Welcome, everyone, to Module 4. In this module, we'll be talking about opioid pharmacology and dosing management. My name is Melissa Wymer. I'm a physician and associate professor of medicine at Yale School of Medicine. I'm also the associate program director of the Addiction Medicine Fellowship at Yale. Our learning objectives today are to describe opioid pharmacology efficacy and safety, and explain how to start, continue, modify, and discontinue or taper opioid therapy. Let's start with a case. This is the case of a 52-year-old man with chronic cervical radiculopathy, cervicalgia, and hypertension. He's been taking naproxen 500 milligrams twice a day for 10 years since undergoing spinal surgery that was not effective. He does not have depression or history of substance use disorder. He has tried multiple medications, including tricyclic antidepressants, gabapentin, pregabalin, lidocaine patches, acetaminophen, and duloxetine. He has tried steroid injections and Botox with little improvement. He works full-time and exercises three days a week. He stretches five times a week. He requests an opioid to help with pain that is not relieved by his non-steroidal medication. He's not currently taking an opioid. Let's review the pharmacology of opioids. As you can see here, there are multiple different types of opioids. They're broken down into the natural and semisynthetic opiates and the synthetic opioids. Collectively, they are termed opioids, which is the more inclusive use of the term. When we're talking about natural and semisynthetic opiates, we're really referring to those medications that are derivatives of morphine and codeine. This can include diacetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone. Synthetic opioids are slightly different and are not derived specifically from opiates. These include methadone, meparidine, and fentanyl. This can be important when you're thinking about where you're going to see these medications show up or these substances show up on a urine drug screen. It's important to recognize that opiates will show up on an opiate drug screen, but synthetic opioids, such as methadone, meparidine, and fentanyl, will not show up on your typical opiate screen. Opioids activate the mu-opioid receptor. In so doing, they turn on descending inhibitory systems in the brain, they prevent ascending transmission of pain signals, they inhibit terminals of C-fibers in the spinal cord, and they inhibit activation of peripheral nociceptors. They do have a real benefit for the treatment of pain. However, one of their activities that we can't prevent when a patient is given an opiate is that they also activate the reward pathway in the midbrain. This unfortunately is an activity of the opioid and cannot be bypassed when given an opioid to a patient. So there are different examples of different choices of the different opioids you can provide to a patient or prescribe to a patient. Typical opioid agonists, also known as full mu agonists, would include morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, methadone, and oxymorphone. Partial opioid agonists, this typically refers to buprenorphine. And then you have your dual mechanism opioids, such as tramadol and dipentadol, and these typically work on the serotonin receptors in the brain as well. We don't use this medication very often, but there's also something, a different opioid that is a mixed agonist antagonist. And again, we don't use this very often, but it's important to know that it does exist. There are different choices that we have when prescribing an opioid. We have immediate release opioids, and then we have extended release opioids. The immediate release opioids, you can see all the various combinations here listed in the list on the left. The extended release opioids are here listed on the right. Important to note that in addition to your typical short-acting medications, you also have methadone, fentanyl transdermal patches, and buprenorphine transdermal patches. Typically, we're using immediate release opioids for acute intermittent pain. And then we're typically using the extended release long-acting opioids for pain that is constant, unremitting, or continuous, and patients are having chronic pain that is not being relieved by other factors. So when we're thinking about the different formulations, we have certainly an oral route that we can give immediate release and extended release opioids. You also have transdermal applications such as the fentanyl transdermal patch or the buprenorphine transdermal patch. This can be helpful in those folks who are unable to be taking a medication orally or have other issues that are reducing their absorption. The oral route of administration can be given by buprenorphine, which can be used off-label for the treatment of chronic pain. There's also a buckle formulation of buprenorphine that is indicated for the treatment of mild to moderate pain. When thinking about the different choice for an opioid, you want to think about the duration and onset of action. Short-acting opioids can increase the risk of opioid withdrawal-mediated pain given that if you take them for a long enough period of time, they have an increased effect quickly, but then the effect actually wears off very quickly as well. So if you have someone taking a short-acting opioid for a long period of time, that short-acting opioid can have what we call periodicity of effect. And when the effect of it wears off, this can cause the patient to have a feeling of opioid withdrawal. Patient's prior experience is actually important when we're thinking about what opioid to choose for a patient, because there are many different mu-opioid receptor polymorphisms, and they're individual differences in pharmacokinetics and pharmacodynamics. So a patient may say to you that they find a medication such as oxycodone or hydromorphone more effective for their pain. It's important that you're listening to the patient's report, taking that into account when you're considering which medication to use for the patient. Also important to note that although there are some new abuse deterrent opioids that have been developed in an effort to reduce a patient's misuse of opioids, there are no proven abuse-resistant opioids or formulations. So even when developed into an abuse deterrent formulation, some of these, the opioid abuse deterrents can be overcome. When we're also thinking about the opioid choice, we want to think about the patient, who is the patient, and what is their experience with opioids in the past, and we also want to think a little bit about their tolerance to opioids in general. When we're considering an immediate release or short-acting opioid, these are really indicated, particularly in the acute pain setting, for those patients who don't have any tolerance to opioids, we're going to want to use a lower dose of those, and in those patients who are opioid-naive. Again, you'd want to think about utilizing these medications in patients who have intermittent or occasional pain or incidental or breakthrough pain when they are prescribed an extended release long-acting opioid. There's no hard and fast rule that if a patient has long-term pain that you have to switch that patient to an extended release formulation. There are some patients who do better on immediate release opioids over time. However, again, as we talked about the periodicity of effect of the immediate release opioids, it's important that you're thinking about that if you have a patient who's taking these medications for a long period of time. The extended release long-acting opioids are not indicated for the acute pain treatment. These really are for patients who have struggled with pain that's persisting for in a chronic period. The duration generally is greater than three months. We're not utilizing these in the acute pain setting, and we certainly want to be careful about their use in that setting. They're not indicated for, say, post-surgical pain or in the perioperative setting. You also want to make sure that the patient has tolerance to opioids. These are not medications that you would start if the patient has no experience to opioids in the past. Generally, they're indicated for patients who have constant severe around-the-clock pain that's not getting better despite use of the immediate release opioids. And generally, what we're trying to do is we're trying to stabilize their pain relief so that they're not having to use multiple doses of the immediate release opioids. Importantly, the formulation is very important to maintain the extended release long-acting effect of the opioids. These extended release opioids should not be broken, chewed, or crushed. One exception to this is methadone, which actually can be crushed and given as a slurry because part of its long-acting nature is part of the makeup of the medication as opposed to the formulation. However, for every other extended release or long-acting opioid, you want to be careful that it's not broken, chewed, or crushed. And certainly, because of risks of unintentional overdose and other side effects, we want to be careful about the dose that we're starting on these medications. And if we're increasing the medication, we want to do so very slowly and monitor carefully. So there are some uncertainties around the immediate release short-acting opioids versus the extended release. There is insufficient evidence to determine whether the extended release opioids are more effective or safer than the immediate release opioids. And there's debate whether bolus dosing of the immediate release or continuous exposure to extended release is more likely to result in tolerance, fibrillaguzia, or addiction. Really, when we're thinking about which medication to choose for a patient, we want to choose a medication that best meets the patient's needs, so we should be individualizing that treatment based on patient or individual's needs. Certainly, ongoing exposure to an opioid can cause tolerance. This is, as we talked about opioids activating the reward system, this is another unintended or, not unintended, but this is another adverse effect that occurs from utilizing an opioid over time. How long does it take for this to occur? That can actually occur over a week and a half to two weeks at a sufficient dose. What tolerance means is that basically patients are feeling the need to have a larger dose of the opioid in order to maintain the original effects, including analgesia, of the opioid. There does appear to be inter-individual variability in who develops tolerance and how long it takes to develop tolerance. It's quoted here to say, there appears to be no limit to the development of tolerance and with appropriate dose adjustments, patients can continue to obtain pain relief. That being said, there is a dose at which you want to think about the real negative effects of these medications. If you're feeling that you need to increase the dose repeatedly over time, it could be that the patient is not necessarily benefiting as much as we would like them to and the risks of the medication could be increasing. Certainly, though this has been quoted and discussed in the past, I think our new understanding is that at a certain period of time, doses can exceed their efficacy and certainly can become risky. There's no theoretical dose ceiling for full opioid agonist, but again, you have to be continually weighing the risks versus benefit. It could be that at a certain point in time, you really want to rethink the therapy in general. We certainly do recognize that morphine equivalent doses greater than 90 milligrams can increase risks to individuals for the development of unintentional opiate overdose, which is a real problem. You can see here that there is a dose response relationship for respiratory depression. Especially with a full agonist such as fentanyl, as you increase the dose of that medication, you can see that it will have effects on respiration and at a high enough dose, it will stop respiration altogether. This is different from buprenorphine, which is a partial opioid agonist, which actually at increasing doses does have a ceiling effect where it does not cause ongoing reduction of ventilation. It is of the opioids that we have available, thinking about risk of overdose related to hypoventilation, we do see that buprenorphine has this property of higher dose not causing a higher reduction in ventilation. Let's talk about some of the different opioids and their unique properties. We talked a little bit about the transdermal preparations, namely fentanyl and buprenorphine. These have convenient dosing. Fentanyl can be dosed every 72 hours and you see the different dosing regimens there. Buprenorphine is given every seven days with the different dosages listed there. They do have a slow peak onset, typically takes about 24 to 72 hours for them to reach steady state and they also have a delayed offset. They provide sustained release of the medication, but you have to have a place for them to be put on the body that will allow for that predictable blood flow and have adequate subcutaneous fat. Those patients who have extreme cachexia could actually not have a sufficient subcutaneous fat for these medications to be safely given. We do generally recommend that they're given on a place such as the upper arm or the upper back where there is adequate and predictable blood flow. The absorption can be increased when an individual has a fever or broken skin. You can increase the absorption of transdermal formulations if you were to place a heating pad on the formulation or you were to be submerged in a hot tub. We don't recommend that patients are doing this. Absorption can also be decreased with edema. And then important to note that the metal foil backing on these formulations is not compatible with an MRI. Methadone is a different long-acting opioid as we kind of alluded to in the past. So the problem, not necessarily the problem, but features of methadone are that it has a very long variable and unpredictable half-life. So that can lead to it sticking around for a very long time. The analgesic effects of methadone last for about six to eight hours, but its half-life can last anywhere from 20 to 120 hours. There are some risks of QTC prolongation, which can lead to a fatal arrhythmia known as Torsades de Pompes. Some possible advantages of methadone, however, are that it has NMDA receptor antagonist properties. This can potentially reduce opioid tolerance so that patients can take the same medication at the same dose for a longer period of time. And given its NMDA receptor antagonism, it may have a better efficacy in neuropathic pain explicitly. It has no active metabolites and it's inexpensive and can be given in small dosage units of five milligram tablets. Tramadol and Dipentadol, in my experience, are poorly understood opioids. It's important to note when you're prescribing these, and I see a lot of people prescribe these, particularly in the acute setting, that these are dual mechanism opioids, meaning that they have both an opioid agonist effect as well as a serotonin effect. So it's important to note, particularly in patients who are, say, in the hospital or those who are on multiple different medications, that there are possible important drug-drug interactions that can occur from the use of these medications. Looking at Tramadol explicitly, this is a weak mu-opioid agonist and it has norepinephrine and serotonin reuptake inhibitor properties. It can increase seizure risk and it can cause physical dependence. It's not a scheduled medication, but it does certainly have addiction potential. And we also find that it does not have a therapeutic dose benefit over 400 milligrams per day. Typically, we would recommend that you don't exceed that dose per day. Dipentadol is another dual mechanism opioid. It has stronger opioid agonist effects than Tramadol and it is a norepinephrine reuptake inhibitor. It also has risk of seizure, physical dependence, and it is a controlled substance with addiction potential. So let's talk a little bit about opioid safety and risks. Allergies to opioids are relatively rare. New data is emerging about the possible immunosuppressive effects of opioids, and we've seen that opioids can increase the risk of pneumococcal disease and community-acquired pneumonia. There can be organ toxicities explicitly for the suppression of the HPA axis, and you can see some men in particular with the development of secondary hypogonadism. At doses greater than 50 morphine equivalents, we've seen an association with fracture risk and the adverse effects are listed here. We've mentioned some of these, but you do have patients who develop pretty significant nausea, sedation, constipation, urinary retention, sweating from the use of medications, opioid medications. Paritis can also be a side effect, and then respiratory depression is one of the most concerning adverse side effects if a patient is undergoing an unintentional opioid overdose. So respiratory depression that occurs, it occurs at the medullary respiratory center. This is when you have a decrease in the tidal volume and minute ventilation. This would be a right-shifted CO2 response. This would typically be seen as hypercapnia, hypoxia, and decreased oxygen saturation. It's immediately life-threatening, and generally prior to a patient having significant respiratory depression, you will see that they are sedated. So sedation is the first sign of a patient at risk for significant respiratory depression, and that is an important warning sign that should not be missed. Managing opioid adverse effects, typically nausea and vomiting resolves in a few days. We can use the anti-emetics or switching the opioid to see if that benefits or reduces those symptoms. If a patient is experiencing sedation, which can typically be seen during the initiation or change of a dose of a medication, this would be a very specific warning and an indicator that the dose of the medication needs to be reduced or reconsidered entirely. Constipation is a very common side effect of opioids and should be anticipated. Patients who are taking long-term opioids or high-dose opioids in the acute setting should be given stool softeners or other agents to ensure that they're having daily bowel movements. Pruritus can usually be resolved by switching opioids or giving antihistamines, though I would caution the use of high-dose Benadryl, which can potentiate the effects of opioids. Urinary retention is another side effect of opioids, and this would typically need to be resolved by switching the opioid. We haven't yet really talked about the risk of overdose or addiction, but this is another medication-related risk factor of opioids, particularly if they're given in a longstanding approach. We do see, and there's good data to suggest, that those patients who are receiving greater than 100 morphine equivalents per day are at risk of unintentional opioid overdose and addiction. Long-term opioid use greater than three months can also place patients at risk for overdose and addiction. The extended-release long-acting opioid formulations can put patients at risk for overdose as well as starting medications. The first two weeks of starting an extended-release long-acting opioid are the highest risk time for opioid overdose. Combining opioids with benzodiazepines also places patients at risk for unintentional opioid overdose. The CDC recommends that when possible, you avoid prescribing opioid pain medications and benzodiazepines concurrently when possible. There are times, and it could be indicated for some patients, but if they are prescribed together, you want to be monitoring the patient very, very closely. There are certainly patient-related risk factors that put people at risk for overdose and addiction as well, and these are risk factors that you want to take into account whenever you're prescribing opioids for a patient. Patients who have a mental health disorder such as depression or anxiety are at risk for overdose and addiction. Those with a personal or family history of substance use disorder are at risk for overdose and addiction. Family history of substance use disorder can be a risk factor for misuse of opioids over time. Being an adolescent can place patients at risk for addiction. Being greater than age 65 can be a risk factor for overdose. Sleep disorder, breathing is a risk for overdose. Legal history here is noted to be a risk for misuse, though this doesn't mean that you shouldn't prescribe patients opioids if they have a legal history. Having a history of sexual abuse in childhood or later can be a risk for misuse, and then having a prior history of opiate overdose means that patients are at much higher risk for overdose in the future. High-dose opioids, which are typically indicated for a dose of opioids greater than 90 milligrams of morphine equivalents, can be indicated for some patients, but it's important to note that when they are indicated and they are prescribed to a patient, you want to manage these patients as higher risk patients, and you'd want to increase the monitoring and support. Higher doses are more associated with tolerance, hyperalgesia, reduced function, and overdose. Again, it doesn't mean that you can't use the higher doses of opioids. However, it does mean that if you are prescribing these, you want to be carefully monitoring patients' response to the opioid and any side effects that they may be having. We also want to think about pill burden to patients and the active number of pills that are in circulation. And it's important to note that when patients are prescribed higher doses of opioids, they are also given higher pills, higher number of pills. When we look at where people are receiving prescription opioids when they're misused, it's important to note that many of them are receiving them from a friend or a relative, and these are freely being given. Just important to keep this in mind. Again, it doesn't mean that you can't ever use higher doses of opioids, but you just want to do so carefully, and you want to make sure patients are aware of the risks of giving these medications to someone who's naive to them. And you also want to just think about the effect on public health and community health when you're prescribing these higher doses. There are the collateral risks of opioids. So if a young child were to ingest these medications, that could place them definitely at overdose risk. Adolescent experimentation can lead to overdose and addiction, and we can mitigate these risks by encouraging patients to safely store and dispose of any medications that they have in their personal belongings. So we do recommend that they're using lock boxes or other safe means of keeping their medications safe. It's important that both the patient as well as their family members are aware of the risks of the use of opioids and are aware of the way to utilize naloxone for overdose treatment if a patient or a person exposed to opioids were to have an unintentional opioid overdose. So we do recommend that all patients who are prescribed opioids have ready access to naloxone and understand how to reach out to poison control or their prescribers if they're having any side effects. Initiation of opioids. So some general principles you want to keep in mind are that when we're starting opioids, we want to view this as a short-term approach. Think about it as a therapeutic trial. Just like any other medication, you're going to be thinking about the effects of the medication, monitoring the medication, and thinking about whether this medication is truly benefiting the patient. Just because we've started this medication doesn't mean that we need to continue it for the long term. When you're starting it, you want to start low and titrate cautiously. You want to avoid doses that are greater than 90 mg morphine equivalents. Certainly in a patient who is opioid naive, giving a dose higher than 90 mg of morphine equivalents would be a risk factor for unintentional overdose. You want to think about the opioid selection and initial dosing, which should be individualized based on the patient's health status and previous exposure to opioids. And you would not want to start an extended-release long-acting opioid formulation on a patient who is naive to opioids. Thinking about the analgesic benefit of opioids, generally, immediate-release opioids are providing pain relief between three to six hours. Extended-release opioids are providing analgesia that's between six to 24 hours, depending on the formulation. When we're thinking about the starting dose per day, it's important to note that you could develop opioid tolerance at the doses that are listed here. So we discussed before opioid tolerance and how opioid tolerance is important. So it's important to note that, say, even a patient in the perioperative setting who's prescribed 60 mg of oral morphine per day for more than seven days can actually go on to develop opioid tolerance. And it can be difficult for that person at that point in time to develop opioid tolerance. So even a patient in the perioperative setting who's prescribed 60 mg of oral morphine per day for more than seven days can actually go on to develop opioid tolerance. And it can be difficult for that person at the end of that seven days to immediately stop those medications. So thinking about this is important in managing this and tapering patients off of their medications may be necessary in some instances. So we talked a little bit about how the different medications, how long they work. So when we're thinking about when to give these medications, it's important to note that the short-acting medications, you can see how their benefit will occur with the red line. So you see the intermittent bolus administration where there is more rapid onset of pain relief, but there's also that quick offset. With the long-acting extended release medications, what you see is the onset of pain relief actually takes a little bit longer, but you can see that the analgesic benefit lasts longer as well. So sometimes this schematic is helpful to understand yourself as well as help patients understand that particularly if they have chronic pain, that if they're only using the intermittent short-acting medications that in that period of time when the medication is wearing off, they can start to experience pain. And they can also experience withdrawal, which can actually be felt as pain. But they can start to have these on and off effects. And for long-term pain relief, that could be an indication that the short-acting medications really aren't the most appropriate medication to use for chronic pain. However, in the acute pain setting, generally the short-acting medications are quite effective. You just have to worry about their effect wearing off over that three to four-hour period of time. You can see here some of the different starting doses of the various formulations. I'm not going to read them out for you, but just keeping in mind that when you are starting these medications, you're utilizing the appropriate starting dose. I think people have gotten pretty savvy about this, but just recognizing that they are different doses here based on the different potencies of the opioids. You can see some various considerations there as well of when you might use one medication over another. I think a classic example of this is in a patient with, say, acute renal insufficiency or chronic kidney disease, you really wouldn't be using morphine explicitly because that has various metabolites that can build up and cause issues. The standard-release long-acting opioids doses are listed here as well, again, to keep in mind when you're considering whether to start any of these medications and some of the other factors to take into account. We talked a bit about how methadone is different, has a longer half-life, and has some properties specifically for neuropathic pain. One of the key factors of methadone is that you really, if you're going to use it for the treatment of pain, we need to be starting at low doses. It needs to be individualized based on the patient's prior opioid exposure. You would not want to use methadone for a patient who is opioid naive because methadone is very potent. We would also want to think about the risk factor for QTc prolongation. Obtaining a baseline EKG can be helpful to assess that risk. In patients who have chronic pain but who are opioid naive, meaning that they're on doses less than 40 to 60 morphine equivalents, the starting dose of methadone is two and a half milligrams three times a day, so a low dose of methadone. You would not want to increase the dose for the patient any more quickly than every five to seven days. Really, this dosing regimen is indicated for the treatment of pain, for the treatment of opioid use disorder, and for the treatment of chronic pain. In the inpatient setting, however, you can legally and effectively start methadone, but again, the dosing regimen is indicated for the treatment of pain, for the treatment of opioid use disorder, and for the treatment of chronic pain. You wouldn't want to be utilizing methadone in the outpatient setting for the treatment of opioid use disorder. In the inpatient setting, however, you can legally and effectively start methadone, but again, the dosing would be quite different, and that's outside of the scope of this talk, but I would encourage you to look at some of the other PCSS education to get some more information about how to initiate methadone for the treatment of opioid use disorder. There are some various resources listed here that I would encourage you to check out if you have questions. It's also important to recognize the different equivalencies of the different opioid medications. This table comes from the CDC. They also have a mobile app that I find quite helpful. You can download it on your phone. So if you're not clear what the morphine equivalent doses are for a patient, you can type that into this calculator, and it will tell you what the morphine equivalents are per day. I think it's important for us all to be using the same calculator. I think it's helpful. The CDC has developed this table, and so when we're thinking about the morphine equivalents per day, I would encourage everyone to utilize this calculator so that we're all really talking about the same morphine equivalents per day and the same way to calculate them. So let's do some examples here of how to calculate morphine equivalents per day. So fentanyl 25-microgram patch. So the way to determine what the morphine equivalents per day would be to multiply the 25 micrograms by 2.4, which is the conversion factor, which would give you a morphine equivalents per day of 60 milligrams. The most common error I see is that people are trying to take into account the 72-hour property of fentanyl. We don't take that into account when we're determining the morphine equivalents per day. When you place on a fentanyl patch, you are providing 60 milligrams of morphine equivalents per day for the entirety of the time the person has the fentanyl patch on their body. So this here, 60 milligrams morphine equivalents per day, is how we would interpret the morphine equivalents of a 25-microgram per hour patch, even if given every 72 hours as indicated. Many patients are on multiple different medications. So if we were trying to develop or calculate the morphine equivalents per day for a patient who's prescribed hydromorphone, 2 milligrams every 4 hours, plus extended release oxycodone, 60 milligrams twice a day, the way to do that would be to multiply the 2 milligrams of the hydromorphone times the 6 tablets because the patient's prescribed every 4 hours. That would give you a total of 12 milligrams of hydromorphone per day. We would multiply by the 4 conversion factor, and that would give us 48 milligrams morphine equivalents per day. The oxycodone total dose per day is 120 milligrams. If we multiply by the 1.5 conversion factor, that gives us a total dose of 180 morphine equivalents per day. In total, 48 plus 180 milligrams gives you 228 milligrams morphine equivalents per day. Finally, for methadone, methadone you saw had differences in the different dosing levels of the different conversion factors. But for a total daily dose of 60 milligrams, it has a conversion factor of 10. So when we're thinking about the morphine equivalents per day for a patient prescribed 60 milligrams of methadone, that is equal to 600 milligrams of morphine equivalents. I would encourage you to do some of these calculations on your patients. Again, it's important that we're utilizing the same conversion factors. Utilize the CDC guideline and start to recognize what the total doses of opioids are for the patients that you're prescribed opioids. Opioid overdose does increase with the dose of opioids. You can see here, based on the study that was done in 2010, how the hazard ratio of patients prescribed the different doses of opioids. As the dose goes up, the risk of fatal overdose or any overdose goes up. And this was replicated in both patients in a VA population and those patients who are part of an HMO. So at doses greater than 100 milligrams morphine equivalents, you have the hazard ratios increasing between 7.2 and 8.9. So we do know that as dose increases, so does risk of unintentional opiate overdose. So we're going to go through some other cases here. So the first case, remember, we talked about was a patient with chronic neck pain. And he was not receiving an opioid at the time. And he was trying lots of other non-opioid medications, but not finding relief. So the patient was in constant pain. He's trying to do what he can to self-manage. He's stretching. He's active. He's not opioid tolerant, meaning he does not have exposure to opioids in the past. He's asking for an opioid for activity as needed so that he can be more active. For a patient such as this, the best initial choice would be an immediate release formulation such as tramadol, oxycodone, or hydrocodone that we could dose once to twice daily as needed for activity. We could use tramadol, but again, also think about the possible other medications this patient is prescribed. If he is prescribed a different serotonin-acting medication, you would want to think potentially about the drug-drug interactions. So for this patient, we could prescribe 28 tablets per month to determine his response to treatment and opioid usage. It's possible that he really finds that he doesn't need to take this every day, but prescribing it for a month as a therapeutic trial, as we've discussed, would be a helpful way to determine if he's benefiting and if he really needs to take the medication this often. If his pain were to progress and he started to need immediate release formulation of opioids around the clock, when would you transition him to an extended-release long-acting formulation? So this would be indicated when he is having worsening pain on a consistent basis when the opioid dose wears off. It could also be indicated if and when he develops opioid tolerance and if his pain progresses. You decide to switch him to immediate-release oxycodone, 10 milligrams every six hours, as needed for extended-release long-acting oxycodone, 20 milligrams twice a day. And he will utilize self-management techniques for breakthrough pain because his pain has progressed. Now let's talk about opioid rotation. And I would just say and caution you, if you're not experienced in switching opioids in patients on long-term opioid therapy, you would want to seek expert consultation from someone who has done this. More often, clinical pharmacists in particular can be quite helpful in this regard. So the definition of opioid rotation is when you are switching from one opioid to another to improve the therapeutic outcome and or to avoid adverse events due to the current drug. The theory is that there are variations in activity at the opioid mu receptor, and this may lead to improved benefit versus the development of adverse events. When switching opioids, we want to consider the patient's wishes, therapy adherence, cost, insurance concerns, and risk factors. When switching opioids, we want to consider the patient's wishes, therapy adherence, cost, insurance concerns, titration, which can lead to adverse effects or poor analgesia and any drug-drug interactions. Other reasons why we may switch to another opioid are to restore analgesic efficacy, limit adverse effects, and decrease overall morphine equivalence per day. And again, you know, this is really based on the large inter-individual variation we have in patients' response to opioids. And we know that there are individuals have different variants of opioid mu receptors. However, the evidence for this is really based on surveys and anecdotal evidence, and it is promising, but we need more validation to see if this is really beneficial to patients and really improves overall analgesia. When considering an opioid rotation, we want to, again, determine what the patient's total dose of morphine equivalence is per day. It's important to note that when we're looking at the different opioid conversion tables that have been developed, and again, I recommended you all look at the CDC guideline, those conversion tables are based on the patient's total dose of morphine equivalence per day. And again, I recommended you all look at the CDC guideline. Those conversion tables are really derived from relative potency ratios that are using single-dose analgesic studies in opioid-naive patients. So it's important to recognize that those conversion tables need to be considered with that in mind. And the conversion tables are also based on limited doses or ranges of doses and does not reflect the clinical reality as a chronic opioid administration. They may not be as reliable due to the individual pharmacogenetic differences as well. So we need to keep that in mind and also recognize that most tables do not adjust for incomplete cross-tolerance. So when we're thinking about transitioning a patient, you'd want to correct for cross-tolerance in any sort of conversion that you're doing. So one of the things we're trying to take advantage of when we change opioids is this variable response to opioids, given that we know there are different polymorphisms in the opioid receptor gene and that some patients will benefit from one opioid over another. And this can differ by individual opioid and by individual patient. So we talked about this a little bit, but just to reiterate, not all patients will respond to the same opioid in the same way. And a trial of several opioids may be needed to find acceptable balance between analgesia and tolerability. Just to reiterate the fact that equal analgesia does not, it's not the same as a conversion table. So again, keeping this in mind, anytime you are rotating a patient and you definitely have to correct for cross-tolerance. So seek expert advice if you're not experienced switching opioids and patients prescribe long-term opioid therapy. In order to even consider an opioid rotation, you'd want to calculate their current morphine equivalent per day using an opioid conversion factor calculator like the CDC one that we showed you. For all opioids other than fentanyl or methadone, apply an automatic dose reduction window of 25 to 50% lower than the calculated equal analgesic dose. You'd want to stop the previous opioid and start the new opioid. You would not want to overlap doses and you'd want to reassess the patient frequently. If you're doing this in the outpatient setting, you would want to be able to have either a phone check-in or other sort of check-in probably the day or two after you undergo this rotation. And then you'd want to see the patient the next week. Methadone is a little different. So if you are rotating a patient from a dose for the treatment of chronic pain from less than 40 to 16 morphine equivalents, remember that this would be considered an opioid naive patient and you would start the patient on a methadone dose of two and a half milligrams three times a day, not increasing the dose more than five milligrams per day every five to seven days. If the patient were prescribed greater than 16 morphine equivalents per day, you would start methadone at a dose that's 75 to 90% less than the calculated equal analgesic dose, but no higher than 30 to 40 milligrams per day. The initial dose increases should be no more than five to 10 milligrams daily every five to seven days, and much lower doses are prescribed when switching to methadone due to the incomplete cross tolerance and the long half-life of methadone. So let's give an example of this. So after one year, the patient's analgesic response to oxycodone extender release 20 milligrams twice a day wanes. You decide to switch him to extender release morphine 50 milligrams twice a day, a dose that is corrected by 50% for incomplete cross tolerance. So for the instructions to the patient, you would tell them to stop the oxycodone extender release 20 milligrams twice a day, wait 12 hours, which would be the effect of the oxycodone, and then at that time start the new medication, the morphine extender release 15 milligrams twice a day. And you'll see that when we do this, we have effectively reduced the patient's overall morphine equivalents per day, and this is to be expected. And this could be one way that for a patient who's prescribed high opioid doses, you can actually reduce overall morphine equivalents per day with an opioid rotation. Now let's talk about discontinuing or tapering opioids, which is a really important topic and something that most of us never received formal education. So when thinking about stopping or discontinuing opioids, it's important that we're evaluating the risk benefits and establishing an indication for the opioid tapering. Are we stopping or discontinuing because we think the patient has developed a substance use disorder? This can include opioids, alcohol, or other substances. Are we concerned about diversion? Are we concerned about immediate harm, such as aspiration, hypoxia, bowel obstruction, overdose? Are we concerned because the patient's refusing any sort of monitoring for us to ensure that the patient is safe taking these medications? Are we stopping or reconsidering therapy because there's been a therapeutic failure, meaning that the patient's no longer really benefiting from the medications despite taking them? Or is there a risk for future harms? So the patient is on a high dose of opioids or they're concomitantly receiving benzos, and we're really concerned that over time this may harm the patient or lead to harms such as overdose in the future. Importantly, any time we are reevaluating the opioid therapy, it's important to use this risk-benefit framework. So we're not asking, is the patient good or bad, does the patient deserve opioids, should this patient be punished or awarded, should I trust the patient? Rather, it's important that we are asking, do the benefits of opioid treatment outweigh the untoward effects and risks for this patient or society? So have we determined that there really is, you know, we need to rethink the treatment? When thinking about discontinuing opioids, you do not have to prove addiction or diversion, so certainly you want to make sure that you are offering patient treatment if you're determining that they have a substance use disorder, but it is important that we are assessing and reassessing the risk-benefit ratio. If the patient is unable to take opioids safely or is not adherent with monitoring, then discontinuing opioids can be appropriate even in the setting of benefits. We need to determine how urgently the discontinuation should be done based on the severity of the risks and harms. We need to document the rationale for doing so and make sure that the patient is part of that conversation. And we need to determine if the opioid needs to be tapered due to physical dependence. Physical dependence is a very complex issue, and we need to adequately understand how to taper these medications, particularly if we have been engaged in the prescription of them over the long term. Even when discontinuing opioids, it's important to remember that you are abandoning the treatment, not the patient. Even if you are no longer prescribing opioids to the patient, you need to continue to see the patient, offer them pain treatment, make sure that they're tolerating it well, refer for additional treatment, and make sure that they continue to be safe. Discontinuation of opioids can be a high-risk period of time for patients. It's important that you're supporting their mental health and that you're ensuring that they are continuing to receive adequate treatment. Step two, you want to create a plan and then start the taper. It's important that you're discussing the goals of the taper with the patient. How and when will you know if this taper has been successful? You want to talk with the patient about the dose target, the timeframe. Talk with them to the best extent you can to maintain current level of analgesia. Understand that in the acute period of reduction of opioids that there could be an increase event of pain. This is somewhat to be expected, but we do expect that that will level out over time. If it does not, then we need to rethink or slow down the taper. We need to discuss the potential withdrawal symptoms. Help the patient understand that there could be some withdrawal symptoms which could manifest themselves as an increase in pain. Make sure the patient is aware of how to contact you. Schedule close follow-up and nurse check-ins. During this period of time, I also find it helpful to identify one self-management goal, something the patient can do to help distract them during this period of time. Increase other pain-relieving activities which are active, which could be stretching or non-medication modalities could be the use of other adjuvant medications. In general, you want to recognize that this can be a challenging time where patients may need additional support. It's important that they are ready and able to access that support when they need it. You can see here some different recommendations of how to approach an opioid taper or cessation based on the indication for the taper or cessation. I think the most important thing that I want you to understand from this table is that these are not hard and fast rules. However, it is important that you're understanding why you're engaging in the taper and that you are offering the patient treatment if they need it, particularly if they've developed an opioid use disorder specifically, and that you are following and continuing to support the patient. For the indication of a substance use disorder, you would want to engage in a taper that is immediate and refer for treatment or initiate treatment in your own setting. This would be a patient that you'd want to ensure, particularly if they have an opioid use disorder, that they have access to medication treatment such as buprenorphine or methadone, that they have naloxone intranasal to prevent opioid overdose, and refer to the appropriate treatment setting if you are not able to provide these treatments such as outpatient-based buprenorphine in your own setting. Diversion can be a quite challenging situation where there could be concern that the patient is not taking the medication at all. If you don't think the patient is taking the medication at all, a taper may not be indicated. However, I would encourage you to really, for a patient who's diverting their medications, really further assess for a possible underlying substance use disorder or other factors such as other social vulnerabilities that could be in place and really help the patient support them in that to get treatment or additional support around whatever that vulnerability may be. If the patient is at risk for immediate severe harms, you would want to engage in a taper that is shorter and provide supportive care. Again, this would be a patient who maybe has a severe, serious bowel obstruction. Maybe they had an unintentional opioid overdose, other factors, and you really want to ensure that you're able to reduce that risk as quickly as possible. If the patient is at risk for harms that are more future harms, the taper may take months to years as listed here. Finally, for those patients that you're concerned the opioids are no longer benefiting them, I think this can be the most challenging taper to approach. For these patients, they may not feel that there's been a therapeutic failure. It may take time for you to help engage the patient in this conversation. To engage the patient in this conversation, I think it's important that you're having an open, honest conversation with them about what you have observed throughout the course of their treatment. I think that non-judgmental conversation where you can provide some reflection of your observations as their trusted healthcare professional is important if you're going to engage them in any sort of taper plan. Again, this should be non-judgmental and empathetic. For those patients who have not been benefiting from opioid treatment, I would encourage them to think about other modalities of treatment, trial the opioid taper, see how it goes, recognize that this may take time, and recognize that for some of these folks, the off-label use of buprenorphine in particular may be a way for them to successfully be able to taper the medication. They may find that physical dependence to the opioids had a larger component of their ongoing pain than the opioids themselves. Just important to talk with patients about this, support them in this, have an open and honest conversation. Always, always, always make sure that your patients are aware of how to use naloxone, being aware of the risks of a taper, and then going directly back to taking their prior dose. This can put them at risk for an unintentional opioid overdose, so it's important that you are providing them these medications. Generally in the outpatient setting, a gradual taper, which includes 5% to 10% decrease of the original dose every 5 to 28 days until 30% of the original dose is reached, and then a weekly decrease by 10% of the remaining dose can be helpful as a general rule of reducing the dose in a way that most patients can tolerate. When thinking about which medication to taper first, you may elect to taper the extended release or the immediate release first, though in general, I find that tapering the extended release medication first and using the immediate release for breakthrough pain typically goes a little bit easier for patients. Provide the patient a copy of the taper plan for reference, and then help work with the patient continually to keep the taper moving forward. If you need to rapidly taper the patient, you can do so daily or every other day over one to two weeks as appropriate. Obviously this would be larger percentage of dose reductions. There's no magic art to how you would do this, but you would generally want to either reduce a specific pill or a specific dose each day. If you are initiating medication for the treatment of opioid use disorder, you would want to use adjuvant opioid withdrawal medications. You would want to consider transitioning to office-based buprenorphine treatment or referring for methadone treatment to an opioid treatment program. Some of the opioid withdrawal medications are listed here. Certainly, if you are rapidly tapering a patient, I would recommend that you are offering these as comfort medications. I think another component to the taper process is your own self-care. It's important that if you have a challenging situation and you're not exactly sure how to approach the situation, check in with a colleague, seek expert advice, take care of yourself, process what went well in your interaction or what was hard. It's important that we are engaging in our own self-care so that we can be better healers ourselves. If you are finding that it's challenging for you to undergo some of these tapers in your setting, or say you have taken over a panel or practice where many patients are on doses of opioids that are higher than you feel comfortable prescribing, or you feel the patients are not benefiting from the medication, it may be helpful to talk with your clinic or hospital leadership about the development of an opioid committee or a safety committee or a stewardship committee, which can support you and your clinic in the endeavor to be able to safely and effectively prescribe opioids. Again, remembering you are abandoning the opioid therapy, not the patient. Keeping the patient's ultimate safety in mind helps us be able to do what can sometimes be quite challenging work. Step four is to make sure that you are aware of the treatment for opioid use disorder, which would be the medication for opioid use disorder, which is the gold standard treatment if a patient has developed one of the most severe harms of opioid therapy known as opioid use disorder. Some patients will ultimately struggle with an opioid taper. If you're finding that the patient continues to have severe risks that are outweighing any benefit they're receiving from opioids, it's important that we're thinking about buprenorphine and methadone as treatment modalities. Generally, I would say that patients who are on the higher doses of opioids, such as methadone greater than 30 milligrams, greater than 200 milligrams of morphine equivalents, those patients who are taking the medication for longer, those who have concomitant mental illness, distress intolerance, history of adverse childhood experiences, history of substance use, weak social supports, these are the patients who may struggle the most and who may be, who may most benefit from the transition to buprenorphine or methadone. They probably would also benefit from interdisciplinary pain programs or additional supports such as mental health support. So let's go through a few cases of how to approach a taper for patients who are having some different levels of risk. So case two is a patient who's having immediate risks related to the prescription of opioids. So this is a 50-year-old man who's been prescribed opioids for chronic low back pain for the last five years who has developed severe constipation that is not amenable to any treatments. You decide the risks outweigh the benefit of him remaining on morphine extender release 15 milligrams per day. For a patient such as this, a way that you could approach the taper plan would be to convert his morphine extender release to immediate release and then reduce the morphine over time, remembering that this is an immediate release opioid so you can cut and split it. So you can reduce it to the smaller doses, increase the time. So in this case, you're going from 30 milligrams per day to the seven and a half milligrams every eight hours, doing that for two weeks, then reducing further to seven and a half milligrams twice a day for two weeks, and then seven and a half milligrams daily for two weeks, and then stopping. Certainly along the way, if the patient were to develop side effects or opioid withdrawal, you could provide some of the adjuvant treatment. So what if that same 50-year-old man was prescribed fentanyl 75 micrograms every 72 hours? So this is a higher dose of opioids. So for this patient, because fentanyl patches inherently are very, very challenging to taper, one example of what you could do is to convert his fentanyl to a different opioid that's easier to taper, such as extender release morphine or extender release oxycodone. An example of this would be morphine extender release. You could dose it as 45 milligrams, 30 milligrams, 30 milligrams, and then going down per doses every couple weeks, two weeks to one month, and then continuing with the 10 to 20% reductions until you're done. So again, if you're going to taper fentanyl, generally you're going to need to switch to a different extender release medication. When you do so, you're going to have to correct for cross-tolerance. And you're also going to have to recognize that in order to taper these medications, you can't cut or split them, so you're going to have to use the doses that are available. And so in this case, you're seeing that we transition the patient from the fentanyl to the morphine, reduce for cross-tolerance, and then we slowly reduce the dose over a period of time until the patient was off of the medication. Case four is a substance use disorder. So this is a 50-year-old man who's prescribed hydrocodone four milligrams every three hours and fentanyl 50 milligram, sorry, microgram patch for chronic pancreatitis. You detect alcohol on a routine urine drug screening and the patient admits that he's had a recurrence of his alcohol use disorder. What do you do? So in this patient, you have determined that the risks of ongoing uncontrolled alcohol use disorder in a patient prescribed high-dose opioids greatly outweigh the benefits. For this patient, you would want to make sure that he is safely able to detoxify from alcohol and opioids, and you'd want to evaluate the opioid dose for safety and taper accordingly. This patient would likely be referred to an inpatient or acute detox setting, and that could be an opportunity for the patient to both taper off of opioids as well as detox from alcohol. The case here, this could also be a patient where you may decide that if he continues to have pain after he goes through the detox period, it could be a time where you would reconsider a medication such as buprenorphine for the treatment of his chronic pain, again, being used off-label. Finally, I'll also say about this case that you would want to make sure the patient is also receiving treatment for his alcohol use disorder, and that could be accomplished by referring to outpatient treatment. Case five is a 28-year-old female prescribed opioids for chronic abdominal pain. She states she's lost her opioid prescription for the third time. She's had two negative urine drug tests for the opioid that is prescribed, and she refuses to come in for a pill count. You suspect aversion. In this case, you've really seen that there's been a pattern of lost or stolen medications. You've tried to do some monitoring, and you really have not been able to, and she's refusing to come in for a pill count. In this situation where there's real high concern for diversion, it would be indicated to stop prescribing opioids immediately to the patient because you have high risk that the medication is not going to the patient. Case six, long-term opioid therapy with therapeutic alliance. So, this is a 68-year-old female with rheumatoid arthritis pain. She's prescribed a total of 350 milligrams morphine equivalents for the last five years with no adverse events. She's moderately functional. Your clinic has developed a new opioid policy stating that opioids that patients prescribe greater than 120 milligrams of morphine equivalents need to attempt an opioid taper. She's concerned she might develop serious harms from her opioids. So, this patient is really concerned about her dose and her long-term risk. So, this would be a patient that you could have an open and honest nonjudgmental conversation with, develop a patient-centered taper plan for the patient, and so you could slowly taper by 10% per month over a year, and you may elect to slow down the taper if she experiences periods of worsening pain and or opioid withdrawal. You would certainly want to also make sure that she's receiving evidence-based treatments for her rheumatoid arthritis. This would also be a patient you'd want to provide education about opioid overdose and naloxone. Case seven, a long-term opioid therapy with difficult therapeutic engagement. So, this is a 30, sorry, 63-year-old man with a history of low back pain and severe depression after a work injury in 1982. He has not worked since and spends most of the day being very sedentary. He has been unwilling to engage in additional pain modalities despite multiple offers. He's prescribed oxycodone immediate release, 30 milligrams every four hours. He tried other opioids, but he has not had improvements. He refuses an opioid taper and states he will seek another provider if you start to taper his opioids. So, this would be a patient where you'd want to, again, have an open, honest, nonjudgmental conversation with, though it appears that you probably have tried to do that with this patient in the past. For someone you really feel is not benefiting from the medication, is not engaged in other chronic pain treatments, this is probably a patient who has, or maybe a patient who has developed a very strong physical dependence to the medication and would likely benefit from a trial of buprenorphine as an alternative. Also working with that patient to get them more active and able to get some functional gains through other non-medication treatments. So, if the patient were unwilling to engage in that, you may need to taper that patient over one to two months, putting some very specific boundaries around his treatment. Given the difficulty that he's had with his pain treatment, it is quite possible that he would really struggle with that taper. And so, again, that would be a situation where the buprenorphine may be quite helpful. Absolutely provide the patient education about opiate overdose and naloxone. So, as we discussed before, maintaining this risk-benefit framework is really helpful and useful in any of the conversations you're having with the patient. You want to ensure that you're looking at the different benefits, such as pain, function, quality of life, balancing those with the different harms related to misuse, addiction, overdose, or adverse effects. You want to have this open, honest, nonjudgmental conversation with the patient, which is supportive and recognizing their standpoint, recognizing what their needs are, but also taking a very measured approach, which hears out their needs, but also is able to safely and effectively prescribe. Some of the different conversations you may have or patients may say is that they really, really need the opioids. They don't feel as though you trust them. They're upset about the relationship and feel that they're being judged. If ultimately you feel that these medications are not indicated or no longer benefiting the patient and there are very high risks, you may have to say to the patient, I cannot continue to prescribe a medication that is not helping you or is hurting you or both. These are uncomfortable conversations to have. Certainly reach out for help or get expert opinion if you're not able to engage the patient in these conversations, but it is important that we as healthcare professionals are able to evaluate these risks with the patient, mitigate these risks, and ensure that our patients are able to safely and effectively take these medications if we are prescribing them. In summary, thank you for your attention. I know this has been a long lecture, but I hope that it's benefited you and helped you be able to understand how to approach what can be a very complex treatment for our patients. Remember that there are several different formulations and routes of opioids that are available, and it's important to understand them, their differences, in order to safely prescribe them. Patients can benefit from opioid rotation to achieve better pain control and less side effects, but you need to have clinical experience in order to safely transition patients. Tapering opioids can be a challenging process, but general principles can help promote success. In the right situation, allowing a patient to share some decision-making about the opioid taper can help taper success. There will be several occasions where shared decision-making about the opioid taper unfortunately is not possible, and it's important to continually support the patient as best you can. For more information, I would encourage you to look at the Scope of Pain, which is an excellent didactic that's freely available through Boston Medical Center. Here are our references, and again, thank you for your attention. Please remember that PCSS has a wonderful mentoring program, and you can always reach out for additional assistance if you need to get some help on challenging cases. Thank you for your time.

Dr. Melissa Wymer

opioid pharmacology

dosing management

types of opioids

individualizing treatment

adverse effects

dosing guidelines

monitoring patients

opioid overdose risk

prescribing opioids

tapering opioids

opioid rotation