulties arise

Dosing:

• Fentanyl: 1-3 mcg/kg
• Alfentanil: 10-15 mcg/kg (note the order of magnitude difference)
• Remifentanil: 3-4 mcg/kg bolus (may get quite Brady) or TCI targeting 4-5 ng/ml effect site

Context-Sensitive Half-Time Considerations

This is crucial for infusion management:

• Fentanyl: Very long context-sensitive half-time – the longer you infuse, the longer it takes to clear
• Alfentanil: Short context-sensitive half-time – preferred in ICU settings
• Remifentanil: Context-insensitive – always ~9 minutes regardless of infusion duration
• Clinical Impact: Fentanyl infusions can complicate sedation holds and delay extubation in ICU patients
  • But you end up with quite a slow and potentially dozey wake up which might be quite good actually in certain patients.

Complex Case Management: Colorectal Surgery

Scenario: Laparoscopically assisted colorectal resection – long case with specific analgesic requirements.

Regional vs IV Approaches:

Epidural Considerations:

• Excellent pain relief if well-sited
• May be excessive for laparoscopic approach
• Risk-benefit analysis: consider their respiratory baseline, conversion risk

Intrathecal Options:

• Preservative-free morphine 100 mcg: 24-hour analgesia, avoids systemic effects
• Spinal fentanyl: Good but potentially brief intraoperative coverage, no post-operative benefit.
• Risk: Delayed respiratory depression (dose-dependent, up to 24h monitoring needed)

IV Techniques:

• Bolus morphine/fentanyl: May require high doses, potential for delayed emergence
• Remifentanil TCI: Titratable intraoperatively but no residual analgesia
• Transition strategy: Must plan post-operative analgesia when using remifentanil

Recommended Approach:

For laparoscopic colorectal surgery with healthy respiratory system:

1. Intrathecal morphine 100 mcg pre-induction
2. Remifentanil TCI intraoperatively
3. Additional opioid on extubation
4. Ward familiar with intrathecal morphine monitoring re: delayed Resp depression

Special Populations and Considerations

Renal Impairment

Morphine: 

• Hepatic glucuronidation → morphine-3 and morphine-6-glucuronide
• Both metabolites active and renally excreted
• Accumulation in renal failure → increased sedation, respiratory depression risk

Fentanyl:

• N-dealkylated to norfentanil (inactive metabolite)
• Safer choice in renal failure
• Challenge: Low oral bioavailability, difficult ward administration (apoplectic registered nurse likely)

Optimal Choice for Renal Impairment:

• Oxycodone immediate-release: Can accumulate but manageable with dose reduction and extended intervals
• Buprenorphine: Completely hepatically cleared, available as patches/IV/oral
• Multimodal approach: Paracetamol first, if end stage renal failure avoid codeine (metabolises to morphine metabolites)

Neuraxial Applications – Comparing Opioids in CNS Adjacent Spaces

Morphine:

• Low lipid solubility: Slow uptake, slow egress
• Spreads widely in CSF: Excellent duration (12-24h)
• Intrathecal dose: 100 mcg (two orders of magnitude less than IV)
• Risk: Delayed respiratory depression, arachnoiditis if not preservative-free

Fentanyl:

• High lipophilicity: Rapid spinal cord uptake, limited rostral spread
• Duration: 2-4 hours, minimal post-operative benefit
• Lower respiratory depression risk: Less likely to migrate rostrally

Understanding the Pharmacology

Why PKa Matters

• Alfentanil (pKa 6.5): 89% unionised → rapid membrane crossing → fast onset
• Fentanyl (pKa 8.4): 9% unionised → slower onset despite high lipophilicity
• Clinical Pearl: pKa drives onset speed, but lipid solubility affects redistribution

Lipid Solubility Impact

• Morphine: Lipid solubility of 1 – “like pouring morphine on butter, takes time to get in”
• Fentanyl: 580× more lipophilic – “gets into butter quickly, but spreads through it quickly too, (spreading itself a bit thinly!)“
• Clinical Effect: High lipophilicity = fast onset but rapid redistribution after bolus

Common Pitfalls and Safety

Dose Accuracy

• Critical for intrathecal use: 10mg morphine IV vs 100 mcg intrathecal
• Potency differences: Fentanyl 100× morphine,
• Always double-check: Use preservative-free preparations neuraxially, and the doses differ massively!

Side Effects

• Chest wall rigidity: All potent opioids, manageable with paralysing agents.
• Opioid-induced hyperalgesia: All opiates capable, remifentanil particularly problematic due to being able to achieve high dose/ receptor occupancy with minimal lingering effects
• Context-sensitive accumulation: Fentanyl duration extends dramatically with prolonged infusion

Key Clinical Pearls

1. RSI opioid choice: Consider onset time vs duration needs
2. Context-sensitive half-time: Crucial for infusion decisions
3. Neuraxial selection: Lipophilicity determines spread and duration
4. Renal failure: Avoid morphine, consider fentanyl or oxycodone
5. Remifentanil transition: Always plan post-operative analgesia
6. Dose verification: Particularly critical for neuraxial and high-potency agents

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Question 1: Rapid Sequence Induction

“You’re doing an RSI on an eclamptic patient. Compare fentanyl, alfentanil, and remifentanil for blunting the hypertensive response to laryngoscopy.”

Model Answer:

The key consideration is preventing dangerous blood pressure spikes in an already hypertensive patient. Alfentanil would be my first choice – pKa of 6.5 means 89% unionised, giving onset in 90 seconds. I’d use ~2mg (20 mcg/kg) to obtund the sympathetic response to laryngoscopy. It’s cardiostable and the short duration means less interference with post-delivery care of baby.

Remifentanil is also excellent – similar onset time and can be titrated precisely. However, it requires TCI setup or using it as a bolus, with drawing up time, which may delay induction. Administering a bolus dose, with its potential CVS effects, and short lived effect is less useful

Fentanyl, despite being cardiostable, has a 3-5 minute onset which may not adequately blunt the laryngoscopy response occurring at 1-2 minutes post-administration.

Question 2: Context-Sensitive Half-Time

“Explain why alfentanil is preferred over fentanyl for ICU sedation, despite fentanyl being more potent.”

Model Answer:

This relates to context-sensitive half-time, how infusion duration affects clearance. Fentanyl has a very long context-sensitive half-time because of its high lipophilicity. After prolonged infusion, peripheral fat compartments saturate and clearance becomes much slower.

Alfentanil has a short context-sensitive half-time due to lower lipid solubility and smaller volume of distribution. This means predictable wake-up times for sedation holds, regardless of how long the infusion has run.

In ICU, this translates to more predictable neurological assessments and shorter ventilator weaning times, even though you need higher doses of alfentanil due to its lower potency.

Question 3: Neuraxial Opioid Selection

“A patient is having spinal anaesthesia for total hip replacement. Compare the use of intrathecal fentanyl versus morphine.”

Model Answer:

The choice depends on lipophilicity and desired duration. Fentanyl is highly lipophilic – it rapidly crosses into spinal cord tissue but doesn’t spread rostrally in CSF. This gives good intraoperative analgesia for 2-4 hours but minimal post-operative benefit.

Morphine is hydrophilic – it has slow uptake but spreads widely in CSF, providing 12-24 hours of excellent post-operative analgesia. However, this rostral spread increases the risk of delayed respiratory depression.

For hip replacement, I’d choose morphine 100 mcg for superior post-operative pain control, with appropriate monitoring for respiratory depression. The patient would need to go to a ward familiar with intrathecal morphine management with naloxone readily available.

Check out Context Sensitive Half Time in More Details, Here!

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Podcast Information

Transcript Comparing Opioids For the FRCA Primary

Introduction and Episode Overview

[00:00-01:06]

Summary:

• Final episode in the opioid series
• Focus: Making sensible comparisons between different opioids for exam preparation
• Goal: Understanding when and where to use specific opioids in clinical practice

Welcome to the final opioid episode of Gas Gas Gas. Today we’re working through making sensible comparisons between different opioids and when and where we might choose to use them, so that when we come up against this in the exam we can deliver a sensible answer and continue progressing through that station. I hope you’ve all had a cup of tea, you’re ready for action, and we’re going to get straight into it.

The Role of Opioids in Anaesthetic Practice

[01:07-03:39]

Summary:

• Opioids form the analgesic component of the anaesthetic triad
• Multiple clinical applications beyond surgical pain
• No single “perfect” opioid – each has distinct pharmacokinetic and pharmacodynamic properties
• Exam expectations: justifying decision-making rather than rote answers

As we all know, opioids are a significant cornerstone of anaesthetic practice. They make up that triad of anaesthesia with their analgesic properties, and we utilise these analgesic properties in a number of manners. Obviously the obvious one is that surgery hurts – if someone’s rummaging around inside your abdomen, then perhaps we need to give pain relief.

But our activities also cause discomfort. For example, laryngoscopy. Now, in a general ASA1 patient, the stimulating effects of laryngoscopy probably aren’t the end of the world. However, if you have a patient who is teetering along that marginal line of physiological stability, causing them to have a significant heart rate and blood pressure response whilst you rummage around inside their larynx might have implications.

The immediate patients that come to my mind are the eclamptic parturient who needs an emergency general anaesthetic – you really don’t want to drive their blood pressure unnecessarily high. You might end up in territory where they have a stroke. Or for example, cardiac anaesthesia – a haemodynamically unstable patient, you push their blood pressure up and their heart now has to contend with a massive afterload. That’s also bad news.

I’m sure we could think of a thousand other reasons why we should be thoughtful with our use of opioids. But as we’ve certainly covered through all these episodes, we know that all opioids are not made equally in this world and there is no one catch-all perfect drug that will solve all your conflicting requirements for analgesia, sedation, etc. Each opioid has a distinct collection of pharmacokinetic and pharmacodynamic properties that make it a better choice or a less suitable choice for an individual scenario.

In the viva, they want you to be able to justify your decision-making as opposed to just saying “alfentanil for RSI” because, you know, you’re not a robot, you’re a physician. So we’re going to compare in a few different situations morphine, fentanyl, alfentanil and remifentanil. We’re going to touch on their pKa, their protein binding, some comparative potencies and then try and tease out when you might be leaning towards one more than another.

How are we going to do it? Well, this time we’re just going to structure it in questions. And for that to take place, the rumbling examiner omnipotent voice has to come back into play from the podcast episodes of old. So without too much further waffle, we’ll get on with it.

Clinical Scenario 1: RSI for Large Bowel Obstruction

[03:39-07:56]

Summary:

• Patient: 75-year-old for laparotomy, suspected malignant large bowel obstruction
• Comorbidities: hypertension and gout
• Comparison of remifentanil, alfentanil and fentanyl for RSI
• Key considerations: onset time, offset time, dosing, and familiarity with agents

Examiner: Hello doctor, welcome to your pharmacology/clinical station. You are anaesthetising a patient for a laparotomy for large bowel obstruction. They have not been vomiting, a suspected malignant obstruction. They’re 75 years of age. Their comorbidities include high blood pressure and gout. Please compare and contrast remifentanil, alfentanil or fentanyl as your induction opioid of choice.

This is a compare and contrast question. It’s important to realise it’s very easy to become bogged down just listing off a ream of numbers and data, and that’s really boring. You might find yourself getting lost in the long grass when you just can’t quite remember the pKa of fentanyl, for example. Now, it may be that the examiners really want to hear the pKa for fentanyl. The odds are they’ll ask you that if it is really pertinent to the question.

So anyway, how I would answer this question: It sounds as if this gentleman has a bowel obstruction picture and no clear respiratory history or respiratory distress at this point in time. When conducting an RSI, it’s important to consider the speed of onset of agents in order to facilitate a prompt intubation with the shortest period of time of lost airway reflexes being present, and to also weigh up familiarity with agents.

When considering fentanyl, alfentanil, and remifentanil, I know that the onset times of alfentanil and remifentanil are a fair bit faster than fentanyl. Fentanyl takes three to five minutes, whereas alfentanil and remifentanil take about 90 seconds to reach peak effect from an IV dose.

Onset time is important, however offset time is also an important consideration if there’s a potential for encountering a difficult airway or an anticipated difficult airway. Alfentanil is very effective but does not last very long. If there’s going to be a prolonged period of airway instrumentation, it may be a better choice to choose remifentanil via a target-controlled infusion. This would mean that you get a consistent level of analgesia on board alongside its favourable onset time.

A counter-argument to this is potentially the use of fentanyl bearing in mind its onset time. An argument can be made either way here, as it takes 3-5 minutes to reach peak effect, and there may be a period of time where the patient has a slightly depressed state of breathing that is longer than perhaps with using remifentanil or alfentanil. However, fentanyl has a prolonged period of effect which might facilitate a greater period of time in order to achieve a safe intubation.

Comparative dosing here between these agents: I would use a dose of fentanyl between 1 to 3 micrograms per kilogram. Alfentanil, in this situation, about 10 to 15 micrograms per kilogram, noting that the dose is an order of magnitude greater approximately than fentanyl – this reflects the potency of fentanyl being greater than that of alfentanil.

With remifentanil, I would be unfamiliar with using this in a bolus dose. I know it’s up to 3 to 4 micrograms per kilogram. However, I would use a remifentanil TCI model such as Minto, aiming for an effect site concentration of 4 to 5 nanograms per millilitre to facilitate intubation.

Context-Sensitive Half-Time Comparison

[07:43-09:37]

Summary:

• Context-sensitive half-time: relationship between infusion duration and drug clearance
• Fentanyl: very long context-sensitive half-time (accumulates in adipose tissue)
• Alfentanil: short context-sensitive half-time (suitable for ICU use)
• Remifentanil: context-insensitive (consistent 9-minute half-life regardless of infusion duration)

Examiner: By moving this hypothetical clinical scenario on, you’ve decided to conduct an infusion of opioids. Tell me, how do the offsets differ between remifentanil, alfentanil and fentanyl?

Ah yes, so the important pharmacological concept to consider here is the context-sensitive half-time of these different agents. Context-sensitive half-time is a concept whereby the period a drug is infused over has a relationship to the clearance of that drug or the half-time of that drug. The longer the infusion, the longer the time it takes for drugs to clear. Drugs that are typically very lipophilic tend to have a longer context-sensitive half-time as they are more likely to accumulate in adipose reservoirs within the body.

Now these three agents are actually almost polar in some regards. Fentanyl has a very long context-sensitive half-time whereas remifentanil and alfentanil have shorter context-sensitive half-times, and remifentanil in particular is entirely context-insensitive. What I mean by that is that for any period remifentanil is infused for, when that period of infusion is stopped, the half-life will not alter – the half-life being around nine minutes for remifentanil.

They might ask you at this point in time, folks, to draw that graph of comparative context-sensitive half-times for drugs. I’ll put that in the show notes. Not to forget that alfentanil has a short context-sensitive half-time compared to fentanyl. That’s why it’s often a typical opioid of use in the intensive care environment. Fentanyl could be used in this patient population however given a patient might be intubated and ventilated for a number of days you would end up complicating and muddying the picture on sedation hold for these patients.

Clinical Scenario 2: Laparoscopic Colorectal Surgery

[09:38-15:21]

Summary:

• Patient: colorectal cancer, laparoscopically assisted anterior resection
• Analgesic options: epidural, intrathecal (with or without morphine), IV bolus, or remifentanil TCI
• Recommended approach: intrathecal preservative-free morphine (100 micrograms) + remifentanil TCI intraoperatively
• Key consideration: respiratory baseline and likelihood of conversion to laparotomy
• Side effects: delayed respiratory depression (dose-dependent), requires appropriate ward monitoring

Examiner: So doctor you find yourself on a colorectal list and you note that there’s a short case, an inguinal hernia, and then a long case for the rest of the day – a colorectal cancer patient who’s having a laparoscopically assisted anterior resection. Talk me through the various approaches to pain relief intraoperatively and postoperatively in this patient cohort.

Ah yes, right, okay. Well, laparoscopic assisted colorectal cancer surgery is painful during and after the operation but is generally confined to quite a small area of the body, i.e. the lower half of the abdomen. So there are a number of overarching techniques that could be utilised in this situation: intravenous versus regional analgesia. I’ll break regional analgesia down into either an intrathecal or epidural approach, and then intravenous anaesthesia down into bolus or continuous infusion.

Thinking about regional approaches first: An epidural will certainly yield excellent pain relief if well sited in this patient. However, it may be excessive and the balance of risk versus benefit shift away from an epidural approach. The chief cofactors I want to understand before making that decision are the patient’s respiratory baseline – do they have COPD? – and whether or not the surgeon expects it to be a laparoscopic case or if it needs to be converted into a laparotomy, in which case an epidural might make more sense.

Intrathecal approaches: If I were to site a spinal in this patient before general anaesthesia, that would likely cover the main pain stimulus of the first half of the operation. These cases can take quite a while. However, that bupivacaine would unlikely be of benefit to the patient postoperatively. A good choice here might be a spinal containing preservative-free morphine, as this would provide analgesia for perhaps the first 24 hours following that intrathecal injection, whilst avoiding some of the systemic side effects of opiate administration. Now, this isn’t titratable, and it may be insufficient to cover the marked pain stimulus of the surgery itself.

Intravenous approaches: I could bolus the patient IV opioids such as morphine or fentanyl and titrate these to pain stimulus intraoperatively. This may require quite high doses intraoperatively of these agents and that might slow the wake-up afterwards or leave the patient unexpectedly sedated and groggy. The opposing option for this is a remifentanil target-controlled infusion during the operation. This allows titratable pain relief which can be easily modified to match the surgical stimulus at hand. The counter to this is that it won’t provide any lasting pain relief postoperatively.

Examiner: How might postoperative pain be managed?

A patient-controlled analgesia delivered through a dedicated pump system into a cannula of either morphine or immediate release oxycodone would be an option to give the patient control over their pain relief postoperatively. However, when comparing this to intrathecal morphine, it would carry a higher risk of having systemic side effects that might limit the dose that could be given and the pain relief that could be achieved.

Examiner: So what are you going to do?

In this intervention, as long as the patient has a disease-free respiratory system and the surgeon is thinking it likely that it is going to be a laparoscopic procedure, unlikely to convert to a significant open incision, I would first deliver intrathecal morphine to this patient before conducting a general anaesthetic. I would use remifentanil TCI intraoperatively and likely give the patient some additional opiate pain relief on extubation and review them from the perspective of how effective their intrathecal morphine is in controlling their pain before they leave recovery.

Examiner: What about the side effect profile of intrathecal morphine?

I would describe the side effect profile of intrathecal morphine as having one chief concern and that is delayed respiratory depression as that morphine shifts throughout the spinal cord and can affect the respiratory centre. Now this is dose dependent. I would like to use a 100 microgram dose. It is important that the patient goes to a ward that is familiar in managing postoperative patients who’ve had intrathecal morphine and naturally are trained in administering naloxone. I would have naloxone preemptively prescribed in case there is respiratory depression.

Examiner: Why not just use fentanyl?

Fentanyl, whilst an effective intrathecal opioid for short procedures, will unlikely provide any clinical benefit in pain relief for this patient postoperatively. It does have a much reduced potential for respiratory depression in the doses used. This is purely because the agent is very lipophilic and it is less likely to shift up the spinal cord. It’s more likely to be cleared by the plasma.

Examiner: Are there any other risks with intrathecal opioid dosing?

The chief risk that comes to my mind is ensuring dose accuracy. Whilst it might be quite commonplace to administer 10 milligrams or more to a patient intraoperatively of morphine, a 10 milligram dose intrathecally would certainly cause a number of problems, the chief being respiratory depression. I mentioned earlier the dose intrathecally is 100 micrograms. This is two orders of magnitude less. The other important component to consider here is that the agent you are administering is preservative-free to avoid any arachnoiditis-type problems.

Opioid Metabolism and Renal Failure

[15:23-18:07]

Summary:

• Morphine: metabolised to morphine-3-glucuronide and morphine-6-glucuronide (active metabolites)
• Active metabolites accumulate in renal failure → increased sedation, respiratory depression risk
• Fentanyl: metabolised to norfentanil (inactive metabolite) – safer in renal failure
• Preferred options in renal impairment: oxycodone (immediate release, reduced dose/extended intervals) or buprenorphine (completely hepatically cleared)
• Multimodal approach: paracetamol, regional/local anaesthesia

Examiner: Excellent. Moving on, more pharmacology questions. Tell me, what are the differences between the metabolism of morphine and fentanyl? And which would you pick in a patient with significant renal failure?

Both morphine and fentanyl are metabolised by the liver before these metabolites are cleared renally. Morphine is glucuronidated in the liver to morphine-3-glucuronide and morphine-6-glucuronide. Both are active metabolites. The chief issue is that these active metabolites are renally excreted and accumulate in renal failure. This can lead to an increased risk of morphine toxicity, chiefly sedation, drowsiness, and respiratory depression, increasing the odds of respiratory failure in this patient as well as postoperative pulmonary complications.

Comparing morphine to fentanyl, fentanyl again undergoes liver metabolism, however it is N-dealkylated into norfentanil and it’s subsequently hydroxylated. Norfentanil is not an active metabolite. If I were to choose between the two I would elect to pick fentanyl as a postoperative opioid analgesic.

Examiner: Now if I give you the room and say what postoperative analgesic would you elect for a patient with marked renal insufficiency?

I would take a multimodal approach ensuring that I have used simple analgesics such as paracetamol before considering stronger opioids. Codeine could be a choice however it is ultimately metabolised into morphine-3- and morphine-6-glucuronide which could accumulate in renal failure. Tramadol also has prolonged clearance in renal failure. I would likely avoid that too.

Whilst fentanyl as we mentioned earlier is a safe choice, administration on the wards of fentanyl is challenging. It has a very low oral bioavailability and therefore its absorption profile can be quite different if the patient has a fentanyl lozenge versus swallowing liquid fentanyl. I would elect to choose oxycodone instead for this patient, immediate release, as modified release would not be licensed. Oxycodone can still accumulate in renal failure and I would use a reduced dose and an extended time frame between those doses.

If the patient had devastatingly poor renal function then I may elect to use buprenorphine. This is completely hepatically cleared. This is available in patch form and there are intravenous preparations as well as oral preparations. It would be pertinent in the patient with renal failure to ensure sensible regional or local anaesthetic-based analgesia is considered and provided.

Pharmacological Comparison: Morphine, Fentanyl, and Alfentanil

[18:08-23:39]

Summary:

• Morphine: reference opioid (lipid solubility = 1); pKa 8.0 (23% unionised); low protein binding; slow onset (20 minutes), long duration; useful for prolonged analgesia and intrathecal use
• Fentanyl: 580× more lipid soluble than morphine; pKa 8.4 (9% unionised); onset 3-5 minutes; cardiostable; μ-receptor specific; less nausea/dysphoria than morphine
• Alfentanil: 90× more lipid soluble than morphine; pKa 6.5 (89% unionised); onset 90 seconds, duration 5 minutes; ideal for RSI in haemodynamically unstable patients
• Key concepts: lipid solubility, pKa, and protein binding all contribute to onset time
• Important reminders: opioid-induced hyperalgesia (remifentanil is worst offender), chest wall rigidity

Oh gosh, that felt like a lot of talking actually. But hopefully we can now compare and contrast and balance up some of the nuance when they’re going to be asking us about opioids. I’m just going to do a quick summary about morphine, fentanyl, alfentanil, just so we’re all on the same page.

Morphine Morphine is still the reference opioid, which everything else is measured against. That’s why we have conversion tables that convert to oral equivalents of morphine. Morphine has a pKa of 8, which means actually its unionised fraction is pretty small – it’s 23% unionised. It’s also got quite low protein binding, and it’s pretty low in the lipid solubility statistics.

If we were to brand it as having a lipid solubility of one, fentanyl would have a lipid solubility of 580. So, you know, morphine – pour morphine on butter, it’s going to take a while to get in there. Whereas if you pour fentanyl on butter, it’s going to get in there. Wait, yes, I’m sure that would be actually quite an interesting experiment.

Now, why do we use morphine? Well, actually it lasts a really long time because it has low lipid solubility. It takes a while to soak in, it takes a while to get to that CNS space looking for those opioid receptors throughout your CNS, which means it hangs around for quite some time because it can’t get out very easily. Gets in slowly, gets out slowly. That’s why it’s also useful from an intrathecal perspective because it soaks in slowly and fails to come out quickly.

Fentanyl We counter that thinking with fentanyl and now we’re all thinking, well why on earth do we even use fentanyl? Morphine’s great isn’t it? Well morphine is pretty good but it binds to most of those μ-opioid receptors and its side effect profile is perhaps a little bit more negative compared to fentanyl. A number of individuals are tempted to just use sufficient fentanyl to achieve adequate pain relief knowing it’s more μ-opioid receptor specific and therefore get a bit less of that woozy, dozy feeling, that dysphoria that sometimes comes along with morphine, and it’s less nauseating.

I often reach for fentanyl for short procedures, you know, the quick and painful perianal abscess that needs to get done – encourage people to give 100 micrograms and then another 100 micrograms of fentanyl and get them pretty comfortable with that. I also reach for it in A&E when transferring a patient either to CT or getting them ready to take them to a different hospital. Why do I do this? Well, you could use alfentanil and set up an infusion. That’s one more line, one more pump and one more thing to go wrong, whereas you could just get the 500 microgram ampoule of fentanyl and give that patient fentanyl and actually you don’t have to worry so much – you know you’ve got a good amount of opioid on board and you can just manage that propofol infusion only. The odds are they are not waking them up today if they’re going for emergent neurosurgery.

Alfentanil Alfentanil is short and sharp. You give it, boom – pain relief, and then it’s gone. Takes 90 seconds to work, five minutes to wear off. When should you be using it? In RSIs that clearly need potent inhibition of the hypertensive response to laryngoscopy. You’re doing a GA in an eclamptic patient? Use a big dose like two milligrams.

Again, like fentanyl, it’s really cardiostable. Important to think about the pKa of alfentanil and comparing it to fentanyl is quite interesting. Alfentanil has a pKa of 6.5, which is well below your physiological pH, you know, your 7.35-7.45 world. This means it is 89% unionised. That means there is a substantial amount of alfentanil crossing those membranes, getting to those receptors and having an agonist party. And we like agonist parties, even though they sound awful.

Whereas if we contrast it to fentanyl? Well, fentanyl is quite different. Fentanyl has a pKa of 8.4. So actually it is only 9% unionised at physiological pH. You’re thinking, well, hell, why is the onset time of fentanyl faster than morphine – morphine being like 20 minutes – when it’s so ionised? Well, it’s because of lipid solubility and it just gets where it needs to go because it soaks across those fatty layers.

If you were to compare lipid solubility between fentanyl and alfentanil, you will find that fentanyl compared to morphine is 580 times more lipid soluble, whereas alfentanil is only 90 times more lipid soluble. So whilst pKa is an important contributor to onset time, it is not the be-all and end-all.

Important Safety Reminders It’s worth memorising the pKas, the protein bindings, and the relative lipid solubilities so that you can smoothly chat opioids in the exam and handle any SBAs that might try and compare and contrast these agents.

Don’t forget about opioid-induced hyperalgesia. All of the opioids can do it, although remifentanil is perhaps the worst offender because we can give so much of it with few side effects because of its offset profile.

Also do not forget chest wall rigidity, which again can cause you bother, but you can paralyse your way out of it if you’ve caused it during induction. If a patient just has it somewhere else, well then you are in a spot of bother – for example you’re doing an awake fibreoptic with loads of remifentanil and then the patient gets all stiff, then you are in a pickle.

Oh and also don’t forget that remifentanil can be used in a PCA and it is purported to be quite nice if you happen to be a labouring lady.

Closing Remarks

[23:39-24:55]

Anyway, that’s me. Thanks for listening to Gas Gas Gas. We have smashed over 10,000 listens now which is brilliant. Over 400 subscribers, so like it, tell your mates and I’ll see you for the next time which is going to be local anaesthetics. I’m ready for a change in direction. We’ve done too many opioids. Anyone would think we have a problem.

Thanks for listening guys. I hope you found it useful but if you found it awful do let me know. Please like and subscribe, register with whichever podcast platform you find yourself using and leave a comment if you think I need to square something away. I just want to make sure that you guys know that every day you are getting better at this. There is a bucket of content to try and consume and it is like drinking from a fire hose. Take it day by day, don’t overcook yourself, don’t freak out and keep studying.