Ep 23 – Tramadol for the FRCA Primary Exam

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and let’s get on with the show. Hi everyone, it’s James at Gas Gas Gas. Today, another quickfire round. We’re covering

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Tramadol. I’m sure there’s a group of you out there who think, ah, Tramadol, yeah, really great, love that drug. And some other people who think, you know what, Tramadol, keep giving it, it doesn’t do anything, what’s the point in it? And well, I’m on the fence. But someone might ask you some questions about it, so it’s worth being able to give them some answers. And naturally, I’ve gone into an excess of detail. So Tramadol is classed as a weak opioid alongside its friend and pal, Codeine.

00:59-01:29
It comes as a racemic mixture of two enantiomers, a positive and a negative enantioma, and it is structurally similar to codeine and morphine. It is prepared as either a clear aqueous solution for injection at 50mg per ml, or as oral tablets generally in iterations of 50mg, sometimes coming as 100mg. There is a modified release preparation also. Interestingly, first synthesised in 1962, but it didn’t make it to being registered for use in the UK till 1994.

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What’s its mechanism of action you ask? Well you’d be forgiven for saying it’s just a weak opiate agonist. Because we probably do need to think about tramadol actually as having more than just opiate activity. So it does three things. It is a mu receptor agonist. It inhibits the re-uptake of noradrenaline in your CNS and it enhances serotonin release in your CNS. Just focusing on mu because that is a very common receptor that we target. Mu receptors are opiate receptors and they’re G protein coupled receptors.

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with a GI subunit on the inside of that cellular membrane and they have several intracellular actions that lead to neurons that are more challenging to depolarize, i.e. you inhibit synaptic transmission. It achieves that by hyperpolarizing cell membranes by increasing potassium conductance, reducing the amount of adenyl cyclase activity in your neuron. That leads to less cyclic AMP, which leads to less calcium availability, and it closes calcium channels.

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Those three things inhibit transmission from an opiate receptor perspective. Tramadol also works with

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NORAD and serotonin. So with NORAD it inhibits the reuptake of noradrenaline within the synaptic cleft i.e. there’s more floating around to bind to receptors. It blocks a noradrenaline transporter protein and it enhances serotonin activity in the synaptic cleft. I think the jury’s out on exactly how this mechanism works. There are serotonin transporters i.e. these contraptions that clear serotonin from the synaptic clefts so they can be tidied up and re-released when a new signal comes along and there are receptors in these clefts which themselves could be agonized and this is why when you give someone a load of tramadol and they’re in a fair bit of pain and then they’re not and you give them naloxone you don’t completely return them to their ouchy pre-tramadol state because obviously you can’t antagonize the effects of its noradrenaline and serotonin modulating activity with naloxone. Now if you were to be quite the pest and give the patient some yohimbine which is an alfacete for two receptor antagonists alongside some ritancerin, a serotonin receptor antagonist, then you would actually fully obliterate their pain response. I don’t think there’s any of that knocking around in the cupboard, focusing back on this mu receptor activity. So if you were to take a pile of tramadol and a pile of codeine and look at how much receptor affinity occurred, tramadol has approximately 10% the affinity to the mu opiate receptor compared to codeine. And if we broaden this out, it’s about 6,000 times less interesting.

03:59-06:59
in the receptor compared to morphine. But this is quite a generic overview because actually I mentioned earlier that tramadol is a racemic mixture. We have to go a step further and also bear in mind that there is a active metabolite of tramadol and as you could expect these have different properties. So O-desmethyltramadol which is the metabolite of the plus enantiomer that has 300 times the interest for the opiate receptor compared to its non-metabolised parent. Other important to think about when giving tramadol before we get into the pharmacokinetics of things is when you give it orally it takes 1.2 to 1.9 hours to reach peak plasma concentration. Its offset is about 6 hours. Generally the classic dosing is 50 to 100 milligrams every 6 hours. Max dose of about 400 milligrams in 24 hours. In kiddies if you’re going down that route 1 to 2 milligrams per kilo although you should definitely be following local protocols because I’m sure you might raise a few eyebrows if you give Tabitha Maybe just keep it simple with some Oromorph otherwise you just make your life hard.

And what’s the side effect profile like? Well I’m sure you guys have all noticed that it doesn’t really seem to cause much bother. It doesn’t alter your heart rate or blood pressure terribly much. There is some research to suggest that if you give it IV you might notice a transitory increase in pulmonary and systemic vascular resistance. At its therapeutic doses it doesn’t cause much respiratory depression. This is probably borne out by the fact that not all of its activity analgesic wise is derived from new opiate receptor activity. Ta-da! But you definitely see some patients who have tramadol and then they get very space cowboy and a bit loopy and a bit weird. But then perhaps that’s just bias because actually if you give lots of people opiates and then ask them questions they’re all a bit loopy and weird. Interestingly you get pupillary dilation with tramadol more so than constriction.

Again suggesting that its opiate effects are a bit sparse compared to its non-opiate pain modulating effects. It does still cause constipation though. Nevertheless if you were to be having it in inordinately large doses, given that it isn’t like codeine, which is a pro-drug that needs to be metabolized for it to have effect. The drug itself has effect. In high doses you might start seeing some opiate toxicity, but also you’re going to start seeing serotonin toxicity and a bit of maybe serotonin syndrome, especially if the patient is having other serotonergic drugs.

The contrary to that is if you have a patient who is taking tons of tramadol because they’re buying it off the internet and that’s what helps their back pain, and then they end up on intensive for another reason and we’re just giving them a bit of Oromorph for their tummy pain now. You might actually get a serotonin withdrawal picture which isn’t going to be fixed with Oromorph is it interestingly enough. Now that’s a theory I might have seen a patient who was doing that we gave them Tramadol and they got a whole heck of a lot better and much less rattly and twitchy and agitated and “radged” as we like to describe them up north. “Rajged” “Rajgy” to be filled with rage irritation and agitation plus a little bit of anger. “Rajged” great word. But I think to summarize the pharmacodynamics of Tramadol it probably does work. It might not work.

06:59-07:29
in quite the manner that we would expect it to. I think we all imagine it as a weak opioid agonist but perhaps it’s a terribly weak opioid agonist. Side effect profile is very stable 50 to 100 milligrams QDS and a side effect profile that isn’t entirely reversible with naloxone because of its other effects. So off to pharmacokinetics now. If you have it orally it’s about 70% bioavailable. That’s because there’s a first pass metabolism that is about 30%. We have to bear in mind though that this first pass metabolism isn’t a disaster in some regard.

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because actually it’s going to be shifting some of the tramadol into a useful and active metabolite that actually favours the mu opioid receptor more than baseline racemic tramadol. So whilst some of it gets mopped up it isn’t completely detrimental. Interestingly in repeat doses there is some evidence to suggest that the oral bioavailability improves i.e that versipass metabolism is knocked back a bit perhaps because there’s a degree of saturation in the enzymes that are doing the metabolising. How is it distributed you are?

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Well, of course, absorption, distribution. It is 20% plasma protein bound. It has a volume of distribution ranging between 2.9 and 4.37 litres per kilo. It does totter across that placenta if a woman was taking it when she was pregnant. And there are tiny amounts to be found in breast milk. We’ve done absorption, we’ve done distribution, and now we’re doing metabolism. And you can probably guess that it is liver metabolised. So it undergoes demethylation in the liver. And this is courtesy of our dear cytochrome friend, 2D6. Remembering guys that 10% or so of the population are non-responders, i.e. their CYP2D6. OD methylation pathway is a bit feckless and therefore some people have different responses to drugs. This is where codeine falls down in some patients. And also the CYP3A4 pathway handling the ND methylation for us. And the ND methylation is the bit that yields our active metabolite of tramadol. We’ve done absorption, we’ve done distribution, and we’ve done metabolism.

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How are these byproducts eliminated? And it is 90% in the urine and about 10% in the feces. About a 6-10ml per kilo per minute clearance overall and an elimination half-life of 270-450 minutes. Its clearance is influenced by renal failure and its metabolites are slowly cleared by dialysis. Of note, if you were to be including it in your anaesthetic, which I imagine some places might have not come across it, it doesn’t mix well with midazolam and diazepam.

09:28-09:58
going down that route. In a blistering high speed summary, at the end of all that waffle, tramadol is a weak opioid agonist with noradrenaline and serotonin effects. It is a racemic mixture. It has an active metabolite. It has a good side effect profile. It has excellent oral bioavailability, all things considered. It’s 20% protein bound with a volume of distribution of 2.9 to 4.37 litres per kilo. It is metabolized by the liver. And remember guys, there is that active metabolite and it is chiefly cleared by the urine. Now just thinking about actual use of tramadol.

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So my current standing experience and opinion is that it doesn’t seem to add too much and that might be borne out by the suggestion that it isn’t a terribly good mu receptor agonist. However having reread through all this and read that chunking paper that is linked at the bottom of the show notes I think maybe I would be tempted to add it in as a weak opioid agonist really to aim for its other properties and then just give the patient oromorph on top instead of being like haha yes tremolodol, ooh codeine, well if they I’ll pick codeine, knowing that codeine is delightfully constipating. And again, why would I give a patient codeine that’s converted to morphine when I could just give them morphine? It depends a little bit about where the patient’s going. My standing feeling is that codeine is deemed a more acceptable agent to discharge someone on after an operation. You might prescribe some codeine. Whereas if you’re prescribing them tramadol to go home on, everyone’s going to raise their eyebrows being like, gosh, you’re giving them tramadol? What? And this might be reflected in the fact that tramadol is now a Schedule 3 controlled drug.

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10 years ago, probably should have known that. Which means that more paperwork, more faff, and it’s because it’s a drug of dependence. You know, I’d argue codeine might be a drug of dependence if we’re actually looking at its mu-opiate receptor influence, but alas, here we go, courtesy of the home office, it’s a controlled drug. Anyway, you’re driving to work, you don’t want to hear me waffling about the home office. So, thank you very much for listening. Next time, we’re going to do methadone, actually, because I am trying to just beaver through all these opiates so we can move on to local anaesthetics, which is a bit more interesting.

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But I think methadone is a worthy conversational given it also has weird extra effects beyond its opiate receptor activity. How exciting. Anyway thanks for listening. See you next time. 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.

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do a bit day by day, don’t overcook yourself, don’t freak out and keep studying.