Ep.38–Peri-Neural Adjuncts to Local Anaesthetics – For The FRCA Primary

GasGasGas – The FRCA Primary Anaesthetics Exam Podcast

Key Clinical Question: Can we safely and effectively prolong regional blocks using adjunct medications, and what are the licensing, safety, and practical implications of these agents?

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Quick Reference Tables

Classification of Perineural Adjuncts

Category	Agents	Primary Mechanism	Licensed Status
Non-Hypnotic	Adrenaline, Magnesium, Dexamethasone, Sodium Bicarbonate, Hyaluronidase	Various (vasoconstriction, NMDA antagonism, anti-inflammatory)	None for perineural use
Hypnotic	Clonidine, Dexmedetomidine, Ketamine, Midazolam	Alpha-2 agonism, NMDA antagonism, GABAergic	None for perineural use
Opioid	Morphine, Fentanyl, Diamorphine, Buprenorphine	Opioid receptor activation ± sodium channel blockade	None for perineural use

Comparative Efficacy Data

Agent	Sensory Block Extension	Motor Block Extension	Onset Effect	Notable Side Effects
Dexamethasone	4h (short-acting LA), 8h (long-acting LA)	2.5-4h respectively	No change	Hyperglycaemia (minimal)
Clonidine	1.25h	2.5h	No significant change	Bradycardia, hypotension, sedation
Dexmedetomidine	4h	3h	Speeds onset by 9 mins	Bradycardia, hypotension, sedation
Buprenorphine	8.5h	Variable	nil	Nausea, vomiting
Magnesium	1.75h	1.5h	No significant change	Potential CNS neurotoxicity

Alpha-2 Agonist Specificity

Agent	Alpha-2:Alpha-1 Ratio	Clinical Implication
Clonidine	220:1	More pronounced alpha 1 effects
Dexmedetomidine	1620:1	8x more specific than clonidine

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Detailed Content Sections

Classification & Basic Properties

Perineural adjuncts are medications added to local anaesthetic solutions to enhance block characteristics, typically duration and quality. These agents work through various mechanisms independent of sodium channel blockade.

Key Licensing Issue: All perineural adjuncts discussed are off-license for this indication. This creates medico-legal considerations that must be weighed against potential benefits.

Preservative Considerations: Only preservative-free preparations should be used. Preservatives like benzyl alcohol and propylene glycol are neurolytic in concentrations achieved during perineural injection.

Non-Hypnotic Agents

Adrenaline (Epinephrine)

• Mechanism: Vasoconstriction reduces systemic uptake of local anaesthetic
• Effects: Hastens onset, prolongs effect (~1 hour), reduces systemic toxicity risk
• Concerns: Potential compromise of vasa nervorum blood supply, increasing neurotoxicity risk

Magnesium

• Mechanism: NMDA receptor antagonism + voltage-gated calcium channel blockade
• Effects: Raises action potential threshold, prolongs sensory (1.75h) and motor (1.5h) blocks
• Concerns: Animal studies suggest potential spinal cord neurotoxicity
• Dosing: 25-100mg

Dexamethasone

• Mechanism: Glucocorticoid receptor activation → increased K+ channel expression → neuronal electronegativity
• Effects: Significant block prolongation (4-8h sensory, 2.5-4h motor depending on LA type)
• Evidence: 2024 BJA meta-analysis suggests IV administration as effective as perineural
• Dosing: 4mg ceiling effect
• Drug Interaction: Crystallizes with ropivacaine – do not mix

Hypnotic Agents

Alpha-2 Agonists (Clonidine & Dexmedetomidine)

• Mechanism: Paradoxically, few alpha-2 receptors on peripheral nerves. Actual mechanism involves hyperpolarization via cyclic nucleotide-gated potassium channels
• Effects: Both prolong blocks, dexmedetomidine superior (4h vs 1.25h sensory prolongation)
• Side Effects: Bradycardia, hypotension, orthostatic hypotension, sedation
• Dosing: Clonidine 150mcg, Dexmedetomidine 50-60mcg optimal

Ketamine

• Mechanism: NMDA antagonism + cholinergic + serotonergic effects
• Effects: Speeds onset AND offset (counterproductive for prolongation)
• Concerns: Neurotoxicity in animal models, systemic side effects limit utility
• Clinical Reality: Prilocaine achieves similar fast onset/offset with proper licensing

Midazolam

• Mechanism: GABAergic via benzodiazepine site on GABA receptors
• Target: High GABA receptor density in spinal cord dorsal horn
• Dosing: 50mcg/kg intrathecally
• Status: Mainly intrathecal use reported, limited peripheral nerve data

Opioid Agents

Standard Opioids (Morphine, Fentanyl, Diamorphine)

• Efficacy: Limited benefit in peripheral nerve blocks
• Rationale: Low peripheral opioid receptor density

Buprenorphine

• Mechanism: Partial mu-opioid/kappa-opioid receptor agonist/antagonist + concentration-dependent voltage-gated sodium channel blockade
• Efficacy: Exceptional 8.5-hour sensory block prolongation
• Side Effects: Nausea, vomiting (studies didn’t include antiemetic prophylaxis)
• Dosing: 3mcg/kg to fixed doses of 150-300mcg

Pharmacokinetics

Lipophilicity Considerations: Highly lipophilic agents may redistribute rapidly from injection site, reducing local effect duration.

Distribution Factors: Vascular anatomy of injection site influences systemic uptake and local residence time.

Special Clinical Applications

Modified Release Formulations

Liposomal Bupivacaine

• Technology: Microscopic vesicles (0.02-40 microns) providing sustained release
• Advantage: Prolonged sensory block with less motor impairment
• Concerns: Potential neurotoxicity of breakdown products
• Status: Previously had UK market authorization, now withdrawn

Specialized Applications

Hyaluronidase

• Primary Use: Ophthalmic blocks
• Mechanism: Degrades glycosaminoglycans, improving tissue penetration
• Effect: Decreases onset time

Sodium Bicarbonate

• Mechanism: pH adjustment increases unionized local anaesthetic fraction
• Effect: Faster onset via enhanced membrane penetration, (lidocaine stings less too)

Safety Considerations

Neurotoxicity Concerns

Evidence Base: Most neurotoxicity data derives from animal histological studies, limited human data.

High-Risk Agents:

• Magnesium (spinal cord toxicity in rats)
• Ketamine (peripheral nerve inflammation)
• Any preservative-containing preparation

Systemic Side Effects

• Alpha-2 Agonists: Predictable cardiovascular and CNS effects 
• Steroids: Minimal acute effects, potential glucose elevation 
• Opioids: Standard opioid side effect profile

Drug Interactions

Critical: Dexamethasone + Ropivacaine crystallization Solution: Use alternative local anaesthetic

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Educational Elements

Three Viva-Style Questions

Question 1: Classification and Mechanism

Q: “Classify the adjuncts used in regional anaesthesia and explain why alpha-2 agonists work when there are few alpha-2 receptors on peripheral nerves.”

Model Answer: Perineural adjuncts can be classified into three main categories:

1. Non-hypnotic agents: Adrenaline (vasoconstriction), magnesium (NMDA/calcium channel antagonism), dexamethasone (glucocorticoid effects), sodium bicarbonate (pH adjustment), and hyaluronidase (tissue ‘loosening’ action)
2. Hypnotic agents: Alpha-2 agonists (clonidine, dexmedetomidine), ketamine (NMDA antagonist), and midazolam (GABAergic)
3. Opioids: Standard opioids have limited peripheral efficacy (compared to intrathecal/epidural), but buprenorphine offers unique sodium channel blocking properties

Alpha-2 agonists work despite sparse peripheral alpha-2 receptors through a different mechanism. They maintain neuronal hyperpolarization by blocking cyclic nucleotide-gated potassium channels during the post-action potential recovery phase. This keeps neurons nearer the hyperpolarized overshoot potential (-90mV) rather than returning to resting potential (-70mV), making depolarization by subsequent action potentials impaired.

Question 2: Clinical Decision Making

Q: “A colleague wants to add dexamethasone to ropivacaine for an interscalene block. What are your concerns and what would you recommend?”

Model Answer: Several concerns arise:

1. Drug compatibility: Dexamethasone and ropivacaine crystallize when mixed – they’re incompatible in solution
2. Licensing: Neither combination is licensed for perineural use
3. Route of administration: Recent 2024 BJA meta-analysis suggests IV dexamethasone is as effective as perineural administration

Recommendation: Use IV dexamethasone instead. This provides:

• Licensed route of administration
• Equivalent analgesic benefit
• No drug compatibility issues
• Reduced medico-legal risk
• Systemic anti-inflammatory and antiemetic effects

If insistent on perineural route, use alternative local anaesthetic (lidocaine/bupivacaine).

Question 3: Risk-Benefit Analysis

Q: “What factors would you consider when deciding whether to use buprenorphine as a perineural adjunct, given its apparent efficacy?”

Model Answer: Efficacy considerations:

• ~8.5-hour sensory block prolongation
• Dual mechanism: opioid receptor activation plus sodium channel blockade
• Superior to standard opioids for peripheral nerve blocks (which add very little if anything)

Safety considerations:

• Off-license use with associated medico-legal implications
• Side effects: nausea, vomiting (though studies lacked antiemetic prophylaxis)
• Limited human safety data compared to standard techniques
• Long duration may impair rehabilitation and increase fall risk

Practical considerations:

• Availability of IV preparations
• Patient factors: day-case vs inpatient, rehabilitation requirements
• Alternative strategies: multimodal analgesia, standard adjuncts

Decision framework:

1. Consider patient-specific factors (pain tolerance, rehabilitation needs)
2. Ensure informed consent regarding off-license use
3. Implement appropriate monitoring and follow-up
4. Consider prophylactic antiemetics
5. Document decision-making rationale clearly

Key Clinical Pearls

Memory Aids

• Adjunct Categories: “NOH” – Non-hypnotic, Opioid, Hypnotic
• Alpha-2 Specificity: Dexmedetomidine is “8 times more specific” than clonidine (1620:1 vs 220:1 ratio)
• Dexamethasone Ceiling: “4mg max” – no additional benefit beyond this dose (when administered perineurally)
• Drug Incompatibility: “Dex + Rop = Rocks” (crystallization)

Essential Facts

• All perineural adjuncts are off-license
• Only use preservative-free preparations
• IV route dexamethasone = Perineural route dexamethasone for efficacy
• Buprenorphine’s sodium channel blockade makes it unique among opioids
• Liposomal bupivacaine was withdrawn from UK market (reason unclear)

Clinical Tips and Tricks

Practical Approaches

1. Start conservative: IV dexamethasone 4mg for most cases
2. Consider patient factors: Day-case surgery Ortho – causing prolonged motor block may not be helpful
3. Consent: Clearly record off-license use and reasoning
4. Follow-up: Ensure appropriate safety net and guidance for prolonged blocks

Exam Strategy

Structure answers by:

1. Location: Regional vs Neuraxial
2. Drug class: Opioid, Hypnotic, Non-hypnotic
3. Mechanism: How each agent works and how it alters block dynamics
4. Evidence: Acknowledge limited licensing and evidence base

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Support Materials Referenced

Primary Literature

• BJA Education (2019) – Comprehensive review of perineural adjuncts
• BJA (2024) – Systematic review: IV vs perineural dexamethasone (doi: 10.1016/j.bja.2024.03.042)
• Kosel et al. (2016) – Buprenorphine as unique regional adjunct (doi: 10.1586/17512433.2016.1141047)
• World Journal of Clinical Cases – Adjunct mechanisms and applications

Related Gas Gas Gas Episodes

• Local Anaesthetics series (bupivacaine, lidocaine, ropivacaine, prilocaine)
• Neuraxial opioid kinetics
• Local anaesthetic systemic toxicity

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Additional Supporting Materials for Consideration

Guidelines and Position Statements

• European Association of Obstetric Anaesthetists recommendations on dexamethasone for LSCS
• AAGBI guidelines on local anaesthetic toxicity
• AAGBI Local anaesthetic adjuncts for peripheral regional anaesthesia: a narrative review

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Common Pitfalls and Safety

Critical Errors to Avoid

1. Using preserved preparations – Risk of neurotoxicity
2. Mixing incompatible drugs – Dexamethasone + ropivacaine = crystallization
3. Dose miscalculation – Particularly relevant for potent agents like dexmedetomidine
4. Inadequate monitoring – Prolonged blocks require appropriate guidance for care of limb

Safety Checklist

• [ ] Preservative-free preparations confirmed
• [ ] Drug compatibility verified
• [ ] Appropriate dosing calculated
• [ ] Patient consent for off-license use obtained
• [ ] Monitoring planned safety netting established for prolonged blocks
• [ ] Clear documentation of decision-making rationale

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Transcript

Episode 38: Perineural Adjuncts

00:00-01:31 Introduction and Context

Hello, everyone. Welcome to Gas, Gas, Gas. We’re here and back for yet another delightful episode.

Just as you thought local anaesthetics was all over, it transpires that whilst I thought that was the case, there is a blind spot. This blind spot could certainly end up being an interesting viva question because you could structure it as intrathecal or epidural and regional or neuraxial and peripheral, and then subdivide the drugs we’re going to talk about into opioids, hypnotics, and non-hypnotic agents.

What are we all about? We’re all about drugs that you could add to a regional anaesthetic preparation to modify the nature of that block. Classically, these things prolong it or specifically prolong sensory over motor. Although, interestingly, ketamine speeds up onset and then speeds up offset. So, I think if we didn’t have prilocaine, you might see that used a bit more.

The important thing to note is that local anaesthetics are licensed drugs for administration in people’s CSF spaces as well as around their nerves. Whereas all of these additives are off-label – there is no licence to put magnesium into someone’s interscalene groove or any of these other drugs. This puts you in a bit of a pickle, because if there is any whiff or hint of neurotoxicity in the conversation we’re going to have, you might find yourself in a slightly more uncomfortable position than you might like. I think this is why this might not have taken off with quite as much gusto over the last 15-20 years as it could have done. We’re all inherently cautious individuals as anaesthetists, and we like to know exactly what is going on before we get involved generally.

01:31-03:32 Why Add Adjuncts to Local Anaesthetics?

Before we get into the meat of things, why did folks start trying to add stuff to the local anaesthetic preparations they were using? Well, we know that block length is somewhat fixed. Therefore, we could just give more and more to that interscalene block and then it would last longer and longer. However, as we know from a couple of episodes ago, there’s only a certain amount of local anaesthetic you can administer before you find yourself in a sticky situation with local anaesthetic systemic toxicity.

This naturally leads to people thinking, “well, what can we do?” The classic additive is adrenaline, isn’t it? You cause some vasoconstriction, you get less clearance from that injection site of the active agent, and you end up with something that lasts longer. But putting adrenaline into someone’s CSF space might raise one or two eyebrows, and we’re somewhat hesitant about causing too much vasoconstriction of the vasa nervorum – that’s the very fine capillary network that supplies blood to a big chunky nerve.

If you’re adding agents that are somewhat irritant to that nerve, and then you’ve caused vasoconstriction of that nerve, you might end up in a situation where you have increased odds of toxicity. Although, bearing in mind, these are all situations that haven’t been tested in humans, because it’s not cricket. Most of the papers I’ve read refer to animal models, chiefly rats, where they’ve exposed them to these agents and then done histology on the nerves and explored for evidence of inflammation and nerve injury.

03:32-05:24 Considerations When Selecting Adjuncts

There’s lots of things in the cupboard. If we could come across an agent that worked synergistically alongside local anaesthetic to prolong the effects of the block and really preferentially prolong sensory block whilst giving the person movement back, that would be great. But the trouble is that these drugs have side effects too – either when you end up with systemic uptake of that drug, or if it has direct local effects on tissues or nerve (if it’s cytotoxic or neurotoxic in those concentrations we’re reaching for).

This takes us back to how could we approach making local anaesthetics last longer? There are attempts at modified release preparations. There’s something called liposomal bupivacaine, which we’ll go into more detail later, that tries to create a bigger reservoir at injection site of local anaesthetic in order to prolong block.

Another thing to definitely keep in your mind if anyone’s reaching for these agents is to ensure that you’re using preservative-free preparations, because a lot of the preservatives used are fine in an intravenous dose because they are rapidly diluted into plasma, but when co-located next to a nerve in the concentrations that you might be administering them, cause bad news. We don’t want to end up like that anaesthetist with those two patients at Chesterfield Royal Hospital, whereby they inadvertently introduced an unknown agent to someone’s intrathecal space and caused disaster – ending up with a nerve-injured patient. That would be bad.

The core concepts that someone’s going to want to explore when considering an agent for this include the pharmacokinetic properties of that agent. If it’s very lipophilic, is it just going to zoom off and end up being quite thoroughly redistributed, or is it going to sit where you’ve injected it?

What are the pharmacodynamic considerations? Is the patient going to end up with a side effect that they’re very much intolerable of? This was found when they were trying to use ketamine next to peripheral nerves – patients just ended up with side effects of ketamine and had a rough time.

Naturally, is it toxic and/or neurotoxic, tissue toxic? Although, admittedly, sometimes we do reach for a toxic drug. Classically, we’re thinking phenol when we’re doing a chemical sympathectomy for pain in palliative care. So, we do obliterate nerves sometimes. Just bear that in mind: there are reversible agents that block nerves and irreversible blocking of nerves.

05:24-05:43 Goals and Drug Categories

The perfect goal of achieving a nice long sensory block that isn’t so dense that it’s weird for the patient but gives them motor function back – that would be a beautiful ideal, but I’m sure we’re never going to get there.

What drugs can we stick next to nerves? I’m going to break it down into a semi-ordered manner. We’re going to do non-hypnotic drugs first.

05:43-12:42 Non-Hypnotic Adjuncts

05:53-06:38 Adrenaline

These are adrenaline, magnesium, and dexamethasone that jump to my mind. We know with adrenaline that it speeds up onset, it prolongs the effect of some local anaesthetic agents – not terribly much for bupivacaine, but certainly lidocaine – and it does so by reducing the systemic uptake of that agent from the site you’ve injected into.

We should caveat that if we’re putting it somewhere that’s particularly sensitive like the intrathecal space, which is certainly not recommended, you’re going to end up with perhaps some cord perfusion issues. If someone’s got a bit of a marginal cord, you might find yourself in a spot of bother.

One of the additional benefits of adrenaline is it causes local vasoconstriction. Classically, if you’re injecting lidocaine at a site, it’s probably because you’re going to operate somewhere in and around that. Vasoconstriction keeps your field nice and tidy. Not one that you would tend to reach for an interscalene block, terribly much by the sounds of it.

06:38-08:06 Magnesium

What about magnesium, you say? Well, magnesium seems to work for everything, doesn’t it? It makes your cup of tea taste better. It seems to make people have less pain. Someone’s got a mischievous little heart rate, you give them magnesium and it all gets magically better. I’m fairly sure it also calms surgeons down by some sort of homoeopathic placebo effect.

But how does it work if you stick it next to a nerve? Well, we know that magnesium is an NMDA receptor antagonist, and also it antagonises voltage-gated calcium channels. What does this mean on a physiology level for that nerve? The nerve ends up requiring a higher action potential to trigger onward conduction. You know, that saltatory conduction hits the synapse, and you have to have enough of a discharge at that synapse to communicate with the next nerve. If that next nerve has actually got a really high threshold – they’re looking for like a 10 out of 10 action potential, as opposed to their normal 7 out of 10 – then you’re going to reduce conduction.

How does it work? Well, in studies with chiefly brachial plexus blocks, it seemed to prolong sensory blockade by about one and three-quarter hours and motor blockade by one and a half hours. There is some concern with neurotoxicity in magnesium. When administered adjacent to the spinal cord in rats, it ended up demonstrating some concerns. But again, there are other studies suggesting it has benefit in doses of between 25 and 100 milligrams in the epidural or intrathecal space. So, swings and roundabouts.

08:06-11:15 Dexamethasone

Dexamethasone is a drug we are all certainly very familiar with. Classically, we are taught that it is an antiemetic, but we know steroids reduce swelling and have a multitude of systemic effects and systemic side effects at chronic doses.

What does it do when we stick it next to a nerve? How does it work? Well, it might act on cellular membrane glucocorticoid receptors, and this might lead to an increased expression of potassium channels. This means that you have impaired conduction because you’re more electronegative in your neuron. The real question there is: does it instantaneously start prolonging block, or does it actually take a while to cook? As your other agent is wearing off, that dexamethasone is starting to cause mischief and slowing down that nerve and making it really negative and, therefore, unwilling to do any work.

Dexamethasone is used for analgesia in other settings as well. The European Association of Obstetric Anaesthetists came out a number of years ago saying we recommend that everyone for elective lower segment caesarean sections should get a dose of dexamethasone because it’s definitely better for pain. That original statement was based off quite a broad range of studies, some which were injecting dexamethasone straight into surgical wounds versus giving IV versus etc. So it seemed like that suggestion was on wobbly ground. However, then there was a meta-analysis to really assess this data with some slightly greater focus and clarity, and their position remains that giving dexamethasone reduces pain post-operatively. So we know it probably does do something.

When they looked at – I think someone’s done a convenient systematic review of 29 randomised controlled trials of dexamethasone adjacent to peripheral nerves – it seems to increase sensory blockade by four hours when you mix it with either lidocaine or prilocaine, and eight hours (that’s quite a long time) when mixed with bupivacaine or levobupivacaine or ropivacaine. It does also prolong motor block by 2.5 and 4 hours, respectively.

So you think, “God, that’s great. You’re saying that my 8 to 16 hour interscalene block might actually last for maybe 12 to 24 hours. That would be great.” The ceiling effect of how much dexamethasone you can administer next to that nerve alongside your local anaesthetic is 4 milligrams. Anything more than that doesn’t seem to do very much.

But I hope that you’re sat there thinking: “well, is it really a direct nerve effect, or is it just that we’re observing an effect of dexamethasone when it’s taken up systemically?” That’s a very sensible question to ask. There’s a BJA article in 2024 which has asked just that question – a systematic review plus meta-analysis that seems to lean towards just giving it intravenously.

Which one am I going to choose? Well, I’m going to give it intravenously because it’s licensed intravenously. You could jump up and down and say, “Oh, yes, but they’re going to have higher blood sugar, maybe, and what if they’re diabetic?” What of a one-shot dexamethasone? Who cares? I think that even if you’re type 2 diabetic, you’re having elective surgery, you should have reasonable diabetic control. So, one-shot dexamethasone, probably not a negative thing. Naturally, follow your local policies and guidelines, and whatever the general institutional feeling is.

11:15-12:05 Sodium Bicarbonate

We should very briefly touch on sodium bicarbonate, although we’ve spoken about it at quite a lot of length before, but if we’re in that viva question and you’re listing these things out, we all know that if you add a sensible amount of sodium bicarbonate to a mixture, you will shift the pH of that mixture, but also the tissue it is injected into into a more alkaline state. This will give you a greater fraction of unionised local anaesthetic molecules, which can then cavort off into those neuronal membranes and dance some sort of classical dance towards those sodium channels and block them once those sodium channels open, and you’ve got your local anaesthetic mechanism of action there.

12:05-12:42 Hyaluronidase

The last non-hypnotic, non-opioid agent that sometimes gets added, although more in ophthalmic surgery, is hyaluronidase. You can probably remember from those amazing Oil of Olay adverts or Pantene Pro-V where you get hyaluronic acid in your facial moisturiser. Well, hyaluronidase decreases onset time in ophthalmic blocks. Mechanism-wise, it degrades glycosaminoglycans. I’m sure you remember those from medical school. These are molecules that help cohere connective tissues. If you inject some of that around your eyeball, you can somewhat dissect out those tissues ever so slightly and lead to a greater spread of agent and, therefore, faster onset time.

So, those are the non-opioid, non-hypnotic additives: magnesium, adrenaline, dexamethasone, sodium bicarbonate, hyaluronidase.

12:42-21:21 Hypnotic Adjuncts

Now we’re going to move on to hypnotics. The hypnotics being generally ketamine, midazolam, alpha-2 adrenoceptor agonists (that’s going to be clonidine and dexmedetomidine), and these will have an interesting gaggle of effects.

13:03-14:44 Ketamine

Ketamine, because ketamine sure is a hell of a drug, as we all know. What does it do? It’s an NMDA receptor antagonist, but it also has cholinergic and 5-HT serotonergic effects.

What does it do when you inject it into someone’s intrathecal space? Well, it speeds up the onset of effect of that agent. Great, you say. But it also speeds up offset. If you were to ask me why, well, I couldn’t tell you. One of the papers I read would argue that this is really super handy in day case because then it’s going to wear off faster and you can achieve higher throughput. But arguably, we’ve got prilocaine and we’ve got 2-chloroprocaine, which are licensed for use intrathecally. Prilocaine does get to work pretty hecking sharpish.

So it seems like maybe ketamine’s a fun thing you could stick in there, but it’s not actually really going to add anything, and you’ll be again playing off licence. There are also some concerns regarding neurotoxicity with ketamine. Again, this is in animal models where looking at nerves, it seems to cause a bit of upset.

If you’re reaching for it for your interscalene block, most of the literature looks like it doesn’t improve block duration at all, which we would expect from its intrathecal behaviours. And actually, folks just get side effects. Do you really want someone who’s having awake shoulder surgery to get paranoid whilst they’re under those drapes? That would be a fiddly one. “What are you doing here? What’s going on? Why am I under these drapes? I don’t like this very much. Why is there drilling? Why am I being banged on? I want to get out of this chair. I don’t like this very much at all. You’re all trying to kill me.” Whilst probably in retrospect an anecdote that you could use, it wouldn’t be a great situation for patients, staff or you really. What are you gonna do? Get them sat up in beach chair? Good luck.

14:44-16:35 Midazolam

How about midazolam? It seems like midazolam has mostly been used intrathecally. There are a couple of reasonably sizeable studies that demonstrate its use with no reported side effects. The trouble is to identify side effects in these cohorts when we know that side effects of local anaesthetic neurotoxicity, for example, given that these procedures are so incredibly safe already, if you’ve got a drug which might be marginally not safe, you’d have to administer it quite a lot of times. Say you’ve done it a thousand times, but there’s a one in five thousand chance of permanent nerve injury. Are you going to catch it? Probably not. It’s hard to be sure.

To be sure, midazolam, how does it work? We know midazolam is GABAergic, it binds to the benzodiazepine site on a GABA receptor and modulates its action. Classically, more chloride into cell, creating a cell that’s more electronegative and therefore less inclined to depolarise. Conveniently, there’s a high density of these GABA receptors in the dorsal horn of the spinal cord. We all know that the dorsal horn is where those sensory cell bodies exist. So, if we modulated those, you’re going to end up with diminished conduction of stuff that is being communicated in a sensory manner. Great!

Doses, about 50 micrograms per kilogram intrathecally, is what seems to be quoted. Again, it is not licensed and it doesn’t seem to do very much in peripheral nerve blockade.

Should you be reaching for intrathecal midazolam? Well, it’s going to soak upwards into their CNS and make them dozy drowsy. The studies say no, but it’s not something we do, is it, folks? But we could talk about it in an exam because the exam isn’t real life because we don’t use pneumotachographs or pitot tubes half as much as we used to, and we certainly don’t use pneumatically powered ventilating devices anymore, do we? But here we are learning about them. Although they are really cool mechanically, the Penlon 200 or whatever is amazing. And you could buy one for £1,200. Oh, £790. Anyway. We don’t need to buy antique ventilators off the Internet, folks.

16:35-21:21 Alpha-2 Agonists: Clonidine and Dexmedetomidine

We’re talking about intrathecal and perineural adjuvants. So what about Alpha-2 agonists? These are clonidine and dexmedetomidine. We know that they classically work on alpha-2 receptors. Although, if you look at a peripheral nerve, you will struggle to find many alpha-2 receptors. So, therefore, they must be doing something else.

Studies seem to have elucidated that they create a hyper-negative neuron. When I say hyper-negative, if you remember that graph of an action potential on a neuron, there’s a bit of an electronegative overshoot. It drops down to minus 90 millivolts before settling down at its resting membrane potential of minus 70. It achieves getting this nerve stuck at minus 90 by modulating the effects of a cyclic nucleotide-gated potassium channel. This means more potassium can escape that neuronal cytoplasm environment and end up being more negative because, remember, stuff that’s inside the cell that can’t get out, like proteins, are quite negative.

So, if you were to be reaching for one of these agents, what would you pick? Clonidine has been more readily available in the UK for quite a bit of time, whereas dexmedetomidine has really been only cheap enough to be around for maybe the past five or six years in places I’ve worked.

Just so we have a bit of a comparison, we’re interested in part by how specific these agents are to the alpha-2 receptor because we don’t really want to go around agonising alpha-1 receptors because you’re gonna end up with high blood pressure, which is a side effect you can see, at least initially. Because remember, alpha-1 tends towards causing high blood pressure, whereas alpha-2 agonism lowers blood pressure.

So how specific in ratio is one to the other? Clonidine has a ratio of about 220 to 1 of that specificity to alpha-2 receptors, whereas dexmedetomidine, 1,620 to 1. So, it very much prefers alpha-2 receptors to alpha-1 receptors, about eight times as much.

Do they work? Yes, they prolong sensory and motor blockade. Both do, but they do both cause systemic side effects when administered, and you will generally see bradycardia, hypotension and/or orthostatic hypotension (when you stand up, you drop your blood pressure, but you look fine in bed). Some people can get a bit sedated from it as well and wake up a bit dozy, depending on the dose you’ve used.

A clonidine-augmented regional anaesthetic gives you a sensory block of 1.25 hours more and a motor block of two and a half hours. Whereas interestingly with dexmedetomidine, you get a prolonged sensory block about four hours and a motor block about three hours. I’m quoting all these like it does this by this and that by that, and I would say certainly not take these with too much more than a pinch of salt because you are relying on someone who’s been very good at citing local anaesthetic next to that nerve. I highly doubt these studies are from one single person who has just done a thousand interscalene blocks, for example, day in, day out for months and months to avoid that inter-observer or inter-practitioner variability that you’re going to see with “actually oh well actually the anatomy’s a bit awkward here.”

So I’m going to say openly, don’t go hard and fast on those numbers, but it generally sounds to me like out of these two, dexmedetomidine yields a longer block than clonidine does. There is naturally greater familiarity with clonidine. Both are used intrathecally, intravenously, epidurally, or regionally.

The dose that has been found to generally do an alright job from a regional blockade perspective with clonidine is 150 micrograms. This is sort of the low end of what you might administer to someone IV for pain. That IV pain dose is sort of up to three micrograms per kilo. So for your 70 kilo patient, you’d be looking at up to 210 micrograms. Although you’re going to end up with a drowsy, dozy patient afterwards because it’s a hypnotic.

Dexmedetomidine dosing. They’ve seemed to identify that intrathecal doses of 5 to 10 micrograms work quite well, and 5 micrograms yields the lowest rate of systemic side effects. It’s been dosed up to one microgram per kilo epidurally and a microgram per kilo perineurally. There’s no explicit dose-response relationship that they’ve been able to identify with dexmedetomidine, but again, they tend to suggest 50 to 60 micrograms seems to do the job.

Interestingly, when you look at these nerves under a microscope, they found that it seems that dexmedetomidine inhibits perineural inflammation because it inhibits something called nuclear factor κB or nuclear factor kappa, light chain enhancer of activated B cells, if you want to know the full term. When comparing a nerve that’s been exposed to lidocaine or bupivacaine or dexmedetomidine, seemingly the nerve is a bit happier with the dexmedetomidine than the other two.

Again, it’s not licensed, so pinch of salt stuff. But out of everything we’re going to talk about, I think dexamethasone is certainly something I’d be giving someone IV. And if you were to ask me to pin myself to the fence on another drug that seems reasonable, maybe it is dexmedetomidine out of everything we’ve explored so far.

21:21-24:07 Opioid Adjuncts

Then, regards opiates. There’s a whole episode talking about neuraxial opiate kinetics, which I would definitely say go have a listen to. The general gist of it is that there’s three opiates that are used in the neuraxial environment commonly in the UK: these are morphine, fentanyl and diamorphine. All of them have slightly differing onset times, durations of effect, and this is based on their pharmacokinetic properties. Go have a listen to that episode.

But the one that jumps out from a regional anaesthesia perspective is buprenorphine. Buprenorphine is a partial mu opioid receptor and a kappa opioid receptor antagonist. It seems to also cause a concentration dependent voltage-gated sodium channel blockade. Remember those voltage-gated sodium channels are the ones that propagate our action potentials down nerves. So it might have more than just an opioid receptor effect when administered perineurally.

Some nerves do have opiate receptors, and you could argue that all nerves have opiate receptors just peripherally in quite scant density compared to in your CNS space where there’s oodles of the things. When used as a regional anaesthetic agent adjunct, it seems to increase sensory blockade by eight and a half hours.

However, the study that we were looking at in that BJA article on perineural adjuncts mentions that patients often get side effects of nausea and vomiting. However, they weren’t given any antiemetics during that intervention. So perhaps that’s what we’re missing out on. Unless we’re missing something dramatically in the literature about some sort of lethal toxicity or something to that effect, or it could just be that getting hold of IV preparations of buprenorphine is just awkward, it does seem to be quite potent at prolonging sensory blockade in regional anaesthesia.

Doses seem to range from about three micrograms per kilo to giving everyone one hundred and fifty micrograms or three hundred micrograms. In one study, 2001, Candido, prolonged the effect of a mepivacaine-tetracaine type mix from 5.3 hours to 17.4 hours. They did it again looking at axillary blocks where they were either administering buprenorphine perineurally or intramuscularly, both at the same dose, alongside their normal block technique. The buprenorphine group averaged 22 hours, whereas the IM injection group 12.5 hours. Again, this bore out with interscalene blocks as well. So it seems quite good.

That’s really probably because it’s not working as an opioid at that site, but it’s working as its sodium channel blocking task.

24:07-25:47 Liposomal Bupivacaine

We’ve explored quite a few different drugs there and how they might behave intrathecally, if that’s interesting, or perineurally in the peripheral nervous system. We’ve pointed out that the use of these drugs is really much off-licence, and that adds a layer of caution, I think, with most of this. We seem to be at risk of being obsessed with making a sensory block last for eons and eons without actually perhaps wondering if it’s quite weird to have a numb arm for a day. What’s the actual patient side of things?

I think personally, I would be keen to be pain-free and avoiding ibuprofen that gives me rip-roaring heartburn and opiates, which I’m sure have a smorgasbord of side effects. I think I’d accept quite a numb arm, as long as you looked after it well. The trouble being, these are all off-licence, so if there was an agent that was on licence, that would be very much reassuring.

And here it comes: liposomal bupivacaine, because surely a modified release version of a drug that we know is already licensed for use next to nerves is great. So, what is it? It’s microscopic vesicles, and they are 0.02 to 40 microns across, and they deliver prolonged sensory blockade. They don’t tend to deliver prolonged motor blockade, and we know we can figure this out because you need quite a high concentration of agent to achieve motor blockade in these big, chunky, myelinated, very metabolically active nerves. Whereas you don’t need quite as much for these slightly smaller sensory nerves. If you’re delivering an agent that is modified release to that site, it’s not going to provide a long duration of high concentration, it’s going to generally provide a long duration of slightly lower concentrational local anaesthetic.

This was licensed in the UK, it had market authorisation, but now it doesn’t. I can’t really figure out why. If anyone knows, feel free to fire me off an email and I’ll add a little note with the reason for that to have occurred and a little thank you to whoever does email me. It sounds like a great idea. Alas, we’re not allowed nice things, so we’ll just stick with levobupivacaine, won’t we, everyone? Maybe some IV dexamethasone, and maybe in the future dexmedetomidine.

25:47-26:47 Summary and Exam Structure

Remember, if you do get lumbered with this in an exam, try and break it down into either regional or neuraxial, and then split these drugs into opioids, hypnotic and non-hypnotic agents.

Those opioids being morphine, fentanyl, diamorphine and buprenorphine should probably get a mention. The hypnotics being your alpha-2 agonists, so clonidine, dexmedetomidine, ketamine and midazolam, and then your non-hypnotic agents: magnesium, adrenaline, dexamethasone, sodium bicarbonate, and if you’re really, really remembering everything, hyaluronidase.

I think it’s really quite an interesting subject area. It was quite a blind spot for me, so I’ve quite enjoyed the reading required to get this conversation where it is today. I hope you’ve got something out of it as well.

26:47-26:53 Closing

I hope you enjoy listening to today’s show. If you do, tell your mates, share the episode, and I’ll see you all next week for more antics. What’s it going to be? Think it’s stereoisomers. We just need to make sure that we don’t miss out all these important but deeply boring pharmacological concepts. Someone could definitely ask you to classify stereoisomers in an exam, so you need to do it, and we will cover it.