Transcript for:
Opioid Side Effects and Reversal

this is Dr Busty and we're in our neurology uh section where we're going to be discussing opioid and opioid related side effects and we're just going to basically go through the main or core side effects that you would be most responsible for for board exams and and also they're clinically relevant in um in the real world practice So we'll first talk about the most important thing which is an overdose situation which is considered a medical emergency mainly due to the fact that patients uh who take too much opioids We slow down their breathing to the extent that they are not ventilating and maybe even to the some degree not oxygenating Oxygenation and ventilation are two different things Um when you're inhaling and you bring in oxygen from the air outside into your lungs that oxygenates the blood going around Whereas ventilation is about getting rid of CO2 uh by exhalation And when you have slow very shallow breathing you don't exhale off very much CO2 And so you have poor ventilation As a result the CO2 accumulates that leads to a respiratory um acidosis Um and obviously as the CO2 levels rise so does the increased chances of altered mental status as a result of that Now obviously they can become hypoxic at the same time And so when these patients come into usually anu emergency care environment or acute care situation um one of the things that you need to do is try to maintain patency or open their airways You can do simple maneuvers like even jaw thrust which is you grab the back of the mandible and you just pull it forward um try to tilt their head you know chin up a little bit and pull forward on the on the mandible to get the basically the uh back of the tongue from resting off the back of the throat so that they can actually exchange air both bringing oxygen in and getting CO2 out Um obviously if you have supplemental oxygen that's helpful but don't be deceived that just because somebody's O2 on the pulse ox is normal that they're still not um hypoventilating um where they're retaining CO2 And that's why we use end title CO2 monitoring in these patients Now one of the ways that we recognize patients who have this is obviously you can just watch them and you'll see that they're breathing but their breathing is very shallow On physical exam you will see that they have a pinpoint uh pupil uh respon and they're I mean really tight like like one one to two millimeters and they're so small uh that you almost can't tell whether or not uh that they're actually constricting in response to light reflex Uh the the the problem with only relying on something like the pupils is that if somebody has co-ingested other uh drugs or molecules then what you can see is a mixed picture where the physical exam doesn't fully uh line up with the typical opioid toxiddrome But you know respiratory depression which are very shallow uh breathing where if it gets to the point where they stop breathing or they're so uh slow with their breathing they become hypoxic then they develop a noxic brain injury and then can go into a coma and even die Um obviously sedation they lack um they're confused uh mainly um uh the I'm sorry there there's confusion about uh sedation and even respiratory depression as it relates to pain control Um that was the point I wanted to make here Sorry about that The the thing that a lot of times clinicians uh especially those who don't have a lot of experience with using opioids and pain managing pain is that the natural antagonist to respiratory depression and sedation is pain itself So if somebody comes in for example and they've broken a a bone and that bone is you know sticking out or is severely deformed uh these patients can be in a severe amount of pain and we would give them very large doses of opioid medications like fentinil morphine dilotted things like that and we would if you would do that to somebody who didn't have a broken bone that patient who didn't have a broken bone would obviously become very sedated and probably develop some degree of respiratory depression But when you have a natural antagonist uh which is pain itself then you won't see that as much Um however uh they will become altered as they start to retain CO2 and become more sedated and confused And so you may not recognize the uh the pattern for the diagnosis unless you have some additional information But one of the things that some we do sometimes for clinicians who do come in the emergency department acute care setting and they have a change in mental status and it's not clear no one's available the patient can't give us information EMS doesn't really know all of the details Uh many times we will prophylactically give them a dose of Narcan which is what we're going to talk about as the reversal uh agent here just to see if the opioid is part of the problem Um now with uh when we do see sedation with normal outpatient sort of ambulatory care chronic pain management situations it's probably due to a recent change in the dose or where the dose adjustment was too high and they started to accumulate either metabolites u or things that now are causing sedation because their pain is under control When you have patients with especially cancer related pain um these patients can be on very high doses of extended release products as well as very high doses of breakthrough pain uh meds that would normally uh probably kill somebody who didn't have that Now they've developed tolerance which is why they've built up to those doses and so it's appropriate for those patients That does not mean that they're addicted It does not mean that they are um uh that that they I'm sorry It doesn't mean that they're addicted and they're using it inappropriately It means that they develop tolerance and they are physically dependent um on that patient Um if that starts to happen and you're in a situation like in hospice where you're trying to maximize the quality of life in sometimes in certain cases we will consider stimulant medications like that we would use for ADHD or a uh ADD patients uh to try to counterbalance some of the sedative uh properties that sometimes happen with highdosese opioids But again we use this um some of these side effects and we monitor for these side effects and we put them in the context of the patient in the clinical scenario that we're managing and that would be appropriate to do Um respiratory uh depression as I mentioned if dose tight dose titration appropriately this does not happen uh to someone mainly in pain because again as I said earlier the natural antagonist to respiratory depression is pain itself Now once you get the pain under control then you need to back off on that that dose and the frequency of medication that you're using because then as a result of the pain being under control now you can start to develop more respiratory depression and sedation that can occur And so we the antidote that is uh used in a more acute emergent situation is Narcan or Nlloxxone Um it is the only drug for reversal we'll see that we have other opioid reversal agents but they work predominantly in the periphery not in the central nervous system and are not reliable uh especially if they are administered by mouth because if somebody's altered I'm not going to try to shove a pill down their throat when they could potentially aspirate And so when we give Narcan I'm going to talk about it here in a minute When we give it our goal is to just slowly bring them out of the respiratory depression and sedation not just slam it into them and cause an immediate reversal because then you put them into withdrawal especially if they have been chronic abusers um and they've developed physical dependence um as well as a certain amount of of uh high doses that would then cause them to have all the withdrawal side effects Now when you look at Narcan or Nlloxxone and some of even the peripherally acting opioid reversal agents that don't pass through the cell uh bloodb brain barrier they have a structure that looks very similar to obviously opioids So the way that um Narcan works is it is a competitive antagonist to the muopioid receptor um and so it binds and competes with the opioid so that the opioid has nothing else to bind to This anti antidote then occupies the receptor to the degree that the receptor can't be stimulated and so therefore it's antagonized and you lose the effect of the opioid and it happens within a matter of a couple seconds of administering the dose depending on how much So it's given the fact that it's a competitive antagonist The more of the Narcan you give the faster and the greater degree of reversal that you'll get because you're competing with more of the opioid So if someone's taking a very large dose of a opioid then you may actually have to give larger doses of Narcan and that becomes very relevant if you start out at a very low dose of something like 04 and you don't get a response that's not a time to stop giving the Narcan really if they haven't responded by four milligrams some people say even up to as high as 10 milligrams and you exclude that diagnosis and you move on to something else Um but you can see here the morphine hydromemorphone which is your delotted oxycodone or oxycontton here you can see that there's a very similar structure um compared to narcan or nlloxxone now narcan or nlloxxone can be administered by almost any route of administration but obviously if you can give it IV it is the best way for the greatest quickest reversal but now now even some states in our country have um outpatient sort of dispensing products that you can um prescribe and give to family members of who are uh around addicts as well as addicts themselves so that if somebody sees them they can you know check their pockets and see if they're carrying it Um and they have intraasal kind of sprays and stuff like that that you can give Now now trexone is also a kind of a a um uh it's a modification to narcan Uh unfortunately this is not something that we use in acute situation because you have to give it by mouth It's an oral formulation And so again if you have an overdose where somebody's airway is being compromised in that situation you're not going to make them swallow something when they are not even cooperative and able to swallow They're just going to increase the risk of aspiration And so we also don't have time for it to get down into the uh GI tract and absorb and then finally get to the receptor Um so we don't use it for acute medical emergencies for that reason When you look at the peripherally acting agents like methyl nylrixone which is used here as an example There are other agents that we'll talk about in a minute Um you'll see that they have functional groups on them that are charged and any chemical structure that is charged is going to be less lipopilic and more hydrophilic or water loving And as a result of being more water loving um it is not going to want to pass through a bi-pid cell membrane like in the bloodb brain barrier um to get into the central nervous system So this will not work and this would be a trick question um it will not work to reverse um opioids um in the central nervous system It will reverse the effects of opioids on peripheral organ systems which is why we use it for opioid induced constipation that has failed to respond to traditional stimulants and other laxatives Now when we go back and try to integrate prior knowledge and information um you may remember from pharmacocinetics and pharmacodnamics topics and lectures that this is a typical dose response curve Dose response being over here on the y ais This is the maximum uh pharmacologic effect that is achieved at a specific concentration here on the uh x-axis And obviously as you go from left to right the dose or the concentration in the body increases Obviously as you increase the dose you see a different and higher degree of pharmacologic effect Now when you give somebody an opioid let's say for example like morphine here in this example and then you add okay so this is this is what opioids would do this is what morphine would do at you as you give it this is the dose response curve that is generated and at some dose you're going to get a maximum pharmacologic effect at some point or you're going to start to get to what is called the LD50 which is the lethal dose of which 50% of patients start to have problems Now if you then administer a second drug like Narcan or Nlloxxone in this situation remember I said it competes and so competitive drug interactions which is basically what this is creates this kind of effect It shifts the dose response curve to the right and that would be an answer choice that could be given to you on a board exam that help you to see uh if that you understand the concepts related to phicodnamics um as well as understanding how the drug works And so if you see an answer choice that says shifting the dose response curve to the right all that is simply meaning is now I have to give more of the opioid to overcome the effects of whatever this other drug is And in this case it's an antidote And so that's how you interpret and read that graph So here is Narcan or Nlloxxone Okay Um you see here that we use it predominantly for opioid um reversal especially when somebody has um opioid related uh CNS depression It is an adjunct also to septic shock um patients It's not something that we use commonly um but it it can be used in those situations um very rare um but uh it is something to consider especially if somebody has low dose of drug on board Okay Um now when we look at um when we look at the dosing here what I want to try to point out here is what you will see is this 0.4 4 mg to 2 mg And you see that you can repeat that in 2 to 3 minute intervals that is listed there And again IV is preferable but you can administer the medication Uh you can give it um uh IO you can put it down into the tracheal tube you can um squirt it up the nose if you have a atomizer that would sort of create a mist These would all situations where you can um utilize the medication Now you'll see here if there's no response after 10 milligrams then you probably need to reconsider the diagnosis Okay And that's important to recognize All right So we give it slow and we administer it slow so that we get them out of the re respiratory depression without causing them to go into immediate withdrawal It has a very short halflife of about 30 to 90 minutes It varies from patient to patient but that's you have about an hour maybe 45 minutes to an hour to an hour and a half before that drug wears off So if you have a long acting opioid you are going to then lose the um you're going to lose the effect um of the reversal and therefore if the opioid is a long acting agent or very very high doses and the Narcan wears off then they start to become having CNS depression sedation as well as respiratory depression again and so this is very important So when you have a patient who overdoses on a long-acting drug like methadone MS cotton oxycontton which is an extended release product zohhydro which is an extended release hydrocodone product all of these long acting agents uh or at very very very high doses you're going to have to repeat the dosing um back Now that becomes important because the dosing that then is used you obviously repeat the dose whatever brings them out of the respiratory depression If after the second dose or having to administer it again now you know that this patient is on a long-acting opioid or there's a presence of a long-acting opioid in their body these patients need to be admitted That is their disposition and they need now to be put on a Narcan drip Then the dosing to kind of come up with that is roughly okay there's no exact science but many people or recommendations say okay well what dose brought them out and you take about twothirds of that dose and you administer it over an hour as an infusion okay and you admit these patients usually to a higher level of care where they can have close monitoring all right so it um but you can't give it by mouth um because it has no oral bioavailability And that's why if some oral dosage formulations of opioid pain medications formulate the the product with Narcan uh if they take the patient takes it by mouth they get the opioid but they don't get the Narcan If they crush the the formulation try to store it or inject it then they get nothing They don't get any opioid effect because now the uh GI tract has been bypassed and now the drug can get into the central nervous system All right Um they do have intraasal sprays You can see here that the uh bioavailability is a roughly about 50% and the onset is a little bit delayed but we can give it through other routes of administration We just don't use it orally Now that's different from now trexone which I mentioned before Okay We do have the auto injector vizio solution uh which can be given as a IM injection or subq by anyone Um it does have a speaker that sort of tells them what to do Kind of like some of the Epi pens that are out there that now have a speaker that gives you instructions because obviously people are panicking They don't know what to do especially if it's a non-healthcare provider Um now when you reverse them you're going to put them into opioid withdrawal So you can see nausea vomiting diarrhea sweating and then they can obviously become very agitated um especially if they were using the uh opioid for inappropriate uses or even wanted to die Um and so it was an overdose attempt So um just try not to rapidly reverse them if you don't have to um because again it just creates more problems and the patients end up usually pulling everything off and walking out of the hospital and then remember the drug war wears off and then they find themselves back in the hospital because the whatever opioid they took especially if it's a long acting agent is now causing them to have respiratory depression again Now you'll see this note here It says do not use nrexone nlloxxol which is one of our periphery acting agents or methylonrexone for opioid reversal because they do not they do not pass through the bloodb brain area Now nrexone yes it can get into the central nervous system but it's remember we have to administer it by mouth and we're not going to do that in acute respiratory uh events where there's respiratory depression and CNS depression because of again risk of as aspiration Okay So we do use uh nrexone for opioid and alcohol dependence um for that reason but those are patients who are awake and alert and are usually being managed as an outpatient for their chronic conditions Whereas these two agents are also being used as an outpatient ambulatory care environment uh where they are suffering usually from um highdosese opioids that cause constipation that's not responding to traditional um laxative medications All right So this is again withdrawal Um nausea vomiting especially if you acutely uh reverse them and then they start having diarrhea Okay Um you'll see other things commonly reported on physical exam like they're yawning they're sweating they're having goosebumps Okay And so they're the pile erection of their hairs on their arms or extremities rhinora Their pupils are then going to dilate Remember in an overdose they're usually pinpoint very constricted um they can obviously start having anxiety their pulse and blood pressure then go up So again this is why we do it slow Now there is a condition called non-cardiogenic pulmonary edema that can also has been you know theoretically associated with reversal with Narcan Um the problem with this condition is it's not known whether it's the opioid itself that causes the pulmonary edema um or the rapid reversal So I'd like to talk just a minute a little bit about this non-cardiogenic pulmonary edema If you look here the incidence which I'm not sure is accurate because that's the evidence based on what is reported and not everybody is able to recognize or even see this So I'm not sure that that's accurate but that is the predicted or rough EV uh incidence which is obviously means it's very low doesn't happen often when we give somebody Narcan we rapidly reverse somebody but it usually develops within four hours after administration but can take up to as long as eight hours to develop And there have been case reports of that And the relevance of that note is that if somebody um does get opioid reversal for an overdose and then they again try to walk out of the hospital they may walk out of the hospital awake and alert But remember uh they can start to develop shortness of breath and worsening breathing because of this uh pulmonary edema that has at least been reported by case reports um as starting as much as 8 hours after the event And so that might be commonly missed even with discharge of the patient That's why checking vital signs and um talking to patients and not rapidly reversing these patients is somewhat relevant On X-ray you'll see fluffy diffused pulmonary infiltrates which is just consistent with pulmonary edema Most of these patients start to require supplemental oxygen So if you do a pulse ox and their O2 sats are on the low end of 90 the 90s or below 90 then you know you have a problem Many of times it resolves uh spontaneously within 24 hours And the reason that I said that we don't know if it's the rapid reversal or the opioid has to do with some of the u proposed mechanisms No one knows for sure Um but one of the reasons why there's this thing uh that they may think it's just the opioid that's doing it itself is this thing called uh a pulmonary capillary leak um syndrome basically um and the reason that this is proposed is because one of the first case reports ever published was by a physician from Johns Hopkins at um uh Sir William Oller who basically uh did a post-mortem you know exam on a patient who uh had received too much um o basically of a morphine like drug and that patient had pulmonary edema Well there was no Narcan given or even available at that time and so it wasn't from that And the reason that opioids might contribute to increases in pulmonary capillary leakage um has to do with their degree of um histamine release that causes vasoddilation and they can change the permeability that cause um some of that leaking itself And we know that to be true with things like morphine in particular which tend to be more likely to cause histamine release compared to other opioids But the other side of the coin here is that rapid reversal OB obviously causes a huge change in the hemodynamics both within the pulmonary vasculature and the cardiovascular system but also the sympathetic nervous system Because if you bring them rapidly right out and then they immediately go through withdrawal you've just generated not only a potential risk of negative introthic pressure as they take a deep breath in um and they um have this huge sympathetic surge that may push fluid acutely into the lungs And again that would make sense that it'll only last for 24 hours um as that situation resolves itself Um so many times you can you know kind of not there's really nothing to do other than monitor them So we admit them for 24 hours and then they usually end up getting discharged if it happens What about opioid induced serotonin syndrome You may be like what in the world Well there are two drugs or two opioids in particular that have been associated with modulating the activity of serotonin The first is uh demorall Okay And it's specifically the metabolite normine Normapiritodine has very little to no analesic properties and has been associated with lowering the seizure threshold causing confusion and so it's a very useless medication Most uh um competent hospital systems have restricted its use and eliminated it from the formulary There are some subsp specialcialized areas of medicine that will still use it as intermittent one-time doses and which is probably fine except in patients usually with underlying seizure histories The other drug is Tramodol or Ultramar And the reason uh that I bring that up is that Ultramar is a uh opioid uh agonist So it works on the muopioid receptor It's a recemic drug and both isomers do activate um and and turn on the muopioid receptor just like morphine would or any other drug But it also has a metabolite u and that metabolite is more potent at binding to the muopioid receptor Unfortunately or fortunately depending on how you you you consider it and when it's being used it does inhibit the reuptake of norepinephrine and serotonin So it has triccyclic antid-depressant like properties and that becomes somewhat relevant um especially if you co-administer um tramodol with other serotonin modulating drugs like triccyclic like SSRIs um and other some of the SNRI agents right and so that becomes very relevant to consider um because serotonin syndrome is quite honestly difficult to diagnose It's many time missed because the presentation is very vague But these patients are very confused They are very they have muscle tremors and uh muscle contractions almost like seizure- like activity clonic features They're febrile They're usually tacocartic and sweaty Sometimes they have seizures themselves Um this is just the diagram um of from of normapiritodine u generation uh normaline generation is going to be also greater if miritine is given by mouth So one of the things that should almost never be done is using demorall by the oral route I mean it shouldn't even exist to be honest with you There's absolutely no clinical indication whatsoever for the use of oral demoral And anybody that prescribes it is probably too old to be practicing medicine anymore and should retire in my personal opinion um the FDA should be embarrassed for even allowing this drug to be even on the market anymore in my personal opinion But um normaritine can accumulate It is renally eliminated And so if someone has renal impairment and you keep giving these uh repeated doses of demoral then your risk of of seizure and or these sort of other side effect potentials is going to um go up All right Now looking at drug interactions with some of these agents that can also increase the risk of serotonin syndrome I had mentioned SSRIs in particular but there are two SSRIs that you do need to be uh more cognizant of and the risk of serotonin syndrome theoretically is going to definitely be higher and that would be with peroxitine which is paxel uh or fluoxitine which is prozzac Um and the reason that those two SSRIs are more concerning with the use of Tramodol has to do with their inhibition of 2D6 Okay So they're pretty strong inhibitors of 2D6 enzyme As a result of that 2D6 uh inhibition they do not uh it prevents the uh formation of the active or more active metabolite of the muopioid receptor And so if you look up here the muopioid receptor you can see that the parent drug has a very weak activation of that receptor whereas the metabolite has a very strong activation of that receptor The reason that that becomes important is because activation of the muopioid receptor also has an impact on the release of serotonin If you lose that effect you now foster or facilitate higher levels of serotonin in the brain simply because there's a lower amount of opioid present The re and remember SSRI themselves are selective serotonin reuptake inhibitors But on top of that Tramodol which is parent drug will still work is known to inhibit the reuptake of norepinephrine and serotonin And so you see this higher elevation of serotonin risk in patients specifically on SSRIs and most specifically on Prozac and Paxel Um and so your risk of of serotonin syndrome theoretically is then going to be much greater as a result of that milo that you've created by the mixing of those drugs Now what about opioid induced constipation Basically everybody who gets an opioid is going to develop constipation It doesn't matter you do not develop tolerance to this problem And as a result um these patients anybody that gets a prescription of an opioid whether it's short acting agents long acting agents should probably receive not only counseling but some sort of laxative that can develop And the reason for that is it starts to create clinical confusion of our other problems So opioids themselves can stimulate the chemo receptor trigger zone in the brain and cause nausea but so constipation So if you're not moving um fecal content through the intestines and it starts to back up because you decrease parastoaltic movements from the use of the opioid as a result of doing that then you may cause nausea and vomiting simply because of the constipation not because the drug is binding the chemoceptor trigger zone although that is also happening Now you've have two things that are contributing to nausea and that can create problems There have even been case reports and I've even seen this in myself patients presenting to emergency department with paralytic ilasis from too much opioid use and not enough bowel regimen um treatment Okay Now some patients like in HIV patients have sometimes used opioids to treat their um anti-retroviral induced uh basically diarrhea So it basically their their bows are in parasaltic movements too fast and by giving them a little bit of an opioid okay uh back in the day people used to use tincture of opium and all that stuff um it slowed down the bowel paristalsis so it may not be a problem So you have to put it in the context of the patient So if a patient already has problems with loose stools and multiple stools throughout the day this opioid induced constipation may not result constipation It may normalize them All right this certainly going to be worsened by um triccyclic antidepressants that have anti and any drug um like even dyenhydramine or benadryil that has antiolinergic uh effects They're going to cause decreased paristalsis And so we should be giving these patients or talking to them at least about the use of laxatives and stimulant laxatives osmotic agents like biscodal senna lactulose Now there are a subgroup of patients that just don't respond to those and these are usually patients who are being treated with chronic opioids for um cancer related pain which you know they're not in many cases unless the cancer is somehow cured uh there many cases these drugs are not going to be stopped and so they're going to develop tolerance and physical dependence but they're also going to have chronic problems with constipation and so there's been a new drug class that is and I'm saying new but new in historical perspective um they are called peripherally acting opioid uh receptor antagonist um and those two drugs I mentioned earlier because we don't use them for opioid reversal in the central nervous system because they don't pass through the bloodb brain barrier that's methylonrexone and the lockxol And the reason that they don't pass through the bloodb brain barrier is because they are modified in their structure to become more hydrophilic or water loving And the more water loving the molecule is the less likely it's going to pass through the cell membrane And you can see that here the charge the molecule on methyl nrexone which is administered subcutaneously And we'll see here in a minute the lockxol all these oxygens carry partial negatives and as a result of all those partial negatives it increases the hydrophalicity of the drug and makes it less likely to pass through the cell membranes Okay So here's methyl trexone oristor and here's nlloxxol or moantic Um you can see that they're used for opioid induced constipation not for acute opioid reversal Methylrixone is given subcutaneously as an injection once a day which is less than ideal people would rather have a pill but again if you can't swallow maybe your cancer is you know nasoparangial cancer or something or maybe you can't swallow very effectively for whatever other reason um so subcutaneous injections can be useful for that situation but the nlloxxol should be administered in the morning on an empty stomach at least 1 hour prior to or two hours after a meal and so that's an important counseling point for its use Um obviously these drugs since they can reverse some of the opioid induced constipation can therefore then cause abdominal pain nausea and vomiting And so that sort of makes sense a little bit They'll develop some loose stools potentially It's usually not that bad You dose adjust the drug around the effect of of them right um really no significant issues other than if you look here at nlloxxol there is a higher risk of drug interactions It is a 3A4 substrate as well as a p glyoprotein substrate P glyoprotein is an e-lux cell membrane transporter and there's a lot of medications on the market that inhibit both of those All right moving on Opioid induced uh spasm of smooth muscle and specifically in this situation we're talking about the sphincter of odi So sphincter of odi uh is uh a band of muscle that is present right at the ampular vader Uh this is where the pancreatic duct uh empties into the small intestine And so if somebody comes in with acute pancreatitis uh they are digesting essentially their pancreas and it's very painful situation And so we do whatever we can to minimize stimulation of the GI tract which would then stimulate the pancreas because anytime you eat you're going to stimulate the pancreas And so these patients go um are are considered to be uh nothing by mouth or NPO We give them bowel rest to try to reduce the stimulation and activation of the pancreas On top of that we give them IV fluids But because it's a significant painful scenario um and since they're an NPO we are we're left with giving um pain medications via the parental route Now we don't use parental NSAIDs like ctorac or tordol We don't use uh you know ibuprofen which is available parentally endomethsin you know we don't use those drugs mainly due to the fact that because you're digesting the pancreas and acute pancreatitis you run the risk of hemorrhagic conversion there are a lot of blood vessels that come off of the aorta um not far away from the aorta that lead to and supply the uh GI tract um and so any damage to those vessels where they start to open up and bleed can cause pretty significant bleeding So we're left with pretty much using parental opioids to treat their pain Well unfortunately all opioids can cause some degree of spasm of the smooth muscle Um that can happen in the urtors of the genital urinary tract It can also happen at the sphincter of odi And if it causes a spasm of that sphincter of odi then what's going to happen is the fluids and the pancreatic enzymes cannot drain out of the pancreas and out of the pancreatic duct and as a result it can stay backed up and cause worsening pancreatic um disease um and worsening pain So if you end up giving somebody an opioid and their pain gets worse after giving the opioid then you need to be suspicious that you've caused a spasm of that band of smooth muscle which would then prevent the release of pancreatic enzymes which would then further cause more damage to the pancreatic pancreas itself Okay Um and so that is why we don't use uh NSAIDs and why we use why we have to be careful with even opioids although you're in a sort of a difficult scenario because they're in pain Now demorall historically has been said to be the drug of choice Um and it is not the drug of choice because many times pancreatitis can be from alcoholism And unfortunately uh patients that who stop drinking alcohol can then increase the risk of developing alcohol withdrawal seizures Um and obviously using demoral lowers a seizure threshold So that creates a bad situation But historically demorall um is thought to cause less spasm of the sphincter and that's probably true because it sucks as an opioid Remember its metabolite normine um has really no analesic properties It's a useless opioid and should not be used in practice I've probably said that a couple times Um at any rate um it does affect the urers as well All opioids like I said so there have been case reports of uh basically obstructive renal failure because they spasm the urer shut and therefore it can't drain urine Um there have been cases of bronchios the bron in our lungs um that can spasm kind of causing like a hyperreactive airway disease which would lead to shortness of breath This is obviously going to be worsened because opioids are known to cause histamine release which can cause that pulmonary leaking um and cause a little bit of fluid to accumulate into the um um alvei Now what about opioid induced uh myocus or neurotoxicity Well remember demorall causes CNS side effects Remember it lowers the seizure threshold It can increase the risk of serotonin syndrome It can incre increase the risk or theoretically it can it can increase the risk of seizures And so demorall um obviously is going to be worsened Uh the risk of this is going to be higher with larger doses that are repeated um especially in the presence of renal impairment because remember the metabolite is renally impaired Now morphine can also do this at some level again these are with high levels of accumulation of metabolites predominantly Um morphine has metabolites a three and six glucuronide metabolite and patients who are on very large doses of MS cotton say for example 600 900 milligrams a day right I mean these are huge doses these patients again can start to accumulate these metabolites and again this is worsened by renal impairment and it can cause some CNS side effects um and so these have been reported or somewhat of concern the itching is related to the histamine release that I mentioned earlier Some opioids are worse than others but it is not and is important to recognize it is not an IG mediated anaphylactic reaction This is not a type one hypersensitivity reaction It is not It is the drug directly stimulating the release of histamine that causes local vasoddilation which can also increase the permeability of the vessels causing like I said earlier concerns for edema and swelling and fluid shifts But it also can cause venodilation reductions in preload which can reduce mean arterial blood pressure So when we use sometimes morphine in pulmonary vascular congestion we're using it not only to make patients comfortable but to reduce the preload to reduce the vascular congestion inside the lungs and benefiting from that side effect However if somebody comes in let's say they've had a broken bone or they have multi-system trauma and they're hypotensive because of bleeding and they're in a lot of pain then giving somebody morphine in that situation yes while treating their pain can worsen their hemodynamic status and make their situation much worse So we have to be very careful about the use of this drug in the wrong situation And sometimes we utilize the effect of this in certain situations for a purpose um to that's uh you know like pulmonary vascular congestion You can give them a little bit of benadryil but obviously that's going to create a little bit of sedation There have been what we call lowd dose nlloxxone infusions and we're talking very very low doses um that are administered per hour um in the with a goal of not causing CNS reversal but more working on the periphery Um these people I used to say I'm allergic to codine which gets metabolized to morphine or they say I'm morphine have a morphine allergy and really what they're talking about is the itching So you know true morphine allergies are pretty rare Okay Um it is possibly related to the six hydroxal group on morphine that is seen with that because coding gets metabolized to morphine So u you know it's not usually um a true allergy It's usually because of this histamine release that is not a type one hypersensitivity reaction and nor and when you ask patients about side effects or allergies they always really report a side effect like they get oh it causes me to get nauseous well that's not a allergy that is a side effect that is actually known Um when we look at the um you know opioids you can see that codin and morphine have this six hydroxal group that's listed here on their structure which is different from the other opioids um which are usually more synthetic right these agents over here um we don't see that but more coding about 20 to 30% of it gets converted to morphine via 2D6 okay cytochrome P450 2D6 and So you see structural similarities between the agents obviously for that reason Um but that's what's thought to maybe if you have a true allergy okay which again is rare uh maybe due to that we talked a little bit about vasoddilation um risk because of the uh histamine release I've already kind of said that here It's known to reduce preload veno dilation but we would not want to use it in a right-sided MI or myioardial inffection because right-sided heart attacks are more preload dependent Um and so this would be one of those contraindications to using morphine um in acute coronary syndrome And and the reason I bring that up is because some people still teach this thing called Mona Mona being um you know Mona being M O N A M being morphine oxygen nitrates aspirin You should give that to all patients No you should not give that to all patients Um in fact there's evidence that oxygen may not be helpful It may be harmful Uh nitrates and morphine can uh reduce preload and can worsen right-sided MIS Morphine has been associated with potentially increasing platelet aggregation and worsening outcomes in N STEMI And so you you don't want to just use these drugs um you know willy-nilly and without thinking and out without knowing some of these things Um and obviously the vasoddilation could put somebody in make them hypotensive if they're septic um or and they're having pain syndromes which again is sometimes why we use a little bit of lowdose peripheral Narcan in those situations um but we don't generally you know um use it um in patients who are hypotensive for that reason So the the uh the opioids that cause the least amount of vasoddilation are fentanyl and hydromemorphone Um and so if you need something that causes the least amount of histamine release those are the ones I had mentioned Um stimulation of the chemo receptor trigger zone and the risk of nausea vomiting Yes constipation can contribute to that But also when you administer the drug IV push rapidly especially remember that drug is going to pass through the bloodb brain barrier and it can stimulate this chemoceptor trigger zone and make people vomit And so giving the drugs a little slower okay um administering them slower can reduce that amogenic potential Obviously preventing them from getting constipated also reduces their uh risk of nausea and vomiting Um opioids are really good uh as an anti-tussive agent They re they suppress or depress the cough reflex And so we use these um drugs a lot of times to uh treat cough um that hasn't been responding to other traditional agents Okay we don't really use it so much for um meiosis but it that's what it causes right It constricts the pupil Um now there are some dosing issues So when we think about side effects I've mentioned a couple drugs where there's metabolites that get renally eliminated I'd mentioned morphine in particular um that accumulates three and six glucuronide metabolites that can contribute to some of the neurotoxic myiocconic effects It can also cause some sedation effects um and so you have to be careful with morphine in that situation Fentanyl 75% of this drug is eliminated in the um kidney mostly as inactive metabolites So plus or minus but the good thing about fentanyl is it doesn't stick around for very long hydromemorphone which is a little bit more potent of an opioid compared to other agents Um you should consider a dose reduction if there's renal impairment where the clearance is less than 60 Uh most of the eliminated metabolites are inactive but 7% are active and so there's a theoretical increased risk especially in patients with more moderate to severe renal impairment on again more chronic doses one time dose here and there is not going to be of concern but it's the repeated doses that start to create problems especially things like morphine um in particular Now I didn't list uh demoral on here because quite honestly you shouldn't be using it right Like I've said before there's really no clinical use for it now that we have so many other medications All right let's talk a little bit about tolerance dependence and addiction Okay we have a lot of problems There's an opioid sort of people have said epidemic in our country and it is true Uh the number of overdoses and abuse of opioids has skyrocketed mainly because people don't prescribe the drugs correctly One and they don't follow advice They don't have contracts and people hop from one emergency department acute care setting and you have providers just signing over drugs which is not right either Any person who takes opioids okay whether it's appropriate or inappropriate on a daily basis will develop tolerance over time That means you're going to need more drug to exert the same pharmacologic effect and or will start to develop physical dependence You will become physically dependent on the drug Having tolerance and physical dependence is not addiction Addiction is a very different beast Okay when because there are people who are on chronic opioids high doses of chronic opioids who use them appropriately every day because they have a chronic medical condition that creates chronic pain syndromes Okay commonly we talk about or think about cancer But there are patients who have had surgeries broken bones they have scar tissue damage and nothing works and you start you can't they can't tolerate NSAIDs and all these other drugs because of side effects And so opioids are appropriate but they need to be used in the appropriate way One of the problems that creates addictive behaviors is the inappropriate use of immediate release agents in chronic syndromes Think about immediate release If you think about the kinetics these drugs have peaks troughs peaks troughs peaks troughs And these peak concentrations are from rapid absorption right Their immediate release Um and the they they start to mimic heroin I mean one of the reasons why heroin is so addictive is that it rapidly goes into the central nervous system and it stimulates the reward pathway and stimulation of the reward pathway causes you to get euphoria and people want that It feels good They like it and they want more of it right And so when you're using immediate release formulations inappropriately I'm not talking about PRN breakthrough pain management That's not inappropriate That is actually appropriate But when you use it around the clock to manage somebody's chronic pain that is not appropriate and you don't know what you're doing and you should stop practicing in healthcare to be all honest But when we do that we stimulate these high concentrations and these peaks that are rapid we start to get that euphoric effect We start to stimulate that reward pathway and that encourages wanting more of that And so when patients go from being under a contract with a physician or provider who knows what they're doing they're on stable doses they come in like they're supposed to to now they're hopping around from clinic to clinic now they're using the drugs outside of their prescribed intended dose and frequency of administration or they're stealing or they're buying it off the street or they're lying and they're manipulating the environment to get medication because they're trying to feed an addiction now that you have somebody who's an addicted patient right So that's very different So development of tolerance physical dependence does not mean you're addicted And so patients have been on drugs for a long time for appropriate indications and they stop taking the medication they will go through withdrawal Now no one is going to die from opioid withdrawal although they feel dying because it's a miserable experience Um but many of times it is not going to kill obviously going to kill somebody whereas coming off of a benzoazipene can cause seizures All right Um and so tolerance is something that is going to happen over time You need to expect that your patients are going to need higher doses over time Now what's going to happen is um it's not going to you don't develop tolerance to constipation and meiosis You don't develop tolerance to the histamine release you don't develop tolerance to the vasoddilation if you're giving it rapidly Um these are usually things like the tolerance is the sedation and the risk of respiratory depression You're not going to get that with over time You're going to need more dose to exert the same pharmacologic effect Okay And so patients who get on on high opioids sometimes need adjustments where you switch from one opioid to another And that's called opioid rotation where we switch drugs around to manipulate And one of the drugs that we will switch somebody to who's developed tolerance is methanone Methanone is known to antagonize the NMDA receptor and doing so may offset some of the tolerance potential and is one of the reasons why this drug is used for analesia after patients have been on high doses Because if you think about someone on MS cotton you know taking 600 900 milligrams a day because they've developed tolerance that's a lot of pills and they can develop what's called pill fatigue So when we prescribe these medications we should be prescribing appropriate quantities of immediate release only for breakthrough use Okay And then we should be prescribing appropriate use of extended release products to reduce those peak concentrations and that euphoric effect that can sometimes happen with immediate rapid release products And we need to be doing it under a appropriate patient relationship that usually is under contract where you are periodically evaluating systems that are now available in many states to look them up to see if they're getting prescriptions filled and other getting other doctors to fill them for them Looking for these patterns are appropriate for appropriate prescribing and or dispensing of these medications We all have an important part to play Nurses pharmacists physicians everybody has an important part to play in appropriately utilizing these drugs And so we um need to take this seriously because unfortunately people are um resorting to uh having you know problems and people are dying from it Now I'm not suggesting or advocating that you don't treat pain We need to treat pain when pain is present and it's real And just keep in mind and this is one of my last points Just because somebody isn't crying and writhing in pain doesn't mean they're not living in pain There are patients with chronic pain syndrome that they don't have the sympathetic response They're not tacocartic They're not sweating They're not trembulous You know like if I break your arm immediately you're going to be screaming right You're going to be in a lot of pain You're going to be crying But patients who have chronic pain syndromes learn to live with it And sometimes they suffer in silence because no one or they're afraid to ask or no one will listen to them Or if they ask for pain medicine the number one or first thing that people think about is "Oh you're an addicted patient I'm not going to give you pain medicine You're just a drug-seeking patient." Well no they may actually be telling you the truth and they're suffering in pain and we need to do something about that So uh I hope this overview gave you a nice broad exposure to the use of opioids and appropriately in practice but also their side effects that can affect you know common things that some that are life-threatening some that are not life-threatening but create problems both for the patient and also can create problems for the clinician