<v ->Welcome, I'll be presenting a module</v> for the Providers Clinical Support System on Opioids for Pain, Understanding and Mitigating Risks. I'm Roger Chou. I'm a professor of medicine at Oregon Health and Science University, and I direct the Pacific Northwest Evidence-based Practice Center. I have no relevant financial relationships with ineligible companies to disclose. The target audience of this module. The overarching goal of PCSS is to train healthcare professionals in evidence-based practice for the prevention and treatment of opioid use disorders, particularly in prescribing medications as well as for the prevention and treatment of substance use disorders. Educational objectives. At the conclusion of this activity, participants should be able to recognize risk factors for opioid misuse, opioid use disorder, and overdose in patients with chronic pain, review methods for screening and assessment for problematic opioid use. Discuss methods for monitoring and evaluating patients prescribed opioids for chronic pain in order to mitigate risks, summarize non-opioid treatment approaches for chronic pain, and describe opioid taper strategies and risks. We'll start with some background first. As you all know, chronic non-cancer pain is very common, and it causes substantial burdens. Chronic pain is typically defined as pain lasting more than three months. It's reported by up to 1/3 of adults. Opioids are very commonly prescribed for chronic pain. Evidence shows that 30% of patients with chronic non-cancer pain are prescribed opioids, and it's important to recognize that what's done in the United States is different from most parts of the world. The United States accounts for about 5% of the world's population, but consumes about 80% of the world's opioids. Globally, countries consume a median of 3.3 morphine milligram equivalents per day, or MED, for medical purposes. In the United States, it's over 100 times higher at 398 MEDs per person. There is some good news. Prescribing peaked in 2012 at 81.3 prescriptions per 100 persons, declining to 43.3 in 2020. Opioids are different from other drugs. It's important to recognize that most drugs only impact the person who's being prescribed, whereas opioids have potential harms to patients as well as societal harms. This slide shows trends that occurred over a relatively quick period from 1999 to 2010, related to analgesic sales, deaths, and treatments for substance use disorder. So you can see over about a 10-year period, sales of opioids quadrupled. And then we can also see that deaths and treatment rose at about the same proportionate levels. Since 2008, we've had about 15,000 prescription opioid deaths per year. In many states, that succeeds the number of motor vehicle accident deaths, which previously were the most common cause of death in younger adults. As you can see, the number of prescription opioid overdoses has leveled off and declined slightly. So there was a steady rise from 1999 to 2010, and since then, deaths have been relatively stable and in recent years, declined slightly. There have been several waves in terms of opioid overdose deaths. So you can see that starting in 1999, the first wave was really related to prescription opioid overdose deaths. Starting in around 2010, we saw a second wave, which was related to an increase in heroin-related deaths. So that's the blue line, the dark blue line that starts to go up. And then around 2013 or '14 is when we saw another marked rise related to synthetic opioid overdose deaths, for example, fentanyl and fentanyl analogs. And so it's important to recognize that all of these have contributed in different ways, and we have gone through different phases of opioid overdose deaths. I had mentioned earlier that opioids have potential harms including treatment admissions for substance use disorder. And it's interesting that we can see the connection between prescription opioid use and illicit opioid use. If you go back to the 1960s and 1970s, if you asked a heroin user what their first opioid of misuse was, overwhelmingly, it was heroin. They started by using an illicit drug. But starting around the 2000s to the 2010s, if you ask a heroin user what their first opioid of misuse was, it's now a prescription opioid. And so the way people are coming into contact and becoming addicted has changed dramatically. A brief word on opioid pharmacology. Opioid mu-receptors mediate both the analgesic effects and adverse events of opioids. Opioids can be classified as natural, so related to the opium poppy synthetic, so made in the lab. So again, things like fentanyl, or semi-synthetic. The half-life for most opioids is two to four hours. It can be up to 15 to 60 hours for a drug like methadone. Opioids are somewhat unique in that ongoing exposure, causes what's called tolerance and physical dependence. Physical dependence means that if you stop the drug abruptly, people will experience a withdrawal syndrome. Tolerance means that higher doses are needed to achieve the same effects, both analgesic and adverse events. There is some individual variability in the development of tolerance, though we think this is a universal phenomenon. And because of tolerance, there's theoretically no dose ceiling with opioids, meaning that if you go slow enough, people should be able to accommodate that and not overdose. It's important to recognize that physical dependence is not the same as addiction. Addiction is a brain disease characterized by compulsive use. Physical dependence is purely a physical phenomenon. Opioid misuse in primary care, of course, does occur. It's likely under-recognized and under-diagnosed. A systematic review found that misuse averaged from 21% to 29% and opioid use disorder from 8% to 12%. There's some variability in estimates. This is due to use of inconsistent definitions for these conditions, poorly standardized methods for detecting these outcomes, as well as some differences in the populations evaluated. For example, a higher risk population versus a lower risk population. We know a number of factors are associated with opioid overdose and patients prescribed opioids. These include aberrant behaviors. So this can mean patients who take extra doses, patients who increase their doses without authorization, having lost prescriptions, calling in for refills after hours, doctor shopping, or obtaining opioids from multiple prescribers, using unprescribed opioids, or other medications or substances, and using opioids to treat non-pain symptoms such as anxiety or sleep. The period right after initiating opioids is a higher risk period. Using methadone as an analgesic is associated with increased risk of overdose compared to other opioids. Using a benzodiazepine with an opioid is associated with increased risk of opioid overdose, having a substance use disorder, having psychological comorbidities, using higher opioid doses, and presence of co-occurring medical conditions. For example, pulmonary conditions like sleep apnea or COPD can increase risk. Universal precautions are recommended in pain medicine. And people will ask, well, why do we need to do universal precautions? And there are several reasons for it. One is that it's actually difficult to predict who's going to misuse. So implementing universal precautions helps you to protect all patients, as well as protecting the public and community health. It helps us to apply precautions consistently. It's consistent with clinical practice guidelines. So this takes the pressure off the provider who, you know, doesn't have to make a decision in every patient about what they're going to do. It also actually reduces stigmatization of individual patients and reduces potential implicit or explicit bias in management, and it helps standardize systems of care. So universal precautions provide a standardized approach. It doesn't mean you have that everybody gets treated exactly the same. It still allows for individualized assessment and management decisions, but provides an overall framework that we can apply to all patients. So common universal precautions include use of a comprehensive pain assessment, including opioid risk assessment, formulating the pain diagnosis or diagnoses, treating the initial opioid prescription as a test or trial, and going into it with a plan to continue or discontinue based on an ongoing reassessment of risks and benefits. This is to prevent the situation where somebody gets started on an opioid, and it just gets continued without clearly assessing whether the patient is benefiting or not. The decision to continue or discontinue opioids should be made on a regular basis with periodic reevaluations, for example, every two to three months. Universal precautions also include regular face-to-face visits, although these may be supplemented or enhanced with TeleVisits, and they require clear documentation. There's a number of strategies that we can use to mitigate risks associated with opioids. These include carefully selecting and assessing patients who are potentially appropriate for opioids using medication agreements, avoiding higher doses when possible, doing routine monitoring, including urine drug testing and reviewing prescription drug monitoring data, avoiding sedative hypnotics, particularly benzodiazepines, which as we showed earlier, can increase overdose risk, consulting with our addiction, pain, and psychiatric colleagues when necessary. doing more frequent refills with smaller quantities using abuse-deterrent formulation, naloxone co-prescription and overdose education. I think it's important to recognize that evidence on the effects of all of these risk mitigation strategies on clinical outcomes is lacking, but there's a consensus that these can help us to reduce and manage risks. So patient selection and risk stratification. Risk assessment is necessary in all patients prior to initiating opioids. It's important to remember that the strongest predictor of opioid use disorder and overdose is a personal or family history of alcohol or drug abuse. Psychological comorbidities are also a factor. Current alcohol use, use of benzodiazepines, and other sedatives, and respiratory depressants are also risk factors. Recognize that aberrant drug-related behaviors can occur in up to 50% of patients prescribed opioids for chronic pain, therefore, we need to only consider opioids in patients in whom benefits are likely to outweigh risks and recognize that opioids are not always appropriate and are usually not a first line therapy. Tools for risk stratification are available. And again, if a patient is appropriate for opioids, if they've tried non-opioid medications and continue to have severe pain, and they're assessed as being not at high risk, opioids may be perfectly appropriate, but we need to do our risk assessment to determine that. Screening for unhealthy substance use. There's a number of ways that we can screen for unhealthy substance use. There's some simple screening questions. So for alcohol, we have the question, do you sometimes drink beer, wine, or other alcoholic beverages? And then asking how many times. Has the patient had five or four for women, or more drinks in a day. And then for drugs, asking how many times in the past year has somebody used an illegal drug or used a prescription medication for non-medical reasons. There are a number of opioid misuse screening tools, so these can help us to identify and/or predict patients who may misuse opioids if they're prescribed. So probably the two most commonly used tools are the Opioid Risk Tool or ORT and then the SOAPP or the Screeing for Opioid Assessment for Patients with Pain. Both of these are meant to be administered to patients before starting opioids and then identifies people who are at higher risk for opioid misuse. For all of these tools, it's important to recognize that there's no gold standard tool and that there is a lack of rigorous testing of them. I think they're still helpful to help us to think about risk factors and to get some idea about what somebody's risk is, but it doesn't replace our other overall assessment. This is the Opioid Risk Tool. So you can see family history, personal history, age, history of preadolescent sexual abuse and psychological disease. All of those can receive a point, and then you add up the total. And then your score indicates if you are low risk, zero to three points, moderate risk, four to seven, or high risk, greater than eight points. We have screening tools for depression as well. The PHQ-2 is probably one of the simplest, so it asks about anhedonia or lack of interest or pleasure in doing things, as well as feelings of depression. And then again, if it's positive, then we can administer a more detailed test like the PHQ-9. The sensitivity and specificity is pretty good. We also should be assessing for other mental illness that can be present in patients with chronic pain like anxiety, PTSD, personality disorders, and suicidality. Medication agreements are part of our universal precautions. They help us to make sure that informed consent is done with patients, including an understanding of goals and risks of therapy. Medication agreements outline the plan of care, including goals of therapy, the follow up and monitoring plan, how opioids will be prescribed and refilled. The medication agreements are signed by both the patient and prescriber. They serve as a patient counseling document and delineate our expectations for patients, and they help document the plan of care for other clinicians. So if you are not available or if you're covering for another patient, the medication agreement can help you understand what the plan of care for their chronic pain is. Again, we don't have good evidence on the effects of medication agreements on clinical outcomes, but these are recommended in clinical practice guidelines. The period of initiation, as I mentioned, is a higher risk period. We should view the initial course of opioids as a short term, for example, four weeks therapeutic trial. The decision to proceed or continue with long-term opioid therapy should really be a conscious one and based on a reassessment of the patient and how they're doing in terms of benefits and harms. Remember that if opioids are used, they shouldn't be the only strategy for treating a patient's pain, they should really be part of a multimodal strategy. And as I mentioned, we want to start at low dose. Because the initiation period is higher risk for overdose, we want to start at low doses and titrate cautiously. It's important to not initiate therapy with long-acting opioids. These confer increased risk in people who are opioid naive. They can be an option later. However, there's insufficient evidence to recommend that all patients need to be transitioned around the clock, long-acting opioids. That used to be the common practice. It's not clear that that actually benefits all patients or that it decreases risks. And so the decision to transition to round the clock, long-acting opioids should really be an individualized one. Methadone and fentanyl are not recommended as first line options. These are less predictable medications and more complicated in terms of dosing and pharmacokinetics. Buprenorphine is a partial agonist that theoretically is lower risk for overdose because the respiratory depressant effects plateau. It may be useful in higher risk patients, however, evidence showing decreased overdose risk is lacking. Some formulations are only approved for treatment of opioid use disorder. So the higher dose sublingual and buccal formulations. Methadone, I mentioned briefly on the prior slide. This is a synthetic opioid. It's used for treatment of addiction and pain. Methadone traditionally was reserved for treatment of opioid use disorder. But around the time where we saw a lot of increase in opioid prescribing for pain, we also saw an increase in use of methadone because this is a inexpensive medication. However, there was a large increase in the number of methadone deaths nationwide. In 1999, we had about 800 deaths related to methadone, and in 2008, this was 4,900. The number of deaths were disproportionate to the... Even though methadone prescribing had increased, the number of deaths was disproportionate to this increase. So methadone accounted for 1.7% of opioid treatments in 2009, 9.0% based on morphine equivalent doses, but were involved in 31% of opioid related deaths and 40% of single-drug deaths. One of the reasons that methadone may be higher risk is that it has a very long half-life. So the half-life of methadone is 15 to 60 hours, it may be up to 120 hours. This means that the drug levels continue to accumulate for a long time after it started. So with a 60-hour half life, it takes almost two weeks to reach steady state. Methadone also is different from most other opioids in that it's associated with QTc interval prolongation and potential torsades, a ventricular arrhythmia. And it's actually recommended that if you use methadone to perform ECG monitoring at baseline in patients with risk factors for arrhythmia, as well as when you get to higher doses and consider monitoring in all patients. This slide just shows the pharmacokinetics. So this is basic pharmacology that it takes about four half-lives or so to reach a steady state. And so again, for a drug like methadone, those levels are continuing to accumulate and get higher and higher. And this may be the patient who's doing fine on day two or three, but then the drug level accumulates to the point where they suffer respiratory depression at say, seven or 10 days. So you have to be really careful about starting methadone, not increasing the dose too rapidly, allowing that drug to reach steady state before making any dose adjustments. This shows a prolonged QTc and torsades. So the upper ECG shows a normal sinus rhythm with QTc prolongation, and the lower slide shows this degenerating into torsades, which again is a ventricular arrhythmia that can be potentially life-threatening. I wanted to talk a little bit about the dose response relationship between higher opioid dose and a risk of overdose. As I said before, the theory with opioids is that because of tolerance, that higher doses shouldn't necessarily cause increased risk of overdose. That as long as you go slow enough, that the body can adjust and develop tolerance. However, when we started studying this about seven or eight years ago, we've had a number of observational studies consistently show an association between higher opioid dose and risk of overdose or death in patients with chronic pain. We see that the risk starts to increase at relatively low doses and continues to increase as the dose goes higher. These studies did attempt to match or adjust for potential confounders. Most of these studies were conducted on administrative databases, so they're restricted to the variables in those databases. So to the extent possible, they try to control for these factors. Of course, there is some possibility for residual confounding, but this relationship between higher dose and overdose risk appears quite consistent across multiple studies now. This summarizes some of the studies. So some of the earlier studies that were conducted between 2010 and 2014. So again, you can see that in each of these studies, as the dose increased, the risk of overdose increased as well. And we saw this starting at 50 morphine equivalents per day. So with dosing, even though there's no theoretical ceiling with opioids, we actually also have some data showing that the benefits of increasing doses are unclear as well, that the analgesic effects seem to plateau in many patients at relatively low doses. People who don't respond to opioids at lower doses may not respond to opioids at higher doses as well. So titrating people to achieve pain relief. So continuing to increase the dose to achieve pain relief is inconsistent with the evidence that we have on benefits. And as we just talked about, there is a dose-related risk of overdose. So the 2016 CDC guideline advised caution at doses greater than 50 morphine equivalents per day, and to avoid doses higher than 90 morphine equivalents per day. These thresholds, of course, are, to some degree, they're arbitrary, but they are based on data that the average dose in overdoses is 98 morphine equivalents per day, and about 50% of overdoses occur in patients on less than 60 morphine equivalents per day. The CDC guideline does not say that you can't use higher doses, but that decisions to use higher doses should be based on a assessment of risks and benefits and require more frequent or intense monitoring to help mitigate the risks of using those higher doses. In terms of monitoring outcomes, patients should be evaluated in multiple domains. In the past, there's been a tendency to focus primarily on pain relief, but we understand now that no therapy for chronic pain is effective in completely relieving pain, and that patients can actually report improvement in pain and have no improvement in function or vice versa. So we want patients to be able to do more as well as experience improved pain. So it's important to measure function and set functional goals. The goals should be achievable and measurable. We need to also monitor for presence of psychological comorbidities and treat and assess those if needed, assess for sleep issues and screen for substance use disorder, and again, treat those if they're present. The PEG Scale, this was developed by Erin Krebs. I believe this was derived from the Brief Pain Inventory. So it's a pretty simple three-item scale. The first item addresses pain intensity, so our standard zero to 10 pain scale, but also addresses how pain impacts enjoyment of life, as well as general activity. So also addresses some of these other domains that we're interested in. So this has been recommended as one of the tools that can be used to monitor patients. Again, not just focusing on pain intensity. Urine drug tests are an important monitoring tool. Urine drug tests provide objective information regarding adherence to opioid plan of care, evidence of use or non-use of illicit substances or unprescribed medications, and may help improve adherence. And again, the reason to use urine drug test is that we know that self-report is unreliable, and you can't always predict who may be engaging in some of these behaviors solely based on observing their behaviors. It's recommended that urine drug tests be performed at baseline and periodically. One to two times per year for low-risk patients may be sufficient, three to four times per year for higher risk patients. They may be performed randomly on a scheduled basis and/or when concerns arise. It's important to discuss expected findings with the patients before performing the urine drug test. Consult with your toxicologist or clinical pathologist before acting if a patient disputes findings. Some of the metabolites can be difficult to interpret, so it can be important to see what the toxicologist is seeing, if there are other reports of contaminants or other issues. Screening tests require confirmation, of course, and always recognize that people who are dedicated to deceiving the system can beat it. So you can't rely 100% on the urine drug test. They're just, again, they're just another tool we have to help assess patients and to help keep them safe. Prescription drug monitoring programs are now available in all states. Prescription drug monitoring programs are registry essentially of all prescriptions for controlled substances dispensed to a patient in that state. Use of PDMPs can help us identify cases of doctor shopping. Unfortunately, use of PDMP remains variable and generally suboptimal. PDMPs vary in who can access them. There is no national PDMP, though some states allow sharing of data. Over 40 states mandate that providers access the PDMP before writing for controlled substances. This is as of May of 2018. Again, evidence showing effects of PDMP monitoring on clinical outcomes is lacking, but the information we think that can be gained by accessing the PDMP can be quite useful. And I personally have found some patients who are receiving opioids from multiple providers and this allowed us to help, you know, develop a plan to help, make sure that they were safer with their opioid use. Opioids and benzodiazepines, as discussed before, using benzodiazepines with opioids is associated with increased risk of overdose. Other medications with respiratory depression effects may also cause similar risks. It's important to remember that benzodiazepines should be tapered gradually. Benzodiazepines withdrawal can be serious, and it can be similar to alcohol withdrawal. And so it needs to be done carefully and may require assistance with people with expertise in this. You know, often benzodiazepines are used to treat things like anxiety disorder or sleep. There are other treatments available for these that are generally recommended before benzodiazepines. So for anxiety disorder, things like CBT, antidepressants that are approved for treatment of anxiety and other non-benzodiazepine medications. For insomnia, chronic cognitive behavioral therapy is a highly underutilized therapy and should be strongly considered. And again, it may be, it's important to try to coordinate care with mental health professionals in patients who require higher doses of benzodiazepines or who are having difficulty tapering. Naloxone is another important risk mitigation strategy. Naloxone is an opioid antagonist that can rapidly reverse opioid overdose. The use of naloxone is because most overdose episodes are witnessed, and because of that, somebody, a bystander or somebody who sees the overdose can administer the naloxone and reverse the overdose. Naloxone is quite impressive when you see it. It's effects are rapid. Patients can actually be quite agitated when naloxone is successful. But again, it can reverse the respiratory depression and potentially save lives. Naloxone has been shown to be highly effective in addiction settings. There is some emerging evidence of effectiveness in chronic pain settings. The CDC, the 2016 guideline recommends naloxone for all patients on more than 50 morphine equivalents per day or other risk factors for overdose and to consider it for all patients prescribed opioids. All states have passed Good Samaritan laws providing civil or criminal immunity for administration of opioids. We have some resources there for those who are interested. There are a number of different naloxone formulations. So there's an FDA-approved intranasal formulation, so that's the NARCAN Nasal Spray. There's also off-label intranasal use of injectable naloxone. So that's the upper picture where you can see that injectable naloxone is in a syringe and then attached to an atomizer, which allows you to administer it intranasally. The issue with the injectable naloxone, the off-label intranasal use of it is that it's not, it's a lower potency formulation. We think it's probably effective in most cases of overdose, but there is some concern that in patients who have overdosed, say on highly potent fentanyl, whether the doses will be sufficient. It's also not, the NARCAN Nasal Spray is designed to be pretty foolproof and to be administered by people without any medical training. And then the jerry-rigged naloxone with the atomizer, it hasn't been tested in the same way. Naloxone can also be administered intramuscularly. There was an FDA-approved autoinjector, but the company that was making that has ceased producing it. So the options really are the ones shown to the right there. Abuse-deterrent formulations are another strategy. So a number of abuse-deterrent formulations have been approved by the FDA or are undergoing the FDA approval process. Abuse-deterrent, formulations are designed to be tamper-resistant, or they're co-formulated with medications that reverse opioid effects or produce noxious side effects if tampered with. So if somebody tries to crush a medication and snort it or inject it, they either won't have any effects or they will experience unpleasant side effects. The effectiveness of abuse-deterrent formulations for reducing misuse or substance abuse and improving clinical outcomes is as yet unproven. This is very difficult to study, of course. And I think it's important to recognize that abuse-deterrent formulations are likely to be primarily effective in patients who crush or inject opioids. We think that many patients who overdose are not doing it. You know, crushing and injecting opioids is a serious high risk behavior, but many people who overdose, they're probably just taking the pills and abuse-deterrent formulations will not do anything to prevent overdoses related to that. There may also be some unintended consequences from use of abuse-deterrent formulations. At least one study showed that some patients may seek other prescription or illicit opioids if they're prescribed an abuse-deterrent formulations, likely because this is unmasking some misuse behaviors. So to be aware of this and again, to assess and offer treatment for those patients if necessary. So it's important to always evaluate aberrant drug-related behavior. So again, this can be patients who take more doses, take an extra dose or extra doses, who increase their dose, who lose their prescriptions, who are doctor shopping, et cetera. Understand that the behaviors vary in seriousness. So it's important to judge the seriousness, evaluate the cause or causes of the behaviors, whether it's likely to recur and the clinical context. So this will help us determine our approach. Some predictors of a high likelihood of future aberrant behaviors include having three or more episodes of aberrant behaviors and/or a sense of losing control. Serious behaviors, which include diversion, so, selling or giving the drug, the opioids to people that it's not prescribed to and injecting oral drugs. Responses to aberrant drug-related behaviors can range from simply patient education and enhanced monitoring to referral to addiction specialist and discontinuation of therapy. Again, it depends on all those factors that are described above. Discontinuation of opioid therapy. It's important to, again, have a plan going in and to be aware that if patients run into trouble or issues with long-term opioid therapy, they may need to be tapered or weaned. Patients should be tapered or weaned if they engage in serious or repeated aberrant drug-related behaviors or drug abuse and diversion. If they're not experiencing any progress towards meeting their therapeutic goals or if they're experiencing intolerable adverse effects. This doesn't mean that we stop managing their pain. We have a lot of other potential treatments for pain. Many of them are similarly effective to opioids, and we should be using those. But again, having an exit strategy is important, and that means knowing what the indications for stopping long-term opioid therapy will be. Plans for tapering or discontinuing opioids. Prior guidance was that tapers could be 10% per week. We found that most patients actually require slower tapers, in many cases, much slower tapers than that. So it's okay to go slow if necessary. We need to provide psychological support while tapering. This can be very anxiety-provoking for patients and distressing. So providing support while going through this is important. While tapering, we should be monitoring and screening for opioid use disorder, which can be unmasked when tapering. We need to know our resources for managing opioid use disorder and mental health issues. I encourage providers to obtain a buprenorphine waiver. This can be potentially life-saving in patients who have opioid use disorder. The rules about buprenorphine waivers have changed recently so that you're not even required to do the eight hours of training, though we still recommend that because we think the training is actually quite useful, but you don't need to do the training to get the waiver now. It's still a requirement to have the waiver because of the federal regulations around treating opioid use disorder. So for patients already on high doses, as I mentioned before, there's nothing in the 2016 CDC guideline or the proposed updated guidelines, which are currently out for public comment that say that patients can't be prescribed higher doses. But there are a few principles to remember. So if somebody's on over 90 morphine equivalents per day and they meet criteria for taper because they're not benefiting, they're having serious risks or they're having severe side effects, you should initiate a taper just like any other medication if it's not working or if it's causing severe problems that are putting the patient at risk. In patients who don't meet criteria for taper, we should discuss evidence regarding dose-dependent overdose risk. Patients should be aware of those risks. Reevaluate continued use of high opioid dosages. Offer the patient the opportunity to taper, and again, screen for opioid use disorder and treat with FDA-approved medications if present. If tapering is done, it's important to collaborate with the patient on the tapering plan. Opioid use disorder. The DSM-5 definition for opioid use disorder is a problematic pattern of opioid use, leading to clinically significant impairment or distress. Again, this is different from tolerance or physical dependence. In 2014, there were nearly two million Americans with opioid use disorder due to prescription drugs, this compared to about 600,000 due to heroin. Opioid use disorder is associated with decreased quality of life, negative impacts, and as well as negative impacts on morbidity and mortality. We have effective treatments for opioid use disorder. These treatments can be potentially life-saving. There are FDA-approved medications including opioid agonist or methadone, which needs to be dispensed in an opioid treatment program. Partial agonist like buprenorphine, which as I mentioned, requires you to have a buprenorphine waiver, but can be administered in an office setting. And again, the regulations around obtaining the waiver have been relaxed. The other FDA-approved medication is naltrexone, which is an antagonist and does not require any kind of waiver because it's not a controlled substance. The naltrexone is probably mostly useful in people who are highly motivated to have their opioid use disorder treated and don't want to be on an agonist or partial agonist. It may be difficult in patients with chronic pain because it may not effectively treat the pain. The treatments for opioid use disorder, block euphoric and sedating effects of opioids, they decrease craving, they help mitigate withdrawal symptoms. They've been shown to decrease illicit use and misuse of medications as well as improved social functioning. They also decrease criminal activity and risk associated with injection drug use. So again, important to assess for and to treat if present. These are the DSM-5 criteria for opioid use disorder. As you can see, tolerance and withdrawal are not considered criteria in patients who are taking opioids solely under appropriate medical supervision, i.e., people who are being prescribed opioids. And then the number of criteria that somebody meets indicates the severity of opiod use disorder. So mild opioid use disorder is two to three, moderate, four to five, and severe, at least six. In patients with suspected opioid use disorder, it's important to discuss this with your patient, provide them an opportunity to disclose their concerns. Again, assess using the DSM-5 criteria if present, offer, arrange medications for opioid use disorder. We already talked about the different options. Buprenorphine, methadone, or long-acting injectable naltrexone. Obtaining a waiver is strongly encouraged, PCSS offers waiver training. But again, you don't need to have the training done to treat up to 30 patients, though it's still encouraged. I wanted to talk a little bit about opioids for acute pain. Opioids are generally considered effective for acute pain, though some recent data indicates that opioids may be no more effective than an NSAID, at least for some types of pain. Use of opioids for minor pain may be associated with increased risk of long term use. So, for example, a study of patients who underwent minor surgery found that using an opioid within seven days of minor surgery was associated with a 44% increased risk of using an opioid at one year. Prescribing excessive quantities of opioids for acute pain results in leftover opioids. This can be a source of diversion and unprescribed use, right? The opioid in the medicine cabinet that, you know, family members or other people in the house can access. So overall, we advocate for more judicious use of opioids for acute pain. It's not indicated for all types of acute pain, and if used, to use a more limited quantity, that should be adequate in most situations. For chronic pain, as we've said, opioids are moderately more effective than placebo for short-term pain relief. The effects average 20 to 30% improvement in pain or one to two points on a zero to 10 point pain scale versus placebo. Data on long-term effectiveness is limited. Until recently, there were no placebo controlled trials longer than six months, and most trials were actually shorter than eight weeks. This is surprising to some people, given that we often prescribe opioids for years, if not decades, in patients with chronic pain. Uncontrolled studies indicate many discontinuations due to adverse effects or insufficient pain relief. In patients who use opioids long-term, some patients who continue on opioids do report long-term pain relief. The effects of opioids on function are generally smaller than the effects on pain. Some trials show no or minimal benefits for function. It's important to recognize that the trials were designed to demonstrate optimal results because they excluded patients who are at high risk for opioid use disorder or misuse, people with psychological or serious medical comorbidities who tend to do worse with opioids. And we also have limited evidence on opioids for commonly treated conditions like fibromyalgia, headache, and others. The SPACE trial was really the first long-term randomized controlled trial of opioids. It wasn't opioids versus placebo, it was opioids versus non-opioid therapy. It focused on patients with chronic low back pain and osteoarthritis and was done in the VA with 240 patients. This was an open label trial, meaning that patients and clinicians knew whether they were receiving opioids or non-opioid therapy. In the VA, all patients receive an individualized medication management using a collaborative telecare pain management model. So the results from the VA trial may not be the same in all settings that aren't able to offer the same type of pain management approach. The opioid daily dose was limited to 100 milligram morphine equivalents per day. You can see that most patients were receiving 25 to 105 milligrams per day. The SPACE trials showed that at 12 months, there was no difference in function and pain was actually worse in the opioid group. To many people, this was a surprising result. I think most people expected that the opioids would be associated with slightly better pain. In terms of patients, the proportion of patients who experience clinically significant improvement for Brief Pain Inventory interference, which is an indicator of function, there was no difference, again, for pain severity. Again, fewer patients in the opioid group, 41% reported a clinically significant improvement in pain versus 54% in the non-opioid group. Opioids were associated with more adverse symptoms. There were no deaths or cases of opioid use disorder in this trial, which again, did not enroll people at very high risk for those conditions. This slide shows the results from the SPACE trial regarding pain intensity. It shows that at baseline pain was identical in the opioid and non-opioid groups, but at 12 months, pain was slightly better by 1/2 point on a 10-point pain scale in the non-opioid group. And then for function, you can see that function was actually slightly better in the opioid group at baseline with basically no difference at 12 months. This summarizes the 2016 CDC guideline recommendations for chronic pain and acute pain. So these are kind of overall approach to chronic pain and acute pain. Again, the CDC is currently in the process of updating the guideline, and they're up for public comment as I speak. Recommendation number one in the 2016 guideline regarding chronic pain notes that non-pharmacologic therapy, and non-opioid pharmacologic therapy are preferred for chronic pain, to consider opioid therapy only if the expected benefits are anticipated to outweigh the risk to the patients, and if using opioids to combine them with appropriate non-pharmacologic therapy and non-opioid pharmacologic therapy. Regarding acute pain, recommendation number six says, when an opioids are used for acute pain, prescribe the lowest effective dose of immediate release opioids and prescribe no greater quantity than needed for the expected duration and severity of pain, which, for most acute pain, is three to seven days. In terms of our approach to treating pain, for acute pain, avoid prescribed bedrest, people do better if they're able to maintain their normal activities to the extent possible. Return to activity as able, heat or cold, over-the-counter analgesics, identify and address psychosocial risk factors early, which may help prevent the transition to chronic pain. For chronic pain, again, it's important to focus on functional goals and improvement, not just pain. Help patients in terms of utilizing self-care, which include coping skills, things like relaxation and meditation, as well as activities and exercises and identify and address psychosocial contributors to pain, including depression, anxiety, PTSD, and sleep issues. There are a number of non-opioid therapies for pain. A number of these are similarly or more effective than opioids and safer as we just showed you with the SPACE trial. So it's important to get away from the idea that opioids mean effective or good pain management. Opioids can be a part of effective or good in pain management, but do not, but those aren't equivalent. It's important to prioritize active over passive modalities. So things that engage patients, help them improve their function. This is all consistent with our biopsychosocial understanding of chronic pain. Active therapies include things like psychological treatments, exercise, interdisciplinary rehab, mind-body interventions. These actively engage patients with a focus on improving function. Passive therapies like medications, physical modalities, complimentary and alternative treatments, interventional treatments, their main focus is symptom relief. They can certainly be used as an adjunct to active therapies, but in general, shouldn't be the main primary treatment. Some considerations include costs, availability. Some of the non-opioid therapies are not available everywhere and whether the patients will adhere to the treatments or not. So no treatment is going to work if a patient does not use it. Cognitive behavioral therapy is psychological therapy that integrates cognitive therapy, which helps to restructure maladaptive thinking patterns and behavioral therapy, which replaces undesirable with healthier behaviors. It's effective for improving pain, disability, mood, and maladaptive behaviors. Some of the effects of CBT appear to be sustained. In general, it may be more effective in persons with psychosocial risk factors, but can be effective in anyone with chronic pain. Meditation and relaxation are a helpful technique for self-management and coping that incorporates some CBT principles. There's a number of theories behind meditation or relaxation. We have increased evidence on its effectiveness, including for mindfulness-based stress reduction, which is a particular type of this therapy. There are a number of techniques that can be used. So meditation, progressive muscle relaxation, hypnosis, guided imagery, yoga and tai chi are movement-based therapies that incorporates some meditation or relaxation principles. And biofeedback is a related technique. Exercise has positive effects on pain and function as well as general health and may help impact fear avoidance behaviors. It helps people learn that some pain is okay. That does not necessarily mean that you're harming the body and to help people to be able to resume some of the activities that helps to make their life fulfilling. There are many different types of exercise. These include aerobic, strengthening, stretching, or mixed techniques. McKenzie, motor control and stabilization, et cetera. Exercise can be supervised or done at home, group sessions, or individually administered. Ideally, exercise should be done within a CBT-informed framework. There's no clearly best technique for exercise. We think that supervised individualized programs maybe more effective initially. Handouts and videos can help people who want to do home exercise. The basic approach is to start slow, increase the intensity or duration incrementally. The goal is really to get people to be able to sustain their engagement and to do this, to make this to be a lifestyle change. Interdisciplinary rehab combines at a minimum psychological treatments and exercise. It's provided by professionals from different specialties and focuses on improving function. The components and intensity can vary. It's been shown to be more effective than non-interdisciplinary rehab. And again, some evidence of sustained effects. The lack of availability and reimbursement continue to be important barriers to its use, we think it may be most effective in persons who fail standard therapies who have severe functional deficits or severe psychosocial risk factors. As we mentioned, there's a number of passive mode of therapies that can be used. The evidence on many of the physical modalities, so things like ultrasound, heat, TENS, other electrical stimulation, laser therapies, et cetera. The evidence is limited, difficult to show consistent or sustained benefits. Some data show that heat is similarly effective to NSAIDs for acute low back pain. Other modalities generally aren't recommended. Manipulation, acupuncture, and massage do have some benefit, some evidence of benefit for certain pain conditions. Again, if used, they should be used as an adjunct to active therapies. All of these things incur costs, so be aware of costs. If they're not effective, they should be discontinued. And recognizing that patient expectations of benefit may help predict effectiveness. So if somebody doesn't believe, for example, in acupuncture, they may be less likely to respond to it, and this can help us guide our selection. There are a number of medications. Acetaminophen and NSAIDs are first line therapies. For many conditions, the benefits tend to be relatively modest. Gabapentin and pregabalin are first line for neuropathic pain. Pregabalin is a Schedule V substance. They're used off-label for non-neuropathic pain. Antidepressants, SNRIs are first line for neuropathic pain. Tricyclic antidepressants have anticholinergic and cardiac adverse effects, so are not used as much now. Duloxetine, which is an SNRI, is approved for both fibromyalgia and chronic back pain. Skeletal muscle relaxants are sedating. Their main use is short term use for acute pain. Cyclobenzaprine, which is similar to a tricyclic and tizanidine, which is similar to clonidine, are the best studied skeletal muscle relaxants. Benzodiazepines, in general, we try to avoid them. They are used like skeletal muscle relaxants, but because of the addiction potential as well as risks when combined with opioids, we generally avoid them for other agents. Topical lidocaine can be used for neuropathic pain and topical NSAIDs for localized osteoarthritis. So in conclusion, we have very limited data on the longterm benefits of opioid therapy with some evidence showing no benefits versus non-opioid therapy. There's accumulating evidence on serious harms of longterm opioid therapy that appear to be dose-dependent. The benefits of opioids appear limited and harms are significant, suggesting a pretty close balance of benefits to harms. All of this supports a more cautious approach to use of opioids for pain. Universal precautions including risk assessment, patient selection, monitoring and risk mitigation strategies should be employed to help manage and reduce the risk associated with opioids. Non-opioid therapies are available and should be used. Again, opioids should be an adjunct and just part of an overall plan of treatment. It's critical that we can't separate out opioid use disorder from opioids for chronic pain. It's important to assess for and treat opioid use disorder. Most patients with chronic pain on opioids will not develop opioid use disorder, but we need to assess for it and then treat it when it's there, and again, encourage everyone to obtain their buprenorphine waiver to be able to offer this to patients when it's needed. There are a number of references that are shown in these slides. This slide provides information on the PCSS Mentoring Program, which is designed to offer information to clinicians about evidence-based clinical practices and prescribing medications for opioid use disorders. PCSS mentors are a national network of providers with expertise in addictions, pain, and use of medications for opioid use disorder. This is a no-cost program. And there's also a PCSS discussion forum for those who have clinical questions. This provides a way to ask colleagues about medications for opioid use disorder. And PCSS is a collaborative effort led by the American Academy of Addiction Psychiatry in partnership with many organizations listed here. And I think that's the final slide. So thank you for attending this module.

Roger Chou

opioids for pain

evidence-based practice

opioid use disorders

prescribing medications

chronic pain

opioid overdose deaths

non-opioid treatment approaches

risk factors for opioid overdose

non-opioid therapies for pain management