hey this is Dr Busty and we're in our neurology section We're going to be talking about opioid uh rotation and dose equivalencies Basically how do you switch patients from one agent to another or if you're know that a patient is on an existing uh chronic pain management regimen how can you switch them to something different If you needed to do that both in acute as well as chronic settings that is kind of our goal for today So there's a number of reasons why we might consider rotating somebody to a different opioid Um part of it may be the again the situation that you're in Is it an acute versus chronic situation Does the drug that the patient is on uh even available in the institution uh where you're at Uh sometimes uh locations geographic locations formularies may influence what drugs are available for you to utilize in managing patients Um the end of the reasons that we also need to consider is that patients do develop differing responses to some of the medications Some of these drugs require a functional activation of the drug in order for it to work Um and we do know of genetic polymorphisms specifically like to cytochrome P450 2D6 that can influence the activity of some of these medicines For example codine gets metabolized to morphine about 20 to 30% in the normal wild type patient Right But if you have a genetic polymorphism you could make uh where the 2D6 enzyme is either not functional where you may not activate the drug or if it's over you're an ultra rapid metabolizer and you have too much cytochrome P4502D6 you may then induce too much activation and overdose the patient So sometimes it's based on the response of the analesia to the patient Other drugs that require functional activation include hydrocodone So drugs like Norco Vicodin those things that have hydrocodone with Tylenol may not work for patients who lack functional cytochrome P450 2D6 activity Um hydrocodone uh gets metabolized to hydromemorphone which is essentially delotted And the reason that delotted works on every single patient just like fentanyl and just like oxycontton and oxycodone and those drugs they are all active in their original form Um and so there are individual varying responses that sometimes warrant that we switch to one agent over another based on the way the body handles those medications Same thing also with even the frequency of administration There are few long acting drugs for example like MS cotton which is traditionally dosed at every 12 hours The FDA and the manufacturing recommendations do allow you to dose it at every eight hours in those patients who in have basically tailing off of the analesic properties towards the end of the 12-h hour period where they're having breakthrough pain problems Um we see the same thing within fentanyl transdermal patches uh which are historically and traditionally prescribed every 3 days but there are occasions that in 48 hours or after 48 hours in that last 12 hours of their 3-day interval that they may start losing some of their pain control and again it's just variations in absorption rates It's variation in the way the body handles the medication metabolizes and eliminates the drug Um there's also reasons of cross tolerance that can u between agents uh that can sometimes occur uh and we need to factor in some of those things as we switch because you're going to see here in a minute that there are dose adjustments that we usually make going down because we'd rather error on the side of not giving them enough versus giving them too much medication There's also balance of control of the pain and the side effects that these patients are experiencing Uh it is very well known that you know drugs like morphine have metabolites the three and six glucaronide metabolites that can cause problems in patients especially in patients with renal impairment Same thing with drugs like maparoditine or demorall which get metabolized to normapiritodine which has very little uh analesic properties but has a lot of neuro side effects including serotonin related issues as well as lowering the seizure threshold So there are issues that we have to factor in um that can consider that an imbalance between the side effects and the overall pain control Um and then you can need to consider other modalities of pain management not don't forget about non-farmacologic treatments physical therapy occupational therapy Uh there are nerve uh stimulators uh that can also be used and then adjuncts to opioids that can sometimes decrease and minimize the amount of opioid that a patient needs For example uh you know if someone is on morphine or highdose opioids and they have metastatic cancer that met with mets to the bone Uh we know that metastatic cancer to the bone does have a higher rate of prostate gland formation and a lot of bone pain that forms So giving patients NSAIDs in those situations can reduce the overall opioid requirement and sometimes warrants even switching the opioid to a different opioid analesic Um and that's reason Now we also have a lot of different dosage formulations that facilitate maybe specific scenarios where maybe patients can't swallow So again that's where a transdermal patch option would be more efficient especially if somebody has like you know nasoparangial or oral fingial um you know cancer and maybe they have mucositis or other things from radiation and chemotherapy and they can't swallow very efficiently or effectively and or it causes them a lot of adonophasia and so there's number of reasons why we need to recognize the ability to switch drugs around and then how do you do that this table is is a very important table because I think that it re reflects the basic recommendations that you will see across multiple sources Now it is not the end all be all It is not a perfect science and you need to recognize that especially with the um development of many more drug formulations that have varying rates of absorption um and frequency of his admin administration Traditionally these dose equivalencies are determined around parental agents predominantly IM IV and then also um versus PO or uh treatments for that particular medication mainly in the form of immediate release So you need to recognize that while we have these dose equivalencies that are listed here they are not perfect Which is why when you see here in a minute when I go through an example we dose down the drug equivalency when we first switch them over to a new agent because we'd rather error on the side of not dosing them sufficiently and then escalating the drug therapy up as needed to control the pain versus overshooting and then now having side effects that we have to deal with um that are potentially life-threatening All right so let's look at this uh table and let me just orient you to it and how do you utilize it Uh you'll see over here on the far left is the drug obviously the different opioids and you'll see that some opioids are not listed here for example like maparidine Meeroditine really is no longer used much in clinical practice has very limited utility given that we have so many other options available So it's almost irrelevant you're not going to convert somebody to uh demorall and and if you have somebody on oral demoral then something is really really wrong with the provider managing that patient Um and so because you should never use oral demorall but there's the drug So we have morphine oxycodone oxymorphone uh hydromemorphone which is delotted methadone fentanyl and then coding Coding gets metabolized to morphine So it has to be one of those functionally activated drugs Um and so then you see the um equal analesic dose Um and again this is within the drug but also then compared from one drug to another So for example within morphine you see that the IM injection of 10 milligrams is roughly equivalent to 30 mg by mouth And so that's kind of how you convert based on somebody comes in on an oral regimen and they can't swallow or they're having nausea and vomiting for whatever situation that you're dealing with and you need to convert them now over to a parental agent So basically a 1:3 kind of ratio in the chronic Okay And then we have some notes over here Um but this is what this equal analesic Now you can also then do cross comparison between agents right and that's how that's how that works So about 20 to 30 milligram sorry 20 to 30 milligrams of oxycodone is roughly equal to 30 mg of morphine Uh many people use 20 mg um as the dose equivalency Again airing a little bit on the side of a lower dose to be on the safer end of the spectrum Um so that's what that column is for And then we have the halflife of the drug Um and that's assuming again not an extended release formulation Uh and then we have comments little clinical pearls notes things to think about Again um some some things are suggested You have to put it in the context of patients liver function You have to put in the context of their their renal function You have to put in the context of the opioid being used Also genetic polymorphisms that could be present um and or drug interactions that may affect the functional activation of some of these drugs So there's a lot of things that go in but there's a few notes there for you Um and so that's how you kind of use this table Let's just look at a few things So I talked about morphine because that one is probably out of the all the ones that you need to know from a board exam standpoint because most drugs are compared back to morphine just mainly because morphine has been around for a long time Um you can see that I put in here also what do we convert the ratios for acute versus chronic condition So one that one to three is for most chronic conditions The one to six is for an acute Remember the natural antagonist to respiratory depression and CNS um sedation is going to be pain itself So you're going to give more in an acute uncontrolled pain situation Um but you know again it says two to three here and so you could theoretically say 20 milligrams but we use 30 milligrams for simplicity and because the other thing that you have to factor into some of this is what dose uh formulations are available that you're going to switch the patient to Um and so part of it is just a feasibility component and again you'll error on one side or the other depending on that clinical situation that you're dealing with Um hydromemorphone is the active form of hydrocodone So you have to kind of think about that vicodin or norco which is hydrocodone gets metabolized to hydromemorphone And then you can see here the IM equivalency versus the PO equivalency and then how it compares to morphine So for example you'll see here that you know up to 2 millig of morphine is equivalent to 10 mg of IM uh morphine So giving somebody 1 milligram of delotted is about giving them four to six milligrams of morphine basically okay in that range Um and again some sort of acute versus chronic conditions Now hydromemorphone tends to be more potent and that's why you look at the milligrams the amount that you're giving is less compared to things like uh morphine So potency does not mean anything about efficacy Potency talks about the amount of drug that you have to give in order to exert a pharmacologic effect And so when you look at your pharmacodnamic sort of dose response curves there are two curves that can be at two different you know distances from each other because the amount of drug that you have to give to exert the same effect That is what is our equal analesic dose and that's how we determine those things So you'll see here that um the ED50 or the EC50 which is the reflective of the potency is going to be much lower for hydromemorphone than compared to u morphine and so hydromemorphone or delotted is more pharmacologically potent um basically its ability to bind the receptor So you don't have to give as much drug in order to exert the same pharmacologic effect They're just trying to integrate phicinetics and dynamic kind of principles into topics so that you learn things and apply them in the proper proper context but also then learn realize why you learned maybe some of those principles in the past Now methodone is an interesting beast Um not only is it a opioid that is highly dependent on the cytochrome P450 system for its metabolism which then means it's at high risk for drug drugrelated interactions But it's also one of the few opioids that does have an isomer that antagonizes the NMDA receptor and as a result can reduce the tolerance that sometimes patients develop when they're on highdose opioids for chronic periods of time Now the unfortunate thing I guess or fortunate depending on how you look at it is about methadone is that it has a very long halflife that is influenced by a number of things liver function the synthetic function drug the presence of other drugs that may inhibit the metabolism of this So you have to be very careful because the dosing frequency for analesia is every 8 hours which is different than in methadone or I'm sorry heroin and opioid dependency programs where we do methadone treatments on a daily basis where they take once one pill once a day for opioid dependent um type of situation So the dosing is very different based on the indication and obviously giving it every 8 hours for analesia with a long half-life drug like this can result in um prolong you know accumulation of the drug and cause um a lot of toxicity So when we do the equal analesic doses we reduce the dose by 75 to 90% of whatever you calculated the dose to be equal to So you you'll see here an example of how to do this but we error significantly more with methadone because of that half-life and the risk of um toxicity with higher levels including even QT prolongation Now fentanyl depending comes in a number of different dosage formulations There is a transdermal patch There are sublingual um and uh buckle mucosal formulations for used for breakthrough pain in cancer patients who have opioid uh experience um with with medications and still need some medication for breakthrough pain Um it also comes as an intraasal spray It comes as IV I can give it IM I mean there's a lot of ways that I can give it but in roughly uh 100 micrograms per hour of a transdermal patch is equal to giving the patient about 4 milligrams an hour Now it's 100 micrograms versus milligrams and you'll see that again the amount of medicine that you have to give is much less to get the same pharmacologic effect Again fentanyl is far more potent uh than compared to morphine So it has a lower ED50 or EC50 compared to morphine Uh and then as I mentioned before coding uh has to get functionally activated or metabolized via 2D6 to the active form which is morphine About 20 to 30% in the normal wild type um will generate that kind of uh morphine equivalent So here are the steps that are involved in in doing an opioid switching one p opioid for another you need to first calculate the amount of the opioid that you're using both in chronic you know long acting agents and plus the immediate release formulation So the total amount of opioid being used per day Um and then you need to calculate the equal analesic dose using those formulas those conversions I just showed you in the previous slide And again I'm going to walk you through that Um when we then convert to the new drug okay when you make come up with here's the equivalent dose we take that dose and we mostly decrease it by at least 25% Um if it's fentanyl and methadone then we make different rules but uh most of the drugs 25 to 50% that becomes the news total daily dose And then you still have to divide that into a frequency depending on the opioids uh formulations that are available Again the reason that we do this is to error because there's a number of things that influence the pharmacologic effect of that drug Again if they have liver disease renal impairment you know if they have a genetic polymorphism drug interactions all these things will influence it So we always reduce the dose by at least 25 to 50% Methadone is going to be up to 90 plus% of what you would normally start them on based on the calculation And that's just again leaning towards the idea of ering on the side of safety Um with these are some special considerations here Fentanel with your doing the transermal patch there's really no dose adjustment down that is needed Um there usually is a delay on onset of analesia because the transermal patch takes about 10 to 12 hours to begin really fully kicking in Methadone as I said we will drop the decal analesic dose by additional 75 to 90% So you're only going to give that patient somewhere between 10 and 25% of the original equal analesic dose that you would normally get when you did the conversion Um there are other factors making coorbidities other than in pulmonary conditions like COPD because you don't want to do anything that would cause respiratory or CNS depression that may cause decrease both in oxygenation as well as ventilation Now you do need to provide the patient with breakthrough or what we call rescue pain dosing regimen and that is taking the total daily equivalent dose and determining 5 to 15% of that total dose that becomes the breakthrough that you add on to the long acting Remember for long acting treatments we're going to be using for chronic pain syndromes And so these patients will have intermittent breakthrough pain and you need to provide them with agents to treat that acute pain when it happens because remember we don't want to be using immediate release formulations to manage patients for chronic pain And the reason for that has to do with the pharmacocinetic profiles The immediate release tend to have a more rapid uh absorption and onset and generate peak concentrations and then kind of trough concentrations So they those peaks and troughs every time you take the medication it's absorbing and then it generates that C CAX or the peak concentration Well having a large peaks and troughs um facilitates the euphoric effect because it penetrates in the central nervous system and that stimulates our reward pathway and that theoretically then begins to increase the addictive potential Whereas long acting agents don't have those peaks they have a smooth sort of steady consistent flow of the drug and it's not stimulating that reward pathway to the same degree but you're going to have breakthrough pain where you need an intermittent dose here and there but you shouldn't be relying on I immediate release formulations you know all throughout the day that means that the long acting agent isn't sufficient but so you calculate the total amount of the equal analesic dose you take 5 to 15% of that total dose then that's your total breakthrough dose And then you divide that into a frequency of every 6 hours 4 hours depending on what you're using And then you need to reassess obviously the pain and then adjust the intervals adjust the doses because again you want to be able to manage the chronic pain using chronic pain medications in their appropriate doses and roots of administration as well as the frequency of administration that is recommended for that opioid Let's do an example and then I work out the math here so you can see exactly how to do it um and implementing some of these rules So we have a 45year-old male with unfortunately a diagnosis of metastatic lung cancer that is progressive um and it is causing worsening pain despite being on long acting morphine So he's on like an MS cotton at 120 milligrams every 8 hours Right Then he has a uh intermediate uh or immediate release sort of breakthrough pain regimen of 20 milligrams that he can give to himself every four hours Um a switch to oxycodone is being considered Um and so because he's starting to accumulate a lot of these metabolites the three and six glucuronide metabolites Okay And if he had renal impairment that would be uh more concerning potentially in this patient So now you have to calculate the total amount of opioid that that patient is receiving on a day and put it in the context of the right drug So thankfully his immediate release and his chronic medicine are both the same drug So you take the 120 milligs that he's taken every 8 hours which is three times a day That gets you 360 milligrams of the long acting morphine Then you have the 20 mg that's given every uh 4 hours which means he gets up to six doses a day of this That's 120 Now assuming he takes it every four hours Well he is um in this situation But if he was only using it twice a day then you would only do that obviously two times Um so the total amount of morphine that this guy is taking per day is a 480 mg in the total amount in the day Now you need to do the conversion And well we look back at our chart and we can see that oxycodone about 20 mg is equivalent to morphine 30 mg Okay again this is not a perfect science but it's a rough rough equivalent So we know that he started out with 480 mg of morphine So you just do simple math so that you cross out the units and we get the number of milligs in oxycodone And so you can do the simple math and you can see that roughly 480 milligrams of morphine is equivalent to 320 milligrams of oxycodone Oxycodone being a little bit more potent Uh it doesn't need to be functionally active It is a synthetic opioid So it works in everybody Um and so assuming you take it correctly but it should work in everybody Now you need to take that total amount of oxycodone in a day and divide it into the frequency of that you want to give and then make dose adjustments So for example if you made no dosage change you would be giving this patient 325 millig 320 milligrams total in a day If you divided it by 12 um then you would be giving that patient 160 mg um obviously every 12 hours Now most people would not do this This is not a recommended thing to do because again you're assuming that the dose is going to be about the same and there's potential error in that So you'd rather error And so we're going to reduce the dose between 25 and 50% of what it started with And so you just take 25% reduction of the 320 You get 240 If you want to go 50% because you feel like that's the right thing to do for this patient and given their scenario then you'll start out at 160 milligrams total in a day right Per day Then you take that 160 mg or 240 milligrams and you make adjustments down here Okay And that's what these are Well you have to factor in what dosage formulations does oxycodone or oxycontton especially if you're going to do long acting Remember we're trying to figure out the chronic uh dose equivalent So this is Oxycontton which is an extended release formulation usually dosed every 12 hours And these are the different dosage formulations that are available So you want to think about well what's my total dose And then what formulation is allow me to get to that So if I drop it 25% um reduction then that would be 240 Well that would be giving 80 mgram tablet is the most efficient thing uh by reducing the number of pills that the patient has to have every 8 hours or you could do 120 mg every 12 hours They're both correct They both would achieve the the the response Um so both are acceptable answer choices if you were to be asked something like that Now if you reduce it by 50% then again 160 milligrams then you're using 80 milligrams twice a day uh would be an option uh that you could do um as well Okay So there's a number of different ways Maybe their pain is worse at night So maybe you give them you know uh 30 milligrams in the morning 30 milligrams in the afternoon and then you know they get another different dose dosage formulation at night because they have problems when they're sleeping You know it doesn't matter or maybe they're maybe during the day You can adjust it based on the patients lifestyle and what they're reporting as their pain control throughout the day Now remember that was all this is the chronic phase right So that was the chronic long acting agents so that we reduce those peaks and troughs We provide stability in their pain control and we want to minimize their breakthrough pain But we still need to calculate the breakthrough pain dose So you take the total dose of equivalency which is 320 milligrams per day and then remember I said you take five to 15% So I just worked it out here to show you what would be 5% of the dose at 16 milligrams 10% 32 you know 15% 48 total in a day of breakthrough Then you have to look at the immediate release formulations again what is available and how are you going to make it work right So then they um you can you can manipulate So it depends on how much pain control you want them to have um and whether it's 5% 10% 15% Again there's no hard fast rule but just this is how you do it Now if you're going to do the total amount let's say it's 32 milligs total in a day and you're going to distribute that out as something that you can give every 4 to 6 hours then you would give something like you know 30 milligrams every 4 to 6 hours as needed for PRN pain But then when you bring them back you're going to look at how much breakthrough pain are you using How much drug do you still have left and it should be lining up because if you're using breakthrough pain every 4 to 6 hours then your chronic extended release pain regimen is not sufficient and not working appropriately So I hopefully that made sense Hopefully you see how to apply it Obviously the percent reductions would be different if I was converting the patient to methadone I would just take those percentages on the chronic and go instead of being 25 to 50% I would do it by 75 to 90% Okay And then the breakthrough pain would still be fif five to 10 five to 15% Uh you know although you know you you may not need to use that uh for methodone Sometimes patients are on two different pay medications because of uh feasibility and dosage formulation availability Obviously you have to other factor you have to think in and consider is the cost uh especially with some of these newer agents that have uh abusive deterrent agents kind of mixed inside of them uh that help with preventing diversion but obviously cost more So at any rate uh hopefully you found it as a good overview um and made some um relevance to you as it relates to you know how to switch patients and then and apply them clinically