this is Dr busty and we're in our neurology uh series where we're going to be doing a drug class review over opioids uh we're going to be discussing yes obviously the mechanism of action um in general of all opioids but also obviously the differences in the individual agents and classes and one of the things you're going to see is that some of these agents need to be functionally activated in order to work especially the older agents u the newer synthetic versions don't need that but it's important as it relates to efficacy um and the overall analesic effects that these drugs have um and then we'll also point out some of the differences in the dosage formulation so that you can understand how to pick one drug over another in a specific situation so let's talk a little bit about the mechanism of action since that's the first topic um the mechanism is actually quite complicated uh and that has to do with a lot of the neurons and the nerve fiber tracks that go from the brain down the spinal cord out to our tissue back to the spinal cord and up through our brain there's all these basically a network of pathways kind of like a very complicated interstate system of highways and roads and tracks and and as these neurons are going up and down there's also what are called inter neurons and all these neurons can have regulatory influence on other neurons and affect their release of transmission of neurotransmitters and the transmission of impulses up and down below so when we think about opioids they're all prototypes of heroin um heroin is a very um acute onset uh drug that when especially when administered parentally uh it rapidly crosses the bloodb brain barrier activates the uh reward pathway in particular and causes a significant amount of euphoria which is one of the things that draws people to it and makes them addicted is because that reward pathway is so act so so much uh stimulated and activated with that euphoric effect that they they want it again and unfortunately it takes more and more drug in order for that same uh response to occur um but what's happening is we have nerve pathways coming from our brain down through our spinal cord uh those are called descending pathways obviously and then we have ascending pathways uh and opioids work on both and in some respects they basically cause a activation of the descending pathways which put inhibitory activity on the inter neurons that affect the ascending pathway so they work on numerous levels um and that's why they're so effective against pain syndromes no matter what the pain is they will generally work um especially if it's noceptive pain um but that's fundamentally what's happening okay uh this is a slide that goes into a little bit more uh uh direct detail about what's happening at the aerant nerve fibers um that are bringing impulses from the periphery into the spinal cord um they like I said in the spinal cord and around the spinal cord are inter neurons and some of these opioid receptors are present in those areas and affect the transmission of the ascending pathway but at the same time we have an increase in the descending pathway fibers that also augment the activity and the net effect is an overall reduction in the ascending nerve pathways to the cerebral cortex of pain stimuli so that the brain basically doesn't receive that input that's fundamentally it but it uses the muopioid receptor in particular to do that and so when it binds to it it's a muopioid receptor agonist now there are different types of opioid receptor i just mentioned the word mu there are also kappa beta there are other different nerve fibers in the body i don't know that that is detail is that clinically well is relevant for board exams and test purposes um it is more important that you understand how these drugs work side effects what makes them different and how to use them and what are some of the issues related to as it relates to developing dependence physical dependence tolerance addiction u which is what we're having faced with across the the uh country this is a diagram of that descending pathway and the ascending pathways you have to kind of put on an imaginoscope um and kind of think about this whole this whole area as a spinal cord and you see that we have nerve endings out in the periphery that bring impulses into the spinal cord and there's these interconnecting communication roads or pieces maybe they're exits or you know loops around other interstates that are affecting this and you can see where opioids are predominantly working on these inner neurons as well as the desending pathway to increase the overall input down on those uh aerant nerve fiber impulses coming in and so this is the why it's kind of somewhat complicated and is beyond usually this level of details beyond the board exams for most part okay this is the take-home point if you want to have that available to you all right let's go through some of the drug classes now centrally acting opioid analesics the classic agent in this group is Tramodol historically known as Ultramar now Ultramar or Tramodol comes in a number of different formulations we have formulations that are extended release um we have uh formulations that are mixed with other drugs they come on and off the market they're constantly changing so don't get bit out of shape if you see one of these drugs that's no longer on it just fluctuates quite honestly most of these formulations are not used in clinical practice mainly due to expense and we have so many other options available that it f it's very difficult to justify using some of these other formulations but that doesn't mean they have no clinical utilization at all but tramodol or ultramar historically ultramar is been something that we still use in practice and still has a clinical utility uh especially for more moderate pain syndromes for short-term periods now this drug is a recemic mixture that means there's two isomers an S isomer and R isomer both of them are active the anantimer or isomers work differently as it relates to norepinephrine effects and serotonin effects but both of the isomers work on their opioid effects so they're both muopioid receptor agonists okay now there is a metabolite it is called the M1 metabolites it's a o desmethyl uh metabolite basically of tramodol uh it is more potent us about four to six times more potent on the opioid receptor than the parent drug and when you do a comparison to morphine it's a it's about a 135ths of the amount of potency that you would see with uh morphine so it's not as strong as a pure opioid agonist like morphine so it's weaker okay and that's why you don't get the same degree of analesia but it also requires it to be functionally active to get to that metabolite and that metabolism pathway is via cytochrome P450 2D6 and so 2D6 needs to be functionally active in order to generate this metabolite in order to get the analesic efficacy that you're looking for with Tramodol in particular therefore if somebody has a pharmaccogenetic or genetic polymorphism where 2D6 is not functional because of genetic reasons or you have a drug for example fluoxitine or peroxitine or paxel that inhibits 2D6 then you will decrease the overall analesic efficacy of tramodol because you're not forming the active metabolite um that exerts the greater analesic effect now when you look at um the different formulations they have different maximum doses um historically the immediate release is around 300 milligrams extended release can be a little bit higher we definitely don't want to go above 400 that is when the seizure threshold starts to drop why is that well mainly because this drug not only affects the amuopioid receptor but inhibits the re-uptake of norepinephrine and serotonin so it works a little bit in theory like a triccyclic antidepressant does and that's good and bad because if somebody has underlying depression this drug could theoretically uh treat some of those depressive symptoms which can clearly worsen patients perception of pain um at the same time it can work on neuropathic pain because we use lowd dose triccyclic antidopressants for the treatment of neuropathic pain and again they're working on norepinephrine and serotonin but any drug that raises the concentrations of norepinephrine in particular is going to known to lower the seizure threshold and increase the risk of seizures and that risk of seizures definitely goes up when you go over 3 to 400 milligrams a day that is very important to know clinically but also for board exams because people love to ask that question because this drug has two different mechanisms that we don't always think about that can lead to increased risk of side effects not only the seizures that I just mentioned but also increased risk of serotonin syndrome if used with other drugs that have serotonurgic activity um and so please keep that in mind as it relates to the activity remember it has to get activated by 2D6 and drugs that inhibit 2D6 especially serotonin drugs like peroxitine which is known as paxel more commonly pel historically and then fluoxitine or prozac are probably pretty strong they're probably some of the strongest cytochrome p450 2d6 inhibitors that we have on the market and that can certainly increase the risk of serotonin syndrome and and the example of that is listed here in this this diagram this is showing SSRIs which are going to clearly increase serotonin concentrations in the synaptic cleft but I just told you that tramodol okay the parent and the active metabolite can also raise norepinephrine and serotonin as well and so when you have two drugs on board especially a drug that inhibits the functional activation of the more active metabolite you then create a net balance that favors too much serotonin that can increase the risk of serotonin syndrome which can also lead to seizures myoconic jerking tremors febra patients developing fevers confusion it it creates actually a very difficult uh diagnosis to capture now there have been warnings from the FDA a couple of them actually they started back a couple of years ago uh mainly due to pediatric patients coming out of the operating room for tonslectomies um and they basically gave a warning to hey really we need to watch out for using and avoid this use in less than 17 years of age especially kids post tonslectomy who are also rapid metabolizers now how in the world are you going to know if someone is an ultra rapid metabolizer unless you do pharmaccogenetic testing which unfortunately is not the standard of practice in all patients at this time but ultra rapid metabolizers means the cytochrome P450 2D6 is now working more efficiently and effective than before uh and so what ends up happening is you make more and more and more of that M1 metabolite and now because you have the more potent form available that binds to more of the muopioid receptor that increases CNS depression and reduces your uh the respiratory drive that causes people to have basically asphyxiation um and so this is why we have to be very careful um and that how it applies to phiccogenetic related issues now there are drug interactions now I told you that that tramodol yes works as an opioid but remember it increases uh serotonin and it also increases norepinephrine okay so it works like a triccyclic antepressant there are drug interactions with its use in flexeril or cyclloenziprne why because cyclloenziprne if you look at its structure okay you can see that it's very much like the triccyclic anti-depressant amatipptalene it lack the only difference is this one double bond and that double bond um does affect its overall effect on the serotonin and norepinephrine but it still has some serotonin and still some norepinephrine reuptake inhibition as a result when you have two drugs that increase serotonin now you increase the risk of theoretically increase the risk of serotonin syndrome although there's no real evidence that proves this uh there's no publications to my knowledge that have actually documented this fact but if you break down the pharmarmacology it theoretically sort of makes sense so the lack of evidence doesn't mean it's not a real issue it just means you need to keep it in in mind all right let's now discuss partial opioid agonist and antagonist so these are drugs that have active activity on the receptor but also antagonize the muopioid receptor so here are some of those agents okay we don't have many we don't use these for a lot of conditions in fact we use them off for different conditions so buprenorphine or buprrenex is the drug formulation that's used for analesia when it's combined with nlloxxone that is like bunavville suboxone subzolve these are formulations that are co-administered and formulated with nlloxxone are not used for analesia but are instead are being used for opioid dependency programs okay so we don't use it for pain management and that's very very important point that you should know and be able to pick out because people love to ask that kind of question as well and in clinical practice it does matter so buprenex or buprenorphine is the opioid it does have a ceiling effect which means at some point you don't get much bang for the buck because of that antagonist activity that is happening and so this sealing effect limits its use in chronic pain where patients develop tolerance over time as they take opioids that opioid and that that dose is not going to exert the same degree of analesia because of receptor changes and so you have to give more drug over time to exert the same pharmacologic effect that you had before that's just tolerance that doesn't mean you're addicted tolerance means you've developed a tolerance to the drug and now you need a greater amount of drug to exert the same effect that's different than addiction and uh physical dependence any patient who takes an opioid on a daily basis will develop physical dependence i don't care who you are you will develop dependency on it if you take it day in and day out on a chronic basis that does not mean you're addicted okay physically dependence is not the same thing as addiction addiction is now when you manipulate your environment and interactions with other people and do things that are contrary to ethical behavior to manipulate situations to achieve getting drugs to abuse them or use them outside of their intended purposes under the structured guidance of a provider who's qualified to manage chronic pain that's a different scenario that's addiction when people are abusing the drugs outside of their proper use and outside of the proper relationship and agreement of an established health care provider who's qualified to utilize it and we have a big problem with that okay and so this is one of the reasons why people resort to heroin which you can find on the streets but a lot of these drugs are on the streets as well and that's why we have opioid dependency program which we use things like bupren subsolve um uh not buprenex uh bunavville suboxone and subzolve to help manage those patients to reduce that craving now there is other formulations that have come out okay probuene this is a surgically um implanted device that basically releases drug over a period of months so they don't have to come in and get medication on a daily basis all right or be dispensed medications that are of questionable you know use of or abuse okay so these formulations are different so bonavville is a film suboxone is a sublingual film subh subzolve is a sublingual tablet so it's important to recognize differences of indication it's important to recognize difference in the formulation and the dosage form and how it's administered it's also important to recognize uh when is it used for analesia versus an opioid dependence situation okay lot of high yield content here now it is a C3 medication not a C2 okay buprenorph uh butphanol is known as stadol and then there's also a stal ns which stands for nasal spray okay it's a controlled for substance um the nice thing about the nasal spray is if somebody has difficulty swallowing or they're nauseous and or vomiting this is still a route of administration if you don't have access to parental medications that's really the only main benefit to it now some patients uh do get dizzy um at the higher dose in the nasal spray especially as um so they need to be sitting or be recumbent when you administer the medication and that's an important counseling point now buenine or new bane um it was uh prior uh it was a C2 drug uh right now has no scheduled um it's utilization in clinical practice is very limited quite honestly I've never even seen the drug used pentazisonin um C4 uh known as Tlwin uh there is a formulation that is combined with TWIN or Nlloxxone it's called Tlwin NX NX being the Nlloxxone Um this formulation is nice because it's an abuse deterrent kind of formulation so if they try to crush it you know and snort it or inject it they're not going to be able to get anything because Nlloxxone then gets released from the dosage formulation and basically antagonizes so Nlloxxone or Narcan is the antidote to an opioid overdose essentially so if you go and you competitively antagonize and compete with the receptor then the opioid can't bind to it and it loses its effect okay um again has very little utility outside of that situation um as abuse deterrent okay trying to integrate previous topics like pharmacocinetics and phicodnamics remember in the phicodnamics this is the typical dose response curve this is the maximum pharmacologic effect that is seen and this is the concentration of the drug obviously the more you go over this way to the right the greater the concentration or exposure the larger the dose that is being administered now as a result of this you'll see that pure opioid agonists like morphine fentinil methadone oxymorphone oxycodone those types of drugs uh you see that you can generate a greater pharmacologic effect compared to partial opioid agonists like buprenorphine like now uh state you know these drugs don't have the same degree of efficacy and if you try to co-administer or use something like bupinorphine buprenex in a patient on morphine you theoretically could antagonize some of the analesic effects of the morphine decreasing the overall net analesia control that that patient gets that's why we don't use these drugs in combination with pure opioid agonist we only use these drugs in by themselves um in scenarios where they're for short term usually because they have sealing effects and because they're just not as effective at controlling pain especially when the patients start to develop tolerance all right now let's talk about some of the opioids we have weak opioids that are pure opioid agonist okay they have no antagonist effects and then we have strong opioids things like fentanyl okay hydromemorphone now coding uh when it's by itself is a C2 drug okay so it requires a special script or prescription no refills those a limitation on the amount that can be dispensed if it's combined with Tylenol okay tylenol number one two three four and number one is just and 2 three four is just talking about the concentration or amount of coating in each tablet so for example Tylenol number three is 30 mg of codine tylen number four is double that 60 that means that Tylen number two is half of 30 um which is uh 15 and then Tylenol number one is half of 15 roughly eight and that's a way that you can try to remember that but when it's combined with Tylenol it is no longer a C2 drug it is now a C3 drug and the reason for that in part is due to the sealing effect provided by the acetaminophen because you're maxed out on the amount of acetaminophen that you could administer which means that you're going to be maxed out on the amount of coding that you can also administer to the patient assuming you're using it appropriately prescribing it appropriately now it's important to recognize this because this is a source of acetaminophen and if patients don't know what APAP is right we should not be using that um on labels or in discussions with patients because they don't know what APA is uh they may overdose themselves because they may co-administer it with Tylenol and not know that they're doing that um so it's important to counsel your patient it's important to know these differences um in the formulation now codin is one of these drugs that has to get metabolized to an active metabolite morphine so approximately 20 to 30% of morphine in normal patients get I'm sorry 20 to 30% of coding gets metabolized to morphine okay now that is via 2D6 so it is influenced by genetic polymorphisms so if you're an ultra rapid metabolizer of 2D6 you're going to generate more morphine than normal and you could theoretically overdose if you lack 2D6 enzyme activity whether it's from genetics or from a drug interaction you are not going to activate the codin to morphine and therefore you don't get any analesic effect that is why some patients say Tylenol number three may not work for me they may not be lying to you and they may not be a drug addict right so before you go labeling a patient inappropriately make darn sure that you understand that the the possibility is that this drug may not be activated in order it and not working if it doesn't get activated it doesn't work okay and so that's important um Propoxifene is only left on this table purely for historical reasons it is no longer available on the market it caused a lot of CNS side effects especially in elderly patients um and it was a terrible analesic medication um but it was discontinued several years back now moving on to our strong opioids now hydrocodone okay which a lot of times is combined with acetaminophen and we'll see that here uh we we this drug also has to get metabolized it is a C2 medication it requires metabolism to become active and it gets metabolized to hydromorphone also known as vitamin D right dilotted everybody loves dilotted because hydromemorphone is active it works in everybody just like fentanel works in everybody okay but if you don't activate the hydrocodone to hydromorphone it may not work and that's why Vicodin and other drugs you know like Norco Vicodin down here they don't always work in patients um and that's important to know now we do have some formulations that allow for an extended release option for chronic pain management that are abuse deterrent formulations for example so Hydro ER is every 12 hours administered versus in Sigma which is a uh 24-hour once a day admin administered they are abuse deterrent formulations okay now what's nice about this is that what it means by abuse deterrent if somebody tries to manipulate the dosage formulation and administer it to themselves in a route of administration other than by mouth they will get no effect or it'll make itself into a situation where it can't be snorted or injected so zohydro is a good example of that it's mixed with something called beec and Btech when it gets crushed forms a viscous uh gel that can't be snorted and can't be drawn up in a syringe to be injected into a vessel okay now alcohol consumption at the same time as hydro use um causes disruption and can increase the absorption potential and then theoretically increase side effects so important to note now you'll see that when it's combined with a Tylenol the amount of Tylenol varies depending on the formulation and I try to designate those for you here okay i don't see much use for some of these formulations to be honest the exception might be with the solution if you have somebody with a tube or who has difficulty swallowing tablets that might be a potential benefit okay um if you don't want to use acetaminophen you need an anti-inflammatory drug there is a combination product vicoprofen uh with ibuprofen as well okay all right hydromemorphone is dilotted now it does not need to be active and nor do any of the drugs that we have left in the list to discuss so coding morphine tramodol generally need to be activated in order to work and that's important to know now with hydromemorphone we have immediate release but we also have extended release options extended release option is exalgo and it's important to recognize that exalgo is only for chronic pain management we do not use it for PRN and certainly in opioid naive patients okay c2 just like the other agents right comes in an immediate release extended release product um and that's important i do point out here we have dose equivalencies listed here um that's relevant this is the IM to PO ratio okay compared to basically morphine okay uh there is a separate lecture on dose equivalencies and if you have access to that please look at that now hydromemorphone not not needing to be active does get metabolized to a glucuronide that's UGT metabolism that's phase 2 metabolic pathway to make it more water soluble so that it can be renally eliminated again alcohol use can increase the rate of absorption in the overall CAX that occurs which could theoretically increase the side effects so hydromorphphone works on everybody everybody likes it uh because it works it's active now it's also one of our opioids that is less likely to cause histamine release okay so morphine is one of the worst uh fentanyl and dilotted are maybe some of the least so the histamine release not only causes itching but it can also cause vaso uh motor dilitation uh that can cause hypotensive or orthostatic symptoms in patients now methadone uh is an interesting medication um it is used both for opioid dependence programs or heroin addiction programs as well as analesia but the dose that is used is different so for example in analesia uh the dosing is every eight hours whereas in use for heroin addiction it's once a day so it's very very important that you understand the use of the methadone and its dosing frequency there okay now this is a drug that has a significant amount of of potency to it and um as a result when you're converting somebody to methadone you really need to convert them to a lower dose of methadone mainly due to the fact that it has a very long halflife and that long halflife allows for accumulation of the drug and cause sedation depending on how it's being administered especially if you are administering it every 8 hours now it also works on the NMDA receptor to basically block glutamate activity that benefit offers or confers a benefit to patients who have developed tolerance to another opioid and this is one of the reasons why we switch from patient from one opioid to methadone to decrease the overall amount of opioid they need and the uh exposure to the amount of drug that they have to uh take to get the effect now unfortunately it is one of the opioids that's known to cause QT prolongation um and is subject to a lot of drug interaction so if somebody overdoses you need to check an EKG on these patients very important especially if they have underlying electrolyte deficiencies or abnormalities like hypocalcemia hypocalemia hypomagnesmia these patients are at high risk of developing QT prolongation that can eventually lead to torsads um the drug interaction is a problem especially given the long halflife so you look at all the different enzymes that it goes through to be metabolized that's a problem uh because you have a lot of drugs that affect things like 3A4 2D6 2C9 so the drug interaction potential is high so there's a lot of high yield content on this slide um both with hydromemorphone and methadone that make them unique methadone having a very unique uh long half-life effects on QT drug interaction potential that's worse than other drugs and is very important to recognize that as it relates to also indication and the use now maparitine is an older drug demoral uh that really is not used much in clinical practice anymore except in maybe intermittent doses and in certain sections or specialties um it is a drug that gets metabolized to an active metabolite called normapiritodine normapiritodine has very little to no analesic effects and is known to lower the seizure threshold and so we don't tend to use it very much cuz it just quite honestly sucks as an analesic um this is this conversion to normine is greater when it's administered by mouth um and there are oral dosage formulations and there are absolutely no indications for its use by mouth and anybody who prescribes it by mouth in my personal opinion is probably too old to be practicing medicine and or is so incompetent that they should quit um there is absolutely no indication for using oral demoral in anybody given all the other options that we have available um so keep that in mind it is a problem and it's mostly a problem especially with repeated doses and accumulation um and this is one of the reasons why people limit the duration to no more than 48 hours or make sure that the total accumulative dose doesn't exceed 600 milligrams now morphine has been around for a long time and the nice thing about morphine is it's available in a number of different dosage formulations tablets immediate release extended release liquids um it can be given IV IM subq right and so it's very very userfriendly and has been around a long time and is cheap now there are formulations that allow for chronic pain management options that are not cheap like MS Cotton Caden Aenza these drugs are for long acting chronic opio uh chronic pain syndromes for outpatient chronic management not acute management okay but it is important to recognize that the dosing frequency is different and that's why you see the 24-hour or 12-hour make sense now MS Continent is unique in that the FDA also allows it to be given every 8 hours so you can give it every eight hours or three times a day um and that's important to recognize same thing with Caden can be given twice a day but again these are not used in opioid um inexperienced patients right all right um this is the dose equivalence from PO to the um IV formulation so that's just important to recognize the difference when you're using it in different um options so if someone comes in on an oral agent how much do you have to convert them over to the parental in order to maintain at least equal pain control so they don't go through withdrawal uh there is no activation needed remember coding gets metabolized to morphine all right but there are morphine glucaronide metabolites that can accumulate with renal impairment patients um they they do exert a pharmacologic effect and they have been associated with increased myoconic effects especially at high levels and so p you do need to be aware of this effect but you just basically monitor these patients it doesn't happen with one dose it traditionally happens with repeated dosing where the renal function is getting worse and and accumulates over time if being used for chronic pain management in cancer patients these patients can develop pill fatigue or pill burdens because they their pill number of pills they have to swallow do get fairly large over time so it's important to recognize this is one of the reasons why we convert somebody to a different drug um and uh reduce that because they can swallow a large number of pills to achieve this effect especially if they've developed a high degree of tolerance now I mentioned this before but remember hydromemorphone and morphine I'm sorry h h h h h h h h h h h h h h h h h h h h hone and fentanyl were the least likely to cause histamine morphine is one of the highest risk of causing histamine release that not only causes itching but can also then lower the blood pressure and so if somebody who's hemodynamically unstable uh we generally try to be careful about the use of morphine for that reason because its vasoddilatory properties so that's where we use short acting um drugs that are like fentanyl at low doses that don't cause as much histamine release in patients like trauma or who are hemodynamically unstable and have pain now there is a formulation that is mixed with nalrexone um and this is an oral option um it is not used for PRN use but again if you were to try to crush it or inject it or snort it then you would not really get much of a benefit for that um oxycodone comes as oxycontton um there is an immediate release abuse deterrent formulation and there's also an extended release every 12-h hour abuse deterrent uh formulation again all these abuse deterrent formulations are trying to re get control over people not you know we need to treat pain patients suffer from pain uh and there are a lot of indications that warrant chronic pain medicine with opioids because chronic naids have side effects and complications and not everybody can tolerate or even are candidates for insaids so there's reasons to use it but so these manufacturers and in collaboration with FDA concerns and the epidemic of opioid abuse in our country has warranted and created a new sort of setup of formulations to help avoid patients using them outside of their approved indications in roots of administration for appropriate use um so oxycodone is a synthetic agent does not need activation we generally don't use these in opioid naive patients usually in opioid experienced patients uh specifically uh the extended release the experienced patients get that one um yes just like with hydrocordone there is formulations with the Tylenol you see we have a solution we have tablets um there's also formulations with ibuprofen aspirin and even nlloxxone nlloxxone is tarenique or extended release formulation again these are abuse deterrent so if they they avoid or try to crush them you get nothing now oxymorphone uh is opana there's opana IR which is immediate release and then there's the ER extended release there's really no significant advantage to this drug compared to the other agents um and alcohol does have an effect uh on the bioavailability similar to some of the other drugs that we talked about uh tentadol is a unique mechanism now it specifically in the product package insert um touts and explains that the mechanism is by increasing uh the descending pathways they they very much focus on that and I don't it's just the mechanism of action of opioids all opioids do this at some level but they specifically talk about this uniquely in their mechanism um upfront so there's nucenta and then there's an extended release option as well there is a contraindication with monomine oxidase inhibitors for at least 14 days um after their use because of the inhibition of norepinephrine reuptake and so yes it is unique and you might want to know that mechanism mainly due to the fact that when board exams like to ask questions they like to pick on things that are different and unusual now our last opioid is fentinyl now fentinil is very nice and it's like morphine in a lot of respects is that it comes in a lot of different dosage formulations to allow its use across a number of acute and chronic spectrums now um it is a very potent drug and what I mean by potent is you don't have to give very much drug in order to exert the pharmacologic or effect that you're looking for and so these that's important to recognize that we don't give this drug in milligrams but instead is being given in micrograms okay now the amount of micrograms being administered is influenced by the indication the patient population and the dosage formulation so I would like to point out that each of these columns represent a different dosage formulation um and what I try to do is put together the dosage formulation and then the different mechanisms of release and how they work um for those of you that are interested the dosage formulation does impact the how fast the drug gets absorbed into the body so from a chronic outpatient standpoint transmal patches are great because again you don't have to worry about swallowing anything if you can't swallow you know so patients with patients with cancers of the throat or who are altered and you don't want them aspirating this is a good option for patients with pain chronic pain syndromes and they come in number of different micrograms per hour um drug elimination into the body but it's transermal on the skin right and so it creates a little reservoir and it slowly depletes in out so as a result of that it takes about 12 hours for the drug concentrations to become adequate to give pain control so that when you first start somebody on a transdermal patch you need to give them something like a 12-hour acting like MS cotton oxycontton or something like that that provides 12 hours of pain control so that as that drug starts kicking in then once you put the patch on and you switch out to patches there also is going to be 12 hours of drug being released still but you're also putting on a new patch so they kind of cross over where there's no breakthrough pain hopefully there is a which is a transdermal patch system that is a button that you push it's a patient controlled analesia patch with a lithium battery and that battery creates electrical current and drives the medicine into the skin faster for a greater absorption so it works almost like an immediate like a PCA pump somebody pushes the button they get an effect they get a delivery of drug and then it goes away uh now this is only used in the acute uh sort of posttop period we don't dispense these drugs home or distribute them dispense them for patients to use as an outpatient it's only in the post-operative setting now these other ones like a teique fentora ensulus those kind of things that kind of come and go they are a buckle mucosal formulations for immediate release breakthrough pain they are largely restricted to opioid experience patients who have cancer so these are patients who need something for acute pain control with their chronic pain syndrome usually from cancer and they have prior experience you do not use these in opioid naive i.e inexperienced never been on an opioid only in patients on opioids in the past and have are have developed a certain amount of tolerance and experience with the drug but it's predominantly used for breakthrough use only now the trans ddermal patch uh this is just an example of the reservoir and the reservoir is important to recognize because you can't cut this so you can cut a little bit around the you know membrane but you got to be real careful about doing that so it's recommended that you just don't do it at all because if anybody gets into the backing or the reservoir then you run the risk of leaking it out theoretically people can stick needles in there and try to aspirate it out i've never seen that happen uh or done but you need to recognize that the the membrane here uh does release the drug and so you really shouldn't be cutting it and you should not also place transdermal patches over um skin that is not fully intact or you don't want to put it over damaged skin or infected skin so it needs to be clean dry and intact um skin okay now you also want to be careful about placing it over areas where it's really warm because warmth will maybe increase the absorption of the drug and so be careful about this also recognize that patients do accumulate these stickers all over their bodies uh because people don't pay attention to them so make sure you take off clothes and you look at patients if this is the first time you've ever seen them turn them over on their back and make sure there's not patches on them especially if they come in altered uh this is the inosyst uh thing as that the button that the patient pushes when they're ready to receive a dose the red light will blink and it blinks to certain tell the the the provider as well as the patient that the medicine is being delivered it also gives you an indication of how many doses are remaining in that system again we don't use this for outpatient management but you can see here that Inosis right here uh does provide a pretty rapid within 15 uh minutes onset of a drug delivery again similar to the IV obviously not to the same degree uh but it works like that without needing an IV all right so these are just more pharmacocinetic parameters uh nothing specific here you don't want to choose some of the buckle mucosal formulations um and you want to be careful with the film tabs not to you know break them there also is an intraasal spray this would be very helpful in patients also who can't swallow um and um again it's only restricted to patients for breakthrough cancer pain now we use uh intraasal sprays of fentanyl for pediatric patients um a lot of times with acute injuries or trauma uh where we don't want to put an IV in quickly or they don't have one yet and you want to give them p uh some pain control um so they don't become too upset because obviously sticking an IV in a child who's already got a problem uh is making the situation worse uh there are sublingual sprays and sublingual tablets again these are only approved for specific patient populations many of them are restricted access because there have been overdoses when these drugs are not being used in the appropriate context or the setting for which they were approved so you need to recognize indication dosage formulation and the patient population that's being used in these to avoid overdose um and also to avoid uh abuse potential um in these situations um and it's important to recognize that when you use these drugs for chronic pain chronic and acute all chronic pain patients will eventually have acute so they need acute breakthrough pain management um but you don't want to be using acute or immediate release products to control chronic pain because those peaks and troughs of the concentrations are what drive up that euphoric effect like the heroin when I talked about the beginning of the mechanism the faster the drug gets moved into the body and the quicker you give it the more it goes into the brain quickly and and stimulates that reward pathway so chronic pain patient should really be on in a long acting sort of extended release formulations but also be given breakthrough pain because they will intermittently have worsening of their pain and they need something for that pain and that's where pain specialists and appropriate use of these drugs with appropriate amounts of of drug supply under contract is very helpful at avoiding abuse potential and risk for that um that lead to addictive behaviors over time but sometimes patients resort to other medications because we as providers are not treating their pain appropriately so you can't blame them if they're not if every you know they say they out of their pain is out of control and the first thing that you think of is they're an addict that is not necessarily true it may be that we're not treating their pain appropriately or giving the drug at the right frequency for their specific situation and that warrants consideration um so anyway hopefully you found that to be uh useful