Ep.26 – Neuraxial Opiate Kinetics

Introduction

In this explainer episode of GasGasGas, James delves into the joyful complexities of neuraxial opiate pharmacology. Why do we bother putting opiates into this space at all? What governs their journey, how do they behave once administered, and what clinical pearls can be drawn from their behaviour? This episode follows the journey of a single opioid molecule through the fatty labyrinth of the epidural space, across barriers, and into its final destination: the dorsal horn of the spinal cord.

Gas, Gas, Gas Episode: Neuraxial Opioids

Introduction and Historical Context

00:30-02:21

And let’s get on with the show. Hello everyone, this is James at Gas Gas Gas. And as promised, I sit here thinking about how opioids potter through the epidural and intrathecal spaces on this joyful Saturday morning. I’ve had my nap, I’ve done my gardening, and I’m ready for action. So let’s get on with the show.

So why do we actually bother putting opioids intrathecally or epidurally? Well, it all actually kicked off in the 1970s when Yaksh and Rudy realised that sneaking opioids in and around the spinal cord achieved heavily saturated cord opioid receptors. This was an ambitious hope because they desired opioids to not squirrel off into other areas of the human, leading to all the side effects of opioids, which we all know and we could all recite. But we’re going to talk about constipation, respiratory depression, feeling sick.

However, whilst lots of people started putting intrathecal or epidural opioids into people, the impression I might have got from some of my readings suggests that people were hoping beyond hope that they didn’t get the sequelae of systemic opioids.

Unfortunately, a bunch of patients stopped breathing, a number of them with terrible consequences. And ultimately, it transpired that concentrated doses of opioids were creeping their way northwards, pickling respiratory centres and leading to respiratory depression. Remembering, guys, that the respiratory centres are in the ventral respiratory group in the medulla oblongata, the VRG.

So this probably harks back to the needs of doctors to be inherently suspicious when confronted with something that sounds too good to be true. We should assume that it is extremely suspicious and that perhaps when someone comes out saying this drug cures 95% of all ailments à la paracetamoxyfrusebendroneomycin – go on YouTube for that cracking song – we should think twice about whether or not we should believe said claim.

Rationale for Neuraxial Opioids

02:21-03:51

Summary: Why neuraxial administration remains useful despite early complications.

So why do we still do it? Well whereas IV administration of opioids achieves a plasma concentration and this plasma concentration is subsequently very close to nerves because nerves require a blood supply and that blood supply is in the shape of capillaries or the vasa nervorum and therefore it’s quite close by to its effect site. So why don’t we just give everyone systemic opioids?

Well it is true to say that giving someone intrathecal opioids does achieve a high concentration of opioid in the cord with lower potential side effects and also alterations in how long that dose lasts for, which we’re going to get into more detail a bit later in the show.

So we probably need to start thinking about the epidural space before we get into all the minutiae and the intrathecal space before we go even deeper.

Anatomy of the Epidural Space

03:51-05:48

Summary: Detailed anatomical boundaries and contents of the epidural space.

Boundaries of the Epidural Space

The epidural space from an anatomical perspective. In an exam they might ask you, “what are the borders of the epidural space?” And if you’ve not thought about it, you’ll be wasting valuable time trying to think it through and remember your anatomy.

So you’ve got to imagine it like a cylinder with capped ends:

• Superiorly: Limited by the foramen magnum – i.e. the hole in the base of the skull that the cord passes through – as the dura fuses with the skull base, therefore creating a barrier
• Inferiorly: The epidural space finishes at the sacral hiatus, where it’s covered by the sacrococcygeal ligament – you know, the place where you can stick a needle and do a caudal epidural

And then the front, back and sides of the epidural space as it goes from top to bottom:

• Anteriorly: Bounded by vertebral bodies, discs and the posterior longitudinal ligament of the vertebral bodies
• Posteriorly: Bordered by the ligamentum flavum – that’s the one we go through when we’re doing an epidural – and the vertebral laminae, i.e. bone
• Laterally: Bordered by the pedicles and the intervertebral foramina because the spinal nerves have to get out somehow

So that’s your anatomical borders of the epidural space. Now if you’re being smart you could also say that the meninges are also the internal border of this because actually it’s a tube in a tube, which most of the human body does seem to be once you take them apart embryologically.

Contents of the Epidural Space

So we’ve talked about what borders the epidural space, but what do we find in the epidural space? Well, it’s full of fat, but also a dual venous plexus. This is called Batson’s plexus, and this is actually a venous network that plumbs from your sacrum all the way up your epidural space. There are no valves, so that means that infection down low can journey up high, and that tumour cells can traverse this space also.

Where you find veins, you find arteries. There are the so-called segmental spinal arteries that ultimately traverse the meninges, delivering blood flow to the anterior spinal artery and the two posterior spinal arteries.

If you were to be tottering around in this space and having a look about, you would also stumble across spinal nerves. Remember, we’ve got intervertebral foramina, we’ve got a spinal cord, those nerves have to get out somehow and they journey through this space.

Journey of Opioid Molecules

05:48-07:35

Summary: The path opioids must take from epidural injection to their site of action.

So we’re just imagining ourselves – we’re a morphine molecule. We’ve been rudely injected down an epidural catheter into a fat space and we’re thinking, “oh, we’ve got our work cut out here. We’ve got to go on a journey.”

And that journey is:

1. They’ve got to totter through epidural fat
2. They’ve got to negotiate around the epidural venous plexi and avoid getting soaked up and squirrelled off into the plasma
3. They’ve then got to eke their way across the dura mater and then the arachnoid mater
4. And then, they’ve got to percolate across the CSF before finding themselves scratching their head thinking about going through the pia mater and ultimately percolating through that spinal cord

Where is the chief site of effect? Well I’m sure you know and I’m going to tell you anyway. The chief effect site in the spinal cord for opioids is in the dorsal horn grey matter, which is where the cell bodies are guys. Remember the white matter is myelin sheath of nerves and it’s in the substantia gelatinosa which is located in Rexed lamina II.

Rexed laminae are a histological way of splitting apart the spinal cord.

Physicochemical Factors Affecting Drug Movement

07:35-09:22

Summary: Key drug properties that determine successful neuraxial penetration.

So that morphine molecule that you’ve been imagining yourself as has to go on quite an adventure. The ability of that morphine molecule to make that journey successfully – what barriers are in its way from a physicochemical manner? And certainly those things are important too. And that’s why we love anaesthesia.

So how lipid soluble the agent is is an important factor. Its protein binding, its molecular weight, and its pKa.

Lipid Solubility

So lipid solubility, what does that really mean? I’m going to tell you a few times throughout this podcast. If you’re very, very lipid soluble, this is actually a detractor, because it means you’re more likely to either get bamboozled, if you’re a fentanyl molecule, for example, into soaking yourself into epidural fat and being quite happy sat there not doing very much and just minding your own business, or getting pulled up from the epidural fat space by blood flow through those veins and then off you totter to other parts of the body, which is less than handy.

Other Factors

• Molecular weight: We can all remember Fick’s law and the crux of that in this case is the bigger the molecule, the slower the rate of diffusion
• pKa: Also relevant from an ionised versus unionised perspective. Remember that ionised molecules aren’t so great at traversing fatty spaces and lipid membranes are quite a barrier to an ionised molecule. So it’s the unionised component that we’re interested in when we’re thinking about how it’s going to get where it needs to go
• Protein binding: If it’s heavily protein bound, you’re going to have less available drug to make that journey

Epidural vs Intrathecal Dosing

09:22-10:42

Summary: Key differences in dosing and side effect profiles between epidural and intrathecal administration.

So now we are all capable of imagining the journey a molecule goes on, the anatomical and some of its implications that govern movement through that space.

So now we need to try and make some sort of best effort at comparing and contrasting opioids when we put them in the epidural space versus opioids when we put them in the intrathecal space.

Now some robust rules of thumb is that you need to put a larger dose in the epidural space than the intrathecal space. That bears out purely logically, doesn’t it?

And that if you are siting drugs in the epidural space, their propensity to cause side effects like nausea, vomiting, etc. are higher because you’ve simply given a bigger dose and it’s a nice vascular area so it’s going to escape off and tickle other receptors in other parts of the body.

This does mean from a safety perspective that you need to be really keeping your head on your shoulders when you’re thinking about where you’re injecting the opioids that you’ve picked so you don’t accidentally give an epidural dose intrathecally.

Another thing to keep an eye on is: if you’re using morphine, morphine comes in 1mg, preservative-free, and that is for intrathecal use, but also 10mg, non-preservative-free. Both are in a millilitre, and it has certainly happened whereby people actually give a massive overdose by inadvertently picking the wrong concentration of morphine. And then some patients will be fine, and they’ll just keep breathing. And other patients will certainly stop breathing later, and that will be very terribly embarrassing.

So you’ve got to really keep your head on your shoulders and make sure you’ve definitely got the right drug and the right concentration.

Comparing Morphine vs Fentanyl

10:42-13:36

Summary: Detailed comparison of the two extremes of neuraxial opioid characteristics.

So we’re going to compare the two extremes first. So morphine versus fentanyl. We all know that fentanyl is incredibly lipophilic whereas morphine is not so lipophilic. Therefore you can imagine that morphine takes longer to work because it takes longer to get where it needs to go, whereas fentanyl will work quite quickly because it can simply get there faster.

However, we know that something that’s more fat soluble is more prone to being sequestered elsewhere. And when we want to compare their duration of action, morphine will last much longer, whereas fentanyl will not.

However, interestingly, morphine prefers water than fat in some ways compared to these other drugs. It’ll have a greater propensity to cause respiratory depression because it will float around in the CSF space when it gets there, or if you’ve introduced it, for much longer before it soaks into the spinal cord. That means it can go up and down more readily. And it’s that cephalad spread – i.e. up to the brain – that has been associated with respiratory depression in neuraxially administered opioids.

Dosing Comparisons

So just to quickly compare potential dosing options, and we’re going to think about the intrathecal doses here: we know that fentanyl is 100 times more potent than morphine, don’t we? It’s like, you know, we give micrograms of it, not milligrams of it. So you would make the argument that you would potentially need to give 100 times less, wouldn’t you, of fentanyl than morphine for the same analgesic effect.

Now this doesn’t actually bear out in reality, and that’s because an IV dose is different to a neuraxial dose, because we’re putting it into a different environment, aren’t we? And therefore they behave differently.

So you might give someone 100-200 micrograms of intrathecal morphine, where you may in fact give them 25 to 50 micrograms of intrathecal fentanyl. So actually only perhaps a quarter of the dose as opposed to a hundredth.

And the reason this bears out from a kinetics perspective is we’re rocking back to fentanyl’s lipid solubility and the space in which we’re putting it where there are buckets of lipid.

Now, I can tell you that myelin sheath is not a place where opioids are going to have a significantly large effect. But myelin sheath is delightfully fatty, isn’t it? And therefore fentanyl likes to float off towards the myelin, whereas the effect site is going to be on those cell bodies.

Octanol-Water Partition Coefficient

13:36-15:06

Summary: Technical discussion of optimal lipophilicity for neuraxial opioids.

Now, this is all spectacularly fascinating, but we don’t want to get too buried off in the long grass of thinking in too much of an excess of detail, although it is a delight about how these things work.

But for anyone who is further curious, there’s a really interesting paper by Haworth and Fernando that explores fat solubilities in greater detail. And they use the octanol-water partition coefficient as a way to think about how these agents partition into fatty spaces versus non-fatty spaces.

Now, an octanol-water partition coefficient, or OWPC, of between 100 and 500 yields a good capacity of an agent to hop across the dura and get where it needs to go:

• Fentanyl has an OWPC of 813
• Morphine has an OWPC of 1.4
• Diamorphine sits very neatly between that 100 to 500 range at 280

So you can see there’s quite a stark difference there, whereas diamorphine, which we’re going to come on to next, actually sits very neatly between that 100 to 500 range, so we can certainly imagine that that’s going to be a nice tidy drug to pick.

Diamorphine: The Middle Ground

15:06-17:05

Summary: Diamorphine as the optimal compromise between onset, duration, and side effects.

So thinking about the behaviour of diamorphine now in this situation, we could just simply imagine that it is middling. It is middle of the road, average. It’s getting C’s in its GCSEs.

• Lipid solubility: Middling
• Onset time: 10 to 20 minutes (Morphine 15 to 30, Fentanyl 5 to 10)
• Duration: About 8 to 12 hours
• CSF spread: Does it escape into the CSF and soak off up into the brainstem in our ventral respiratory group causing depression? Well it causes less of that. It’s in between morphine which certainly likes to go there and fentanyl which can’t be bothered to go that far. It’s quite happy soaking up the fat, living in the butter.

And this is why diamorphine is probably quite a nice choice in anaesthesia for caesarean sections where you need pretty robust pain relief pretty quick but actually it doesn’t need to last forever, because maybe we patriarchally think that it’s not that painful having a caesarean. Now it probably is and actually if anyone knows about any research that compares epidural versus intrathecal diamorphine following caesarean section and opioid requirements that would be cool. I think I came across something but I don’t want to imagine that I know what I’m on about on that front.

Clinical Experience with Shortages

When there was a diamorphine shortage in the United Kingdom there was a protocol whereby for elective sections where there wasn’t a time pressure we were carefully drawing up a dose of intrathecal morphine and adding 20 micrograms of fentanyl to it so that we got some quick pain relief and then some prolonged pain relief for the elective section patients.

We are fortunate enough to have pre-made 300 microgram doses of diamorphine that are mixed up in a sterile manner that we can aspirate into our spinal anaesthetic and therefore it’s nice and quick instead of having to channel your internal potions master drawing up, diluting, measuring a dose of diamorphine into your local anaesthetic.

Clinical Summary and Applications

17:05-18:34

Summary: Practical clinical implications for different surgical scenarios.

So just to summarise there from a clinical implications for you guys perspective:

• Fentanyl: Quick to work, quick to wear off, doesn’t really escape anywhere, good for short procedures
• Morphine: Slow to work, has a prolonged effect, carries a risk of respiratory depression. However, in the doses used, like 200 micrograms as opposed to the 500s, etc., that were perhaps slightly more old hat, the incidence of respiratory depression is less. It is proportional to the dose
• Diamorphine: Middle ground

So you can imagine that a patient who’s having a laparotomy where you don’t want an epidural or maybe a big laparoscopic procedure like an anterior resection clearly would benefit from intrathecal morphine because they’re still going to need a general anaesthetic. And really you’re using that intrathecal morphine to cover their pain when they wake up. You’re not really putting it in there to cover your anaesthetic.

Side Effects and Management

18:34-20:48

Summary: Common side effects of neuraxial opioids and their management strategies.

Now when you administer neuraxial opioids the chief clinical effect is obviously analgesia and it works really well doesn’t it? But patients still get nausea and vomiting and they’re going to get it more with epidural agents versus intrathecal agents.

I’m actually tempted to slightly alter my practice. I’ve been putting 5 milligrams of ondansetron in epidurals at the end of epidural top-up caesarean sections. I think I’m actually going to back off to 3 because there’s some evidence that suggests that’s less nauseating. But do whatever happens in your shop. Maybe I’ve just been overdosing people.

Managing Pruritus

And then I’m sure we’ve all seen it. People get itchy and you can definitely spot it towards the end of a caesarean section. They’re sewing them up and then this poor lady who’s been through quite a whirlwind of emotions starts just you know a little bit of a scratch here, a bit of an itch there. You can spot it. You can look very sage if you go “oh you’re feeling a bit itchy are you?” It makes it look like you’re paying loads of attention, which obviously you should be.

But often what happens in recovery or on the wards is when patients are itchy the nursing team think they need antihistamines. Now unfortunately this isn’t really a histamine mediated mechanism for itchiness and I try and explain to patients that really they’ve got an itchy spinal cord and the only real way to stop the itching is to give them naloxone and that generally doesn’t help, as naloxone would obviously impair the analgesia.

Now if the itching is absolutely intolerable then counsel the patient and give very small doses of naloxone until the itching is resolved like maybe 25 micrograms or 50 micrograms – just the teeniest amount until their itching is manageable. You might have to go back and give this again because we know that the half-life of naloxone is quite short compared to these opioids.

But if you just rock up to someone and say, “ah well you’re itching and we can do something about it but you’re going to be in loads of pain so just buckle up and bear it, bite on this leather and put some socks on your hands so you don’t scratch yourself to smithereens,” you’re probably not managing that communication scenario very well. But really I think the most important thing is to explain why. And I don’t think that mechanism is truly fully understood.

Conclusion

20:48-End

And it is like drinking from a firehose. Take it day by day. Don’t overcook yourself. Don’t freak out. And keep studying.

---