Hi. I'll be presenting the PCSS training module 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 Director at the Pacific Northwest Evidence-Based Practice Center. In terms of disclosures, I've received funding from the Centers for Disease Control and Prevention and the Agency for Healthcare Research and Quality to conduct systematic reviews on opioid and pain-related topics, but otherwise, I've no financial relationships related to the content of this presentation. The overarching goal of PCSS-MAT is to make available the most effective medication assisted treatments, to serve patients in a variety of settings, including primary care, psychiatric care, and pain management settings. We have a number of educational objectives for this module. At the conclusion, participants should be able to describe risk factors for opioid misuse, opioid use disorder, and overdose in patients with chronic pain, explain methods for screening and assessment for problematic opioid use, explain methods for monitoring and evaluating patients prescribed opioids for chronic pain in order to mitigate risks, and describe non-opioid treatment approaches for chronic pain. First, let's start with some brief background. As we all know, chronic non-cancer pain is highly prevalent and associated with substantial burdens. Chronic pain is typically defined as pain that's been present for more than three months. This is reported by up to one-third of adults depending on how pain is defined and who has been asked. Opioids are commonly and increasingly prescribed for chronic pain in the United States and some populations, about five percent, are on long-term opioids. What we do in the United States is different from many other parts of the world. Although, we account for only about five percent of the world's population, we use 80 percent of the world's opioids and nearly all of it hydrocodone, which is the number one prescribed drug in the United States. Trends also indicate that not only are more people receiving opioids, but we're also prescribing opioids at higher doses and using more scheduled II opioids. Opioids are unique, although all medications are associated with potential harms, opioids are associated with harm not just to the patient that they are being prescribed to, but also to society. These are largely related to their potential for abuse. This slide is from the CDC and it shows trends in sales of opioid analgesics, deaths, and treatment for opioid use disorder. So the green line shows that over about a 10-year period, sales of opioids increased about four-fold, and in parallel, you can see that deaths associated with opioids and treatment admissions also increased of nodes. Since about 2008, we've had approximately 15,000 deaths per year related to prescription opioids, this exceeds the number of deaths related to motor vehicle accidents in most states now. This slide shows some more recent data on prescription opioid overdose deaths. So you can see that the numbers increase to about 2010 or 2011, when they leveled off slightly. But this slide shows that we've had a spike in heroin-related death since 2010. So the green line shows heroin related deaths which were really pretty stable from 2000 to 2010 and have spiked in the last few years. This slide shows how those trends may be related. This was a survey of heroin users in which they were asked what their first opioid misuse was. You can see that in the 1960s, 1970s, and 1980s, the vast majority of heroin users said that their first opioid misuse with heroin. That pattern has reversed itself so that now the majority of heroin users say that their first opioid abuse was a prescription opioid. So we think that the increase in heroin related deaths is related to exposure to prescription opioids. Just a brief word on opioid pharmacology. Opioid mu-receptors are what mediate the analgesic effects as well as adverse events associated with opioids. Opioids can be classified in several ways. One is related to their structure, so they can be natural opioids. Are those derived from the opium poppy, things like morphine, heroin, and related drugs. We have synthetic opioids, things like fentanyl and methadone, as well as semi-synthetic opioids such as oxycodone. You can also think about opioids in terms of their half-life. Most opioids have a half-life of two to four hours, but in particular, methadone has a half-life of 15-60 hours. Unique characteristics of opioids include the fact that ongoing exposure causes tolerance as well as physical dependence. Physical dependence means that when the drug is stopped, the patient will experience withdrawal symptoms. Tolerance refers to the phenomenon where higher doses are needed to achieve the same effects, including both the analgesic and adverse effects of the opioid. So the longer somebody is on the opioid, the higher doses are needed to get the same level of pain relief. There's individual variability in the development of tolerance in terms of how quickly it develops, but we think it occurs in everybody. Theoretically, there is no dose ceiling, with opioids meaning that people can be, as long as you increase the dose is slowly enough, people can continue to have their dose level raised. It's important to note that physical dependence is not the same as addiction. Addiction is a brain disease characterized by compulsive use. So it's defined by behavioral effects, whereas physical dependence and tolerance are biological physical effects. Opioid misuse in primary care is likely to be under-recognized and under-diagnosed. Published rates are prescription opioid misuse, among those prescribed opioids ranged from four percent to 26 percent. However, in a study that did a detailed standardized interviews, much higher proportions of patients reported are problematic use patterns. In this study, 26 percent of patients reported purposeful over sedation, 39 percent reported increasing the dose without a prescription, eight percent reported obtaining extra opioids from other doctors, 18 percent used opioids for purposes other than pain, 20 percent drink alcohol to relieve their pain, and 12 percent hoarded their pain medications. One of the problems with interpreting the data on opioid misuse in primary care is that the definitions for misuse or inconsistent across studies. Also the behaviors vary quite a bit in seriousness, so handle the other studies often lump these together. The methods used to detect opioid misuse have been not well standardized, and we do have some data from efficacy trials, but these are likely to underestimate risks because they evaluate selected populations who are at lower risk. We have better evidence over the last decade or so about factors associated with opioid overdose in patients prescribed opioids. These include aberrant behaviors. This can be taking extra doses, unauthorized dose escalations, loss prescriptions, after hours refill requests, obtaining opioids from multiple prescribers, using unprescribed opioids or other medications or substances, or using opioids to treat non-pain symptoms. A recent initiation of opioids is also a higher risk pain because patients aren't tolerant yet. Using methadone as an analgesic is associated with increased risk of opioid overdose. This has to do with the pharmacologic properties of methadone. Using benzodiazepines along with opioids is associated with an additive or synergistic risk of overdose. Having a history of substance use disorders is also associated with increased risk of opioid overdose, presence of psychological comorbidities such as depression, anxiety or PTSD, and being prescribed higher opioid doses. The concept of universal precautions is important in pain medicine. We think universal precautions are important because predicting opioid misuse to the imprecise science. We can't always easily predict who's likely to engage in misuse or develop opioid use disorder. So using universal precautions helps us to protect all patients and protect public and community health. It also helps to be more consistent in how we apply our precautions and is consistent with clinical practice guidelines. This help to take pressure off the provider, reduces stigmatization of individual patients, and bias on how patients are managed and helps to standardize systems of care. It does not mean that you don't individualize assessment, but it allows for individualization within a standardized approach. Some common universal precautions include: A comprehensive pain assessment including opioid risk assessment, formulation of the pain diagnosis or diagnoses, approaching the initial opioid prescription as a test or trial, and then making a ongoing reassessment to determine whether opioids should be continued or discontinued. The decision to continue or discontinue opioid therapy should be made regularly. For example, every 2-3 months, and it requires regular face-to-face visits and clear documentation. There's a number of strategies we can use to help mitigate the risk associated with opioids. These include careful patient assessment and selection, use of medication agreements, avoidance of higher doses and monitoring including urine drug testing, reviewing prescription drug monitoring data, avoiding sedative hypnotics in particular benzodiazepines, consulting with our colleagues and addiction, pain and psychiatry, doing more frequent refills with smaller quantities, utilize an abuse deterrent formulations and the naloxone co-prescription. Unfortunately, evidence on the effects of risk mitigation strategies on clinical outcomes such as overdose or opioid use disorder are currently lacking, but these strategies all have a sound basis for thinking they can help reduce risks. So patient selection and risk stratification. Risk assessments should be performed in all patients prior to initiating opioids. We know that aberrant drug-related behaviors can occur in up to 50 percent of patients prescribed opioids for chronic pain. The strongest predictor is a personal history of substance abuse, family history is also an important predictor, psychological comorbidities are also a factor. Opioid should only be considered in patients in whom benefits are likely to outweigh the risks, and an important principle is that opioids are not always appropriate. There are patients in whom the risks of opioids are likely to outweigh the benefits. There are some tools for risk stratification that are available and can help in the risk assessment. This slide shows a couple of simple screens that can be done for unhealthy substance use. So for alcohol, there's a simple question, a single question, do you sometimes drink beer, wine, or other alcoholic beverages? If so, how many times in the past year have you had five for men, four for women or more drinks in a day? Positive responses are greater than never. For drugs, the question is how many times in the past year have you used an illegal drug or used a prescription medication for non-medical reasons? Positive responses are greater than never. So positive responses can lead to more detailed assessments and can signify patients who are at risk for unhealthy substance use. We have a number of opioid misuse risk screening tools. This includes the ORT or opioid risk tool, the SOAPP, the COMM, the STAR, the SISAP, PDUQ. Unfortunately, there's no gold standard at this time and all of these tools require more rigorous testing to validate. But as I said before, they do provide a useful framework for thinking about patient risk and can be useful tools. This is the opioid risk tool. It's administered on the initial visit prior to opioid therapy and can help predict misuse behaviors in patients prescribed opioids. You can see it's a simple point system. The points are slightly different for females and males. They're based on family history of substance abuse, personal history, age history of preadolescent sexual abuse, and presence of psychological disease. In the original cohort, people who scored 0-3 points had a six percent likelihood of engaging in aberrant behaviors after being prescribed opioids, persons at moderate risk at 28 percent, and people who scored greater than eight points are at high risk greater than 90 percent. So at least in the initial studies this helped to differentiate risk. Screening should also be done for psychological comorbidities including depression. The PHQ2 is a widely used instrument. As an initial screen, it asked two questions over the last two weeks. How often have you been bothered by any of the following problems? Little interest or pleasure in doing things or anhedonia, and then feeling down, depressed, or hopeless. If this patient scores more than three points, then they get administered more full PHQ9. It's also important to assess for other mental illnesses such as anxiety, PTSD, personality disorders, and suicidality and to address these issues if they're present. Medication agreements are another risk mitigation strategy. There's a couple of different goals for medication agreement. One is to provide informed consent, so patients understand the risks and benefits of therapies as well as goals. They also outline the plan of care. Again, including the goals of therapy, a follow-up monitoring plan, and how opioids will be prescribed and refilled. The medication agreements are signed by both the patient and the prescriber. They serve as a patient counseling document and also help delineate expectations. They also help when patients are being seen or managed by other clinicians in order to document the plan of care and help provide some consistency in how they're being managed. Again, the evidence on effects on clinical outcomes are lacking, but we think that these are important and useful tools. The initiation and titration of opioids is an important period for helping to mitigate risks. Again, the initial course of opioids should be viewed as a short-term, for example, four weeks therapeutic trial and the decision to proceed or continue with long-term opioid therapy should be a conscious one. We think that oftentimes patients are started on opioids for an acute pain problem or a chronic pain problem and then six or 12 months later before even realizing it, the clinician realizes that they're still on opioid therapy. So this really should be a conscious decision requiring regular reassessment. If opioids are used, they should be used as part of a multimodal strategy. Remember that chronic pain is best understood in a biopsychosocial framework and that simply giving somebody an opioid doesn't address the important psychosocial contributors to pain. Opioid should always be started at low doses and titrated cautiously. Opioid therapy should not be initiated with the long-acting opioid. This is associated with increased risk of overdose during the initiation period. The old teaching was to transition all patients on long-term opioid therapy to round the clock long-acting opioids. However, on looking at the evidence, there really is insufficient evidence to show that strategy associated with increased effectiveness or decreased risks of opioid use disorder, opioid overdose, or other harms. So we think that both of these are reasonable options, either putting somebody on immediate release as needed opioids or round-the-clock long-acting opioids. Methadone and fentanyl are not recommended as first-line options. They are less predictable and have more complicated dosing and pharmacokinetics. Buprenorphine is a partial agonist with theoretically lower respiratory risks and might be useful in higher risk patients. Evidence showing decreased overdose risk is lacking and some formulations of buprenorphine are not approved for chronic pain, they're only approved for opioid use disorder. So if they're used for chronic pain, they would have to be used off label. A few more words about methadone. This is a synthetic opioid that's used for treatment of addiction as well as pain. We've observed an increase in the number of methadone deaths nationwide. So from 1999, we had 800 deaths and in 2008, it was nearly 5,000. The number of deaths with methadone is disproportionate to the amount that it's prescribed. So methadone accounted for 1.7 percent of opioid prescriptions in 2009 and 9.0 percent of morphine-equivalent doses in 2010, yet it was involved in 31 percent of opioid-related deaths and 40 percent of single-drug deaths. This we think is related in part to its half-life. Again, methadone has a long half-life compared to most other opioids and it's also unpredictable. So the half-life ranges from 15- 60 hours and can be up to 120 hours. In a patient with a 60-hour half-life, this means that it takes 12 days or almost two weeks for methadone to reach steady-state, so those methadone levels continue to increase over those 12 days. These can be the patients that five or seven days after starting the methadone have respiratory failure. Methadone is also associated with a QTc interval prolongation and torsades which is the ventricular arrhythmia and it requires ECG monitoring at baseline as well as when prescribed at higher doses. This slide illustrates just the pharmacokinetics, the time to reach steady state. We think that's about three-and-a-half to four-half lives. So again with the 60 hour half-life, it takes almost two weeks for the drug to reach its steady state level. So one of the problems with methadone can occur not just with the drug levels continuing to accumulate, but if patients increase the dose before those two weeks are up. If they increase the dose every three days or every five days, that set point will continue to go up higher. Again, these can be the patients who experienced overdose due to respiratory depression. This slide shows a patient on the top strip, it shows a prolonged QTc in a row, and then that deteriorates into torsades in the bottom rhythm strip. Which again is a ventricular arrhythmia that can be a perfusing Relenza, can also be life-threatening or degenerate to ventricular fibrillation. Another factor to be aware of is the relationship between overdose and higher dose. There seems to be a dose-response relationship. We've had a number of observational studies in the last 5-10 years that consistently shown association between higher opioid dose and risk of overdose or death and patients with chronic pain. We see the risk starts to increase at relatively low doses and continue to go up as the dose goes up. The studies matched or adjusted for potential confounders available in administrative databases such as other medications and other diagnoses. This slide summarizes several key studies that have looked at the association between opioid dose and risk of overdose. So you can see at 20-50 morphine equivalents compared to being on less than 20 morphine equivalents, the risk of overdoses increased about 30 percent to a 100 percent when you get to 50-100 morphine equivalents the risk of overdose is anywhere from two times to five times, and then when you get over a 100 morphine equivalents, it can be 7-9 times higher. So in terms of dosing although there's no theoretical ceiling with opioids due to the tolerance effects we discussed earlier, the benefits of higher doses are really pretty unclear. We don't have a lot of data showing that continuing to increase the dose in patients with chronic pain actually results in greater function or reduce pain. In fact, in clinical practice, we often see patients who appear to be what I would call an opioid non-responder, that people who don't respond to lower doses of opioids often don't respond to higher doses of opioids. We also know that titration to achieve pain relief is inconsistent with the evidence we have on benefits. The randomized controlled trials that are placebo-controlled, show about a 20 percent reduction in pain relief on average. So trying to increase the dose to get complete or near complete pain relief is just inconsistent with what we see in the studies. As we just mentioned, there seems to be a pretty clear dose-related risk of overdose. So one of the risk mitigation strategies is to apply dose thresholds. The 2016 CDC guideline recommends caution at doses of more than 50 morphine equivalents per day and to avoid doses more than 90 morphine equivalents per day. This is based in part on a couple of data points. One is that the average dose and overdoses in a VA population was about 98 morphine equivalents per day. You actually see about 50 percent of overdoses in patients on less than 60 morphine equivalents per day. So even at that lower threshold, there's still risk of overdose. If higher doses are used, clinicians need to apply more frequent or intense monitoring and additional risk mitigation strategies to help mitigate those risks. In terms of monitoring outcome, it's important to evaluate patients in multiple domains. We want to move away from focusing on pain as the main goal of treatment. As noted before, there's no therapy for chronic pain is affective at completely relieving pain. We know that patients can report improvement in pain with no improvement in function, and this may not be a true meaningful outcome for most patients. I think we often assume that patients want their pain to be gone, and I think that is true to some extent, but if you talk to patients and you ask them what they really want, they often will say something like, I" want to have my life back", which is really a functional goal. We know we can be quite effective at improving function, even though we know from the trials that we are often not effective at completely eliminating pain. So it's important to measure function and to set functional goals. The functional goals should be achievable and measurable. We also want to screen for and address psychological co-morbidities. Pain is often associated with sleep issues and it's very difficult to control or manage pain in people who are not sleeping. So it's important to address the sleep issues as well and to screen for substance abuse. This is the PEG scale. This is developed by Erin Krebs. This is derived from their brief pain inventory and has been validated. It's a simple 3-item tool that has been adopted by many health systems and incorporating to some EMRs. It helps to monitor both intensity of pain as well as effective pain on enjoyment of life and on general activity. So it addresses the functional component as well. Urine drug tests are another important risk mitigation strategy. They help provide objective information regarding evidence of problems. We know that self-report is unreliable, behavioral observations only detect a proportion of problems. They help provide evidence of adherence to the opioid plan of care, whether illicit substances or an prescribed medications are being used or not used, and they might help improve adherence. Urine drug test should be performed at baseline and periodically in low-risk patients one or two times a year, maybe sufficient, three or four times a year maybe necessary. Higher risk patients are even more frequently. There are a number of strategies that can be used. Urine drug tests can be random, scheduled and or when concerns arise, again, it's important to have a defined approach and to apply it in a consistent pattern. It's helpful to discuss expected finding with the patient prior to testing. It can be pretty informative what patients will tell you before their testing, and it provides an opportunity to discuss this rather than kind of coming after the patient with the got you kind of thing after receiving the results. It's important to consult with toxicologists or clinical pathologists if the patient disputes the findings. Urine drug tests can be tricky to interpret especially on patients on multiple opioids or high doses, and we do see unusual metabolites, contaminants, etc. So it's important that talk with your clinical pathologists and it's also important to know that you're in drug tests are not infallible, that people who are really intent on deceiving the system can do. So urine drug tests are really just one more tool that we can use to help guide our care. Prescription drug monitoring programs are now available in almost all states. They can help identify cases of doctor shopping. The use of PDMPs, however, continues to be variable and it's generally suboptimal. PDMP is very and who can access information is not available across states in many instances. There are a number of policy measures related to PDMPs with more than 20 states now mandating use of prescription drug monitoring programs before writing for controlled substances. Again, evidence showing effects of PDMP monitoring on clinical outcomes such as overdose or opioid use disorder are currently lacking. The combination of opioids and benzodiazepines is associated with a markedly increased risk of opioid overdose. Other medications with respiratory depression effects may also be associated with similar risks, we just don't have the same kind of data yet. Benzos should be tapered gradually. Withdrawal can be serious especially in patients on higher doses. We have other effective evidence-based therapies for anxiety. These include cognitive behavioral therapy, antidepressants, other non-benzodiazepine medications. These should be used in preference to benzodiazepines, and it's important to coordinate care with mental health professionals when trying to taper patients off of benzos. Naloxone is an opioid antagonist that can rapidly reverse opioid overdose. This takes advantage of the fact that most overdose episodes are witnessed, so the naloxone can be administered by a bystander who sees the overdose event. Naloxone is highly effective in addiction settings and there is some evidence of effectiveness in chronic pain settings, though more limited. The CDC recommends naloxone for all patients on more than 50 morphine equivalents per day or who have other risk factors for overdose. It can be considered for all patients prescribed opioids. All states have passed Good Samaritan laws providing civil or criminal immunity for administration of naloxone. There are resources and education on naloxone and on administering it. Again, this is going to be administered not by the patient, but by family members or friends. So they need to be educated about this. Naloxone is available on FDA approved intramuscular and intranasal formulations. Also, is used off label as an injectable hooked up to a nasal atomizer. Abuse-deterrent formulations; a number of these have recently been approved by the FDA or are undergoing the FDA approval process. These are designed to be tamper-resistant or co-formulated with medications that reverse opioid effects or produce noxious side-effects when tampered with. The effectiveness of abuse-deterrent formulations for reducing misuse or substance use and improving clinical outcomes is unproven. It's important to remember that they're likely to be primarily effective in patients who crush or inject opioids, meaning that people who overdose because they're, for example, combining opioids with benzodiazepines, or taking extra doses of opioids. Abuse-deterrent formulations are not designed to prevent overdoses associated with those types of behaviors. There's also some evidence that there may be unintended consequences with use of abuse-deterrent formulations, where some patients may seek other prescription or illicit opioids in preference. It's important to always evaluate aberrant drug-related behaviors when they are observed. Remember that behaviors can vary quite a bit in terms of seriousness. So for example, taking one extra dose of an opioid because somebody is having a lot of pain that day is probably not as serious as somebody who injects or snorts an opioid or combines them with heroin. It's important to judge the seriousness of the overdose, excuse me, of the behaviors, the cause or causes of the behaviors, how likely it is to recur in the clinical context. Some predictors of high likelihood of future behaviors include three or more episodes of aberrant behaviors or a sense of losing control. Responses to aberrant behaviors can range from patient education, going back over the medication agreement, setting parameters about how the opioids will be used, enhanced monitoring, up to a referral to an addiction specialist with discontinuation of therapy. Discontinuation of opioid therapy can be an important risk-mitigation strategy. Patients should be tapered or weaned off of long-term opioid therapy when they engage in serious or repeated aberrant drug-related behaviors, or drug abuse, or diversion, if they're not experiencing progress towards meeting therapeutic goals, or if they're experiencing intolerable adverse effects. It's important that we're not discharging patients. We're still trying to manage their pain off of opioids. There are many non-opioid therapies that can be used. When initiating a trial of long-term opioid therapy, it's important to have an exit strategy. So to know how you're going to stop and when you're going to stop opioids. Before even starting the trial, you should have plans for tapering or discontinuing opioid therapy. Reasonable starting point is a reduction in the daily dose of 10 percent per week. Some studies have shown that doing this minimizes withdrawal symptoms. In practice, we see that many patients actually require slower tapers. Know your resources for managing addiction and mental health issues, which may be exacerbated by attempts to discontinue. Patients already on high doses represent a challenge in many practices. I think there's several categories for thinking about established patients on high doses. So for those who are on over 90 morphine equivalents per day who meet criteria for the taper, it's pretty clear they should be tapered. We haven't been good enough about doing this. So if people are engaging in aberrant behaviors, if they're not having any benefit from opioids, there's no reason to continue them on those high doses. For patients who don't have clear criteria for tapering, the CDC guideline recommends that clinicians discuss recent evidence regarding the dose-dependent overdose risk, re-evaluate continued use of high opioid dosages, and offer at least the opportunity to taper. Many of us would say that most patients on high doses deserve at least a trial of a taper. It's important to work with and collaborate with the patient on a tapering plan. We found that this becomes easier with experience that many patients can be tapered successfully to safer doses, that they often do not report worse pain, they'll either report that the pain is similar or a little bit better, and they may be able to function better or be experiencing less side effects. Opioid use disorder is defined in DSM-5 as a problematic pattern of opioid use, leading to clinically significant impairment or distress. In 2014, about 1.9 million Americans were estimated to have opioid use disorder due to prescription drugs, about 600,000 due to heroin. Opioid use disorders associated with decreased quality of life, negative impacts on morbidity and mortality. The treatment for opioid use disorder includes FDA approved medications, which are the primary treatment. There's agonist medications; methadone, partial agonists; buprenorphine, as well as antagonists; naltrexone. The treatments block the euphoric and sedating effects of opioids, decrease craving, and help mitigate withdrawal symptoms. They are associated with decreased illicit use and misuse of medications, and improved social functioning, decreased criminal activity, and decreased risk associated with injection drug use. This slide shows the DSM-5 criteria for opioid use disorder. To meet the criteria for mild opioid disorder, you have to be positive for 2-3 of these criteria. For moderate opioid use disorder, it's 4-5 criteria. For severe opioid use disorder, it's greater than equal to 6 criteria. It's important to remember that tolerance and withdrawal are not considered to be criteria for individuals taking opioids under appropriate medical supervision. So in patients who have suspected opioid use disorder, it's important to discuss with your patient and provide an opportunity for them to disclose their concerns. Assess for opioid use disorder using the DSM-5 criteria. If present, offer arranged medication assisted treatment. Buprenorphine can be prescribed through an office-based buprenorphine treatment provider or by an opioid treatment program specialist. Methadone maintenance therapy can only be dispensed in an opioid treatment program. Oral or long-acting inject-able formulations of naltrexone can be administered in office-based settings, as well as in OTPs. Consider obtaining a waiver to prescribe buprenorphine for opioid use disorder. We know that there's gaps in access to treatment for opioid use disorder and that many patients can benefit from this therapy. In terms of using opioids for acute pain, opioids have generally been considered effective for acute pain, but some recent data indicates that opioid maybe no more effective than an NSAID alone for some types of acute pain. In low-back pain adding oxycodone-acetaminophen to an NSAID did not improve pain or function at one week, compared to the NSAID alone. We also know that using opioids for minor pain is associated with an increased risk of long-term use, compared with no opioid use. Having an opioid within seven days of minor surgery was associated with a 44 percent increased risk of use at one year. Prescribing excessive quantities of opioids for acute pain also results in leftover opioids. This is a source of diversion and unprescribed use. So all of these factors support more judicious use of opioids for acute pain. The CDC guideline recommended that if opioids are used, to limit the supply to 3-7 days for most acute pain. For chronic pain, as I mentioned before, opioids are moderately more effective than placebo for short-term pain relief. The effects average 20-30 percent improvement in pain, or 1-2 points versus placebo. Data on long-term effectiveness is quite limited. Until recently, there were no placebo-controlled trials more than six months. In fact, most trials were shorter than eight weeks. Uncontrolled studies show that many discontinuations occur due to adverse effects are insufficient pain relief. Some patients who continued on opioids have reported long-term pain relief. In most studies, effects of opioids on function are generally smaller than effects on pain. Some trials show no or minimal benefits. Remember that these represent optimal results. The trials typically exclude patients at high risk for abuse or misuse, people who have psychological or serious medical comorbidities. We also have very limited evidence on the effectiveness of opioids for a number of commonly treated pain conditions, including fibromyalgia, headache, and others. The SPACE trial was just published in 2017. Actually, it was presented in 2017 and published in 2018. This is a first long-term randomized controlled trial of opioid therapy versus non opioid therapy for chronic low back pain and osteoarthritis pain. This is a study done in the VA and primary care, and the sample size was 240 patients. Now, the study was open label for patients and clinicians. Assessment of outcomes was massed to whether patients were receiving opioid therapy or non opioid therapy. All patients in the trial received individualized medication management using a collaborative telecare pain management model. The opioid daily dose was limited to 100 milligrams of morphine equivalents per day. Most patients received between 75 to 120. The results of this study were quite striking. At 12 months, there was no difference in function between opioid therapy versus non-opioid therapy. Pain was actually slightly worse than the opioid group. There was no difference in the likelihood of clinically significant improvement. So you can see that the likelihood of clinically significant improvement in the brief pain inventory interference scale was 59 percent versus 61 percent. For the BPI severity scale, 41 percent versus 54 percent. Opioids were associated with more adverse symptoms. Excuse me. More adverse effects. There were no deaths or cases of opioid-use disorder in this trial. So this slide shows the effects on pain intensity. You can see that over the first six months or so, the effects of opioids and non-opioid therapy on pain were virtually identical. From 6-12 months, the non-opioid group actually had decreased pain by about half a point point on a 10-point pain scale. This slide shows the effects on the BPI interference scale, where there's virtually no difference between the groups at any time point. So the results of the SPACE trial are very consistent with what the 2016 CDC guideline says. The first recommendation in that guideline is that non-pharmacologic therapy and non-opioid pharmacologic therapy are preferred for chronic pain. Consider opioid therapy only if expected benefits are anticipated to outweigh risks, and if opioids are used to combine with appropriate non-pharmacologic therapy, and non-opioid pharmacologic therapy. Recommendation number 6. For acute pain. When an opioids are used for acute pain prescribed the lowest effective dose of immediate release opioids, and prescribe no greater quantity than needed for the expected duration and severity of pain, usually 3-7 days. So the approach to treatment of pain for acute pain. Avoid prescribed bed rest, early return to activity is actually preferable for almost all types of acute pain. Heat and cold can help reduce pain. Over the counter analgesics. Identify and address psychosocial risk factors early. This can help prevent the transition to chronic pain. On chronic pain, again, we want functional goals and improvement, not just on pain relief. It's important to help patients in terms of self-care for their chronic pain. This includes coping skills, relaxation and meditation, strategies, activity and exercise, and again, identifying and addressing psychosocial contributors to pain, which can include depression, anxiety, PTSD, and sleep issues. Non-opioid therapies are critical for managing chronic pain. A number of non-opioid therapies are similarly or more effective than opioids, and safer. We need to get away from the concept that opioids equal effective or good pain management. All the data that we have show that opioids are not any more effective than non-opioid therapy, or only slightly more effective, and associated with far greater risks. We want to prioritize active over passive modalities in terms of which non-opioid therapies we use. This is consistent with a biopsychosocial approach to chronic pain. Active therapies include things like psychological treatments, exercise, interdisciplinary rehabilitation, and mind-body interventions. These all actively engage patients with a focus on improving function and movement. Passive therapies include things like non-opioid medications, physical modalities, like ultrasound, TENS, etc. Complementary and alternative treatments such as manipulation, acupuncture, massage, and interventional treatment like epidural injections or other steroid injections. The main focus for passive therapies is symptom relief, and they're passive in the sense that they're not actively engaging the patients, or getting them to move and improve in terms of their function. So passive therapies can be helpful, but they should be used as an adjunct or a bridge to active therapies. Some factors that will influence which non-opiate therapies are used include costs, availability, and patient preferences. So talking about some of the non-opioid therapies for pain, an important one is cognitive behavioral therapy. This is psychological therapy that integrates cognitive therapy, which involves restructuring maladaptive thinking patterns, or thinking patterns that actually make the condition worse. Behavioral therapy, which replaces undesirable with healthier behaviors. So it's very goal-oriented, it works on having patients set functional goals, trying to achieve them, if they're not able to achieve them, trying to understand why they can't achieve them, and then helping them troubleshoot, and learn strategies for overcoming those obstacles. Cognitive behavioral therapy is effective for improving pain, disability, mood, and maladaptive behaviors. Some of these effects appear to be sustained, and it may be more effective in persons with psychosocial risk factors. Meditation and relaxation is a helpful technique for self-management and coping, it incorporates some CBT principles. Ways that meditation and relaxation work include distraction, reducing anxiety, reducing sympathetic arousal, reducing muscle tension, and altering central processing of pain, and other stimuli. Meditation and relaxation have increasing evidence on effectiveness, in some studies, mindfulness-based stress reduction is similarly effective to formal CBT. There are a number of techniques for meditation and relaxation, these include meditation, progressive muscle relaxation, hypnosis, guided imagery, yoga and Tai Chi which are both movement-based therapies that incorporates meditation and relaxation principles and related technique is biofeedback. Exercise is also an important active therapy. It has effects on both pain and function as well as general health. Exercise helps to address a maladaptive behavior that we refer to as fear avoidance behavior. This is a belief that hurt equals harm. We want patients to understand that it's okay to be active and to move even when there's some pain and that continued movement will actually help them in the long run. There are many different types of exercise. These include aerobic, strengthening, stretching, and mixed techniques, Mckenzie, motors control and stabilization, active trunk exercises and others. Exercise can be supervised or done in the home, they can be done as a group, or on an individualized basis. As mentioned before, there's a number of related techniques including yoga, and Tai Chi, and things like Pilates and the Alexander technique. Ideally, exercise is done within a CBT-informed framework. No technique appears to be clearly superior. Supervised individualized exercise programs may be more effective initially. Handouts and videos can help facilitate home exercise regimens and home exercise may be just fine for a highly motivated patients. It's important to start slow and to incrementally increase the exercise. You want to have sustained engagement, so if you do too much, too fast, patients are likely to not stick with it. Interdisciplinary rehabilitation combines psychological treatments and exercise, it's provided by professionals from at least two different specialties and again, focuses on improvement and function. The components and intensity of interdisciplinary rehabilitation vary. It's more effective than non-interdisciplinary rehab with some evidence of sustained effects. An important barrier to use of interdisciplinary rehab has been the lack of availability and reimbursement. It may be most effective in persons who fail standard therapies who have severe functional deficits or who have severe psychosocial risk factors. As mentioned before, passive therapies can be used as an adjunct to the active therapies. There are a number of physical modalities, these include things like ultrasound, tense, other types of electrical stimulation, traction, back supports, those kinds of things. The evidence on most physical modalities is limited, it's difficult to show consistent or sustained benefits. We do have some data showing that heat is similarly effective to NSAIDs for acute low back pain. Most other modalities are not generally recommended though they're fairly safe, so they can be considered as an option. Manipulation, acupuncture, and massage are complimentary and alternative therapies that we have some evidence of benefit for certain pain conditions. Some of these effects are likely to be nonspecific and related to the hands-on nature of these therapies. Again, if they're used, they should be used as an adjunct to active therapies. Be aware of the costs. There's no point in continuing the therapies if they're ineffective in initial trials. Expectations of benefit can predict whether one of these therapies is going to be effective. If somebody doesn't believe in acupuncture, they're unlikely to benefit from it. We do have enhanced access to complementary and alternative therapies through the Affordable Care Act. Number of non-opioid medications are also available. Acetaminophen and NSAIDs are first-line therapies for many conditions, the benefits are modest, but we understand the risk well and they can usually be managed well in most patients. Tramadol and tapentadol are drugs that have a dual mode of action, they have effects on the opioid receptor, and also some centrally acting effects. Tramadol is schedule IV and tapentadol schedule II. Gabapentin and pregabalin are anticonvulsants that are first-line for neuropathic pain. Pregabalin is a schedule V drug. Both of these medications are off-label for non-neuropathic pain. Antidepressants, the SNRI's or serotonin and norepinephrine reuptake inhibitors are first-line drugs for neuropathic pain. Tricyclic antidepressants can still be used, but they have a lot more anticholinergic and cardiac adverse effects, and SNRI's have supplanted them. Duloxetine which is an SNRI's approved for fibromyalgia as well as for chronic back pain. A number of skeletal muscle relaxants are available, these are generally all sedating, mostly used short-term for acute pain. Cyclobenzaprine which is quite similar to a tricyclic antidepressant and tizanidine which is similar to clonidine are the best-studied skeletal muscle relaxants, a number of these drugs are quite old and have not been studied in recent rigorous trials. Benzodiazepines, again, should generally be avoided in combination with opioids. There are some topical medications that are available including topical lidocaine for neuropathic pain and topical NSAIDs for localized osteoarthritis. So in conclusion, we have very limited data on the long-term benefits of opioid therapy, with some evidence showing no benefits versus non-opioid therapy. There's accumulating evidence on serious harms of long-term opioid therapy that appear to be dose dependent. Benefits of opioids appear limited and the harms are significant. This suggests a close balance of benefits to harm. These all justifies a more cautious approach to use of opioids for pain. This includes utilizing universal precautions including risk assessment, patient selection, monitoring, and risk mitigation strategies. Non-opioid therapies are preferred for treatment and it's important to assess patients for and to treat opioid use disorder when present, training for prescribing buprenorphine in office-based settings is available and encouraged. So the next few slides just show references for those interested in reading up more. So the PCSS Mentor Program is designed to offer mentoring assistance to those in need of more one-on-one interactions with one of our colleagues to address clinical questions. You have the option of requesting a mentor from our mentor directory or we're happy to pair you with one. To find out more information, please visit our website using the web link noted on this slide. PCSS also offers a discussion forum which is comprised of our PCSS mentors and other experts in the field who help provide prompt responses to clinical cases and questions. We also have a mentor on colleague's month that is available to address any submitted questions to the discussion forum. You can create a new login by clicking the image on the slide to access the registration page. This slide simply note the consortium of lead partner organizations that are part of the PCSS Project as well as our contact info website, and Twitter and Facebook handle to find out more about what we offer. Thanks.
