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Buprenorphine and Naloxone (Suboxone) Pharmacology

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Hi! This video is about the rationale behind combining buprenorphine with naloxone. I explain why the route of administration of the drug product influences the effect the user will experience.

Hi everyone and welcome to my very brief presentation on suboxone or buprenorphine and naloxone i’d like to first say that this is for educational purposes only and nothing in this presentation is intended to be medical advice so the purpose of this presentation is to describe how suboxone works specifically what is uh buprenorphine in the what is the naloxone

Component and why are they combined in one in one dosage form and why why are they administ why is that administered sublingually which is under the tongue or in the cheek which is called the buccal membrane and why why is it not uh swallowed um and why is it not injectable okay so as you can see here i have the two major dosage forms that would be the the thin

Strip uh which has the n8 for example on there that’s one one of them that you can get that’s a thin strip that would be used under the tongue or in the cheek or the tablet that which is typically used sublingually which again is under the tongue so again suboxone has two major active ingredients just to show you the actual names because i already stated them that

We buprenorphine which is opioid receptor agonist i’m not going to get into great depth on what that means other than for the purposes of this presentation an agonist just means that it’s an activator and specifically it activates the mu opioid receptors which we associate with things like pain relief respiratory depression constipation and you know even the

Euphoria the euphoria that we think of they’re all associated primarily with that mu opioid receptor okay an agonist is an activator that actually causes all those effects naloxone as most people probably know by now is the opposite that blocks opioids effects that is an opioid receptor antagonist so what is suboxone prescribed for first of all a lot of you may

Already know this you may be taking it you may have a relative that takes it or a patient but you just you know you you may or may not be interested in what what is it actually used for primarily and the simple answer is uh patients that are addicted to opioids or opiates which i won’t get into the difference between an opioid and opiate in this presentation but

For the most part it’s the same idea any substance that activates the opioid receptors people that are dependent on those could be heroin it could be a prescription one how do we get them off of those so suboxone is one of the one of the the drug products that’s used for that purpose so i want to focus on the first component uh which is the component that actually

Activates the opioid receptors that would be buprenorphine you can get buprenorphine alone as a product but the purposes of this presentation the main purpose is to explain why it’s used in combination with naloxone buprenorphine is an opioid with a lower ceiling effect than others that’s really important for everyone to understand um first of all that so so

What what are the effects that i’m talking about so those effects would be every almost everything you could think of that opioids would do that would be again causing euphoria but causing pain relief which is a good thing right the second one is a good thing um causing constipation causing so many other things respiratory depression a lot of side effects most of

Those side effects are directly related to the effects on opioid receptors okay and there may be some other receptors that are involved for euphoria and things like that but we’re going to focus on the opioid receptor so so buprenorphine when i say it has a lower ceiling effect that means if you took grams and grams and grams of it which nobody should do i’m not

Advising anyone to do that there is a ceiling so that means you reach a limit of its maximal effect so every drug has a limit for its max but other drugs like morphine has a much higher maximum effect okay so if you you had an escalation of a morphine or or heroin um or again a stronger agonist dose you’d reach a higher maximum effect i’m going to show a graph

On that in just a little bit to make it more clear so even with an overdose you have a limit to the the extent of the side effects okay the only warning i’ll give a big warning here is that if you’re combining buprenorphine with any other drug that can cause the same side effects you know you may not be protected in that case right if you’re using buprenorphine

With a benzodiazepine such as ativan et cetera et cetera et cetera those uh that combination could still give you severe respiratory depression if you if you have too much okay so uh once you’re combining it with some other things then any of these rules are kind of uh you know a moot point you know at that point so it the reason why is having a stealing effect

Is because it is a partial agonist um so i’m going to describe exactly what a partial agonist means pharmacologically on the next slide but first here i’ll describe so why do we use a partial agonist in opioid addicted patients okay so in other words why do we use an opioid with a sealing effect the reason for that is if a a patient that a b has abused opioids in

The past we’re trying to get away from that if they take extra buprenorphine they they won’t be able to get to the same high that they would ever get to with a stronger agonist because of the ceiling effect and that means even if 100 of their opioid receptors are occupied with this drug they still won’t get the same maximum effect that they would get with morphine

Heroin oxycodone okay so it’s it’s at the level of the receptor you’re literally binding to it in in changing the receptors conformation in a different way than you would with these stronger agonists so could never reach the maximum effect that you would see with other ones so that said so what does it actually look like on a graph so on this graph i have on the

Y-axis the response we’ll say max pain relief or the percentage of max pain relief the percentage of euphoria anything associated with the mu opioid receptor on the x-axis is the concentration of opioid agonist in the blood now a pharmacologist which is what i am um in a toxicologist what they would typically look at is the concentration of the drug in the blood

Or the opioid in the blood in the amount of receptors that are occupied for our for our purposes i think it’s just easier to look at it as the percent of max pain relief or euphoria okay because this is uh for a general audience but the idea is that if we had a full agonist uh believe it or not this is endogenous this is already in your body it’s called leu and

Keflan lewin keflan to my knowledge is probably the strongest agonist of the opioid new opioid receptor that we are aware of and that’s already like it’s already in the body so that would give you the maximum response the maximum response is defined honestly it’s just defined as whatever chemical we’ve found that produces the highest possible response we call

That the maximum so it means something in the future could be discovered that produces a higher maximum but this is where baseline is right now highest maximum and that’s lewincephalin believe it or not tramadol is an opioid receptor agonist particularly it’s a metabolite and that’s only a partial agonist that means if i keep giving more and more and more and

More and more guess what i still reach a plateau that’s lower than lou and keflan or other full agonists so i can never reach the same effective effectiveness and pain relief or the same effectiveness in euphoria okay so we don’t use suboxone for pain relief use it for uh getting a patient that’s addicted getting them away from the stronger opioids okay now this

Is just tramadol but if i went with buprenorphine it’s an e it’s one of the weakest partial agonists that means a sealing effect or maximum effect is much lower than than the majority of opioids probably all them that i’m aware of okay so that means it’s going to be you know really hard to get any significant high however if you happen to have again a patient

Going through withdrawal you could you should be able to get enough of an effect to reduce the withdrawal severity and that’s the whole idea you know they feel like they’re getting some stimulation some maybe some of the high some of um you know reversing some of the agitation that comes from withdrawal and things like that but it’s not enough that it’s going

To be like heroin or something that strong okay so just to reiterate a partial agonist cannot fully activate its receptor even when all copies of the receptor are occupied with the drug and those receptors would be on the cell membrane of course and you could saturate them and you’ll still get you know a lower max and that again that’s a really interesting concept

That i won’t get into in too much detail but it means that when it binds to the receptor the same receptor as these other ones it does something different to the receptor okay and in the pharmacologists believe there there might be an infinite number of conformations or shapes that the receptor can take and then um and that will subsequently affect what happens

Inside the cell that signaling pathway so naloxone structurally is very similar both of these drugs naloxone and buprenorphine both of those chemicals are pretty bulky on this amine group but naloxone is a pure opioid receptor it’s a mu opioid receptor antagonist so that means it’s it has no partial agony stability it has no full agonist stability that means

It’s just a essentially just a blocker for simplicity’s simplicity sake we’ll just call it a blocker it’s of course it’s commonly used to reverse the respiratory depression from opioid overdose most of us probably know about naloxone or narcan as you know it’s used in emergencies again for someone who’s overdosed so on the surface so if this is blocking opioid

Activity but buprenorphine is supposed to give us opioid activity in these patients that are independent um it would appear that this is futile right that buprenorphine would would be opposed by naloxone and the medication uh suboxone would be pointless so what is the rationale for having an opioid antagonist combined with an agonist i’m going to answer that

Question in just you know basically within a few minutes here so this is going to be basically explanation of why uh why we combine an antagonist with an agonist of the opioid receptor and this is one of the really interesting instances where it all comes down to something called biopharmaceutics and that’s the absorption i’ll call it differential absorption

Of buprenorphine and naloxone so so just to simplify it it means that depending on the route of administration for example sublingual or buccal which would be in the cheek per oral means that technically that is swallowing it so by way of the oral mucosa you’re swallowing it goes to the stomach goes the intestines or parenteral means any injectable form for the

Most part which means the entero is intestinal but this is you know outside of that or near intestinal but essentially you know i’m just breaking down the word there but essentially just means injected okay it could be iv it could be intermuscular it could be subcutaneous it’s all injected so why so what why is there difference and what is the difference between

These dosage or administration routes so first of all if you took it sublingually what will happen is the buprenorphine will get absorbed very well but the naloxone is not absorbed very well there so what will happen is you won’t get that inhibition effect you’ll mostly get the the just the buprenorphine in the blood you’ll get that nice well kind of subtle

Stimulation of the mu opioid receptor if you took it per orally or swallowed it the problem is well neither naloxone nor buprenorphine would get absorbed in fact they would start getting absorbed through the intestinal wall but then they get modified in the liver and that’s called first pass metabolism because it everything for the most part everything that you

Swallow goes in to the blood in the portal vein which goes right to the liver before it goes to the rest of the body and then at that point the liver can do what it wants with it and in this case it metabolizes naloxone and buprenorphine they both get broken down and neither one of them will be effective orally but what about this this is the big concern here

What if i gave if so you know someone gave this by dissolving if you could dissolve this sublingual film or the tablet if you got a bunch of it for some reason and you dissolved it and tried to filter it or purify it and then you injected it well doesn’t that allow a patient to abuse it well remember we have first of all we have our first kind of uh checkpoint or

Our first check we’ll say checks and balances or the two checks and balances the first one would be the fact that we have a partial agonist but that’s that’s not the focus here but i’ll just say because it is a partial agonist even if someone injected it it should not have a strong effect right it definitely will not however if you combined it with something else

And injected it yeah you combine it with another opioid and injected it there might be concern about getting a strong effect the reason why that concern is not not valid is because once you inject it a hundred percent of the naloxone will get into the blood in a hundred percent of the buprenorphine will get into the blood but then the amount of naloxone available

Is enough to completely block the effect of the buprenorphine or other medications other opioids so if someone tried to abuse it through injection they would get no effect okay in fact it might reverse any effect that was there from a prior dose so there’s no incentive to abuse it this way there’s no incentive to swallow it so there’s really no easy way no no way

You know unless you had a really uh you know really sophisticated background in chemistry to separate these two things out it is uh there’s really no incentive to to try to abuse it in this way so what i’m showing you is the outcome is that sublingually or in the buccal membrane buprenorphine is significantly absorbed in the blood naloxone is not orally or per

Orally it’s going to go and get into the intestine but then the liver get broken down so you get a very low concentration in the blood of both of those so essentially no noticeable effect and then iv they both get in the naloxone then can shine and do its job which is to block buprenorphine so this doesn’t work for a patient if they want to get high per oral

Doesn’t work sublingual won’t work because it’s base essentially a slower administ slower route or how could i put it it is um right it’s it’s not a way to rapidly get you’re not going to rapidly get a lot of buprenorphine in your system this way because of the dosage form okay but you will avoid getting too much naloxone so you will get some effectiveness or

Efficacy okay so that’s it i mean that’s that’s you know i just wanted to make this a very kind of clear-cut kind of like a little chunk of information on exactly uh why suboxone is formulated the way it is why does used sublingually not orally and how it deters abuse so thank you for listening

Transcribed from video
Buprenorphine and Naloxone (Suboxone) Pharmacology By Dr. Adam VanWert Pharm.D. Ph.D.