Welcome to today's educational webcast titled Chronic Opioid Use and Sleep Disordered Breathing, Waking Up to the Association, sponsored by the American Academy of Sleep Medicine and co-sponsored by the AASM Education Committee. Today we have Dr. Nisha Arora joining us to discuss this timely topic. Dr. Arora is an Associate Professor of Medicine at Rutgers Robert Wood Johnson Medical School. She is currently involved in human-based research examining metabolic outcomes in sleep disordered breathing. She has been committed and active in the American Academy of Sleep Medicine. She is currently serving on the Board of Directors on the Executive Committee for the AASM Foundation and as Chair for the Guidelines Advisory Panel. She is also an Associate Editor for JCSM. Thank you for joining us, Dr. Arora. Thank you so much for having me. I have no conflict of interest to declare for this topic. I'd like to go over the agenda and plan for today. We'll start by giving some background, including some history and epidemiology. Then I'll discuss mechanisms of respiratory depression that are associated with chronic opioid use and how they can lead to manifestations and different patterns of sleep disordered breathing. I'll then focus on central sleep apnea and obstructive sleep apnea specifically, as these two entities are more likely to be seen in clinical practice. Finally, we'll discuss therapeutic modalities. To give you some idea of the history, opioids actually came over on the Mayflower in the 1600s, but they weren't legalized in the United States until 1775 with the American Revolution. In fact, opioid use became so widespread that as you can see on the slide, this is an advertisement for Mrs. Winslow's soothing syrup. This is meant for children. It had both opiates and alcohol in it. The advertisement claimed that it helped allay all pain, soften the gums, soothe the child, relieves wind, regulates the bowels, and is the best known remedy for diarrhea and dysentery from teething and all other causes. It was widespread use. It wasn't until Teddy Roosevelt came to office at 1906 that the Pure Food and Drug Act were passed. He required that any dangerous or addictive substances be labeled such. In 1914, the Harrison Narcotics Tax Act came into play. A federal registry was developed, and anyone involved in the distribution, dispensing, manufacturing, or production of narcotics or opioids was required to pay a heavy tax. While physicians were spared from this, it became increasingly difficult for them to actually prescribe any kind of opioid medications for their addict patients. In 1920, with the prohibition of alcohol, the use of opioids and opiate medications spiked, as one can imagine. And by the time prohibition ended in 1933 and alcohol became socially acceptable, opiate users were marginalized and declared junkies in many places. After 1945 and the end of World War II, synthetic opioids came into the market. There was a spike, however, with heroin use with Vietnam War in the 1960s, and this basically led to the development of the Controlled Substance Act in 1970 and the formation of the DEA in 1973, which was designed specifically to limit access to opioids. However, 25 years later, there was a statement issued by the American Academy of Pain Medicine and the American Pain Society that suggested that health care providers were under-treating pain and fears about respiratory depression were unfounded. This declaration actually coincided with three seminal events. The requirement by the joint commissions for hospitals to be more aggressive and comprehensive in pain management, the renewed and expanded use of methadone in chronic pain, and the introduction of new sustained release opioids, long-acting opioids primarily advocated by pharmaceutical companies. The statement says that it is now accepted by practitioners in the specialty of pain medicine that respiratory depression induced by opioids tends to be short-lived and that withholding opioids for a patient experiencing pain is unwarranted on the basis of respiratory concerns. The central tenet of this recommendation rested on the belief that long-term use of opioids led to tolerance and diminished side effects, especially sedation and, more importantly, respiratory depression. We know that this actually might be true in wakefulness but has not been shown for sleep. Over the next six years, from 1997 to 2003, the distribution of methadone increased by over 800 percent and the distribution and availability of oxycodone increased by over 600 percent. And as you can see here, over the next 10 years, opioid use in the U.S. but also globally escalated in an unprecedented manner. And you can see here that in North America especially, we go from having some opioid use to the highest level of opioid availability and use. Focusing back on the United States, in 2006, the rate of opioid dispensing, which is the number of prescriptions per 100 people, was approximately 72. In 2012, we reached a peak of opioid dispensing with 259 million prescriptions written and the dispensing rate going up to 81 per 100 people. It was mostly the internists, general practitioners, family practice, people that were seeing the increase and relating the increase after the 1997 declaration. In 2016, the CDC actually issued opioid prescribing guidelines and since then, we've seen a decline in the prescribing rate to 47 prescriptions per person, per 100 people. So, you can see here there's been a decline. So, that is the good news that by 2019, we almost cut that dispensing rate by half. However, here is the bad news. Despite the fact the prescriptions have come down in terms of opioid prescriptions, most of the deaths, even up to 2019, still involved an opioid. And year over year, from 2018 to 2019, you can see that there's an increase in the opioid-involved deaths. Prescription opioids, while they were still involved in about 28 percent of all opioid overdose deaths, there was a decrease year over year from 2018 to 2019. The problem was that the prescription opioid increase had already created the problem. And when they came down, people were looking for alternate sources. And one of the biggest sources was synthetic opioids, whether illicitly manufactured or prescribed. And this is primarily fentanyl and fentanyl derivatives. So, these death rates increased by 15 percent. Opioid prescription has led to a lot of problems with misuse and addiction and laid the foundation. So, the rates of misuse and addiction were actually already high, as seen in 2015, reported to be 21 to 29 percent in misuse and 8 to 12 percent of people on opioids addicted. However, in 2020, there was more bad news regarding problematic opioid use. When the whole population of chronic opioid users was considered, it was actually much higher in terms of a problem opioid use at 36.3 percent. This included misuse, addiction, dependence, and aberrant behavior. And as we can see here, deaths from opioid overdose and use have continued. So, you can see this first wave here started in 1999. This was after the statement came out in 1997, and there was a wave or increase in prescription opioids. In 2010, there was a second wave, which was related to heroin overdose deaths. But you can see here in 2013, the latest wave, which continues to climb upwards, is secondary to synthetic opioids, specifically fentanyl and fentanyl derivatives, whether prescribed or illicitly manufactured. One of the biggest problems is that many of these deaths occur during sleep. And that's why we, as healthcare providers, and specifically with sleep providers, need to be concerned about this opioid epidemic. To really understand the effects of how opioids affect breathing during sleep, it's important to understand the mechanisms by which opioids induce respiratory depression. There are three opioid receptors, mu, kappa, and delta, that are distributed throughout the central nervous system. In particular, the mu receptor has the highest affinity for opioids. There are three mechanisms by which opioids cause respiratory depression, and we're going to go over each of these in detail. The first one is that they bind to areas of the brainstem, especially the ventral medulla, where they cause respiratory depression or inhibition of the respiratory drive by binding to respiratory rhythm generator neurons. They also affect chemoreception, both centrally and peripherally, and lead to changes in the ventricular responses to hypercapnia and hypoxia. And finally, they suppress direct activity at central respiratory motor neuron pools that innervate respiratory muscles. Rhythm generation is actually the most sensitive aspect of opioids on respiration. Respiratory rhythm is controlled by centers in the pons and medulla in the brainstem in most animals. In humans, it's specifically controlled by a small area in the ventral lateral medulla known as the pre-Botzinger complex. This pre-Botzinger complex is active primarily during inspiration, and opioids binding here cause suppression of the pre-motor drive, both in terms of the rate and the depth of respiration. So when you have opioids on board, you see a slowing of the inspiratory drive, both in wake and in sleep. Second, opioids affect chemoreception, both centrally and peripherally, and lead to changes in the ventilatory response. The interaction between respiratory generators and the central and peripheral receptors are a large part of the control of breathing. Metabolic control of breathing involves input from both peripheral and central chemoreceptors that detect changes in carbon dioxide levels, oxygen levels, or pH. The central chemoreceptors are located in several locations, especially the nucleus tractus solitaris, the dorsal respiratory group, the medullary raphe, and the pre-Botzinger complex. These receptors are sensitive to changes in the partial pressure of carbon dioxide and the pH, and they increase tidal volume or respiratory rate in response to hypercapnia or acidemia. Peripheral chemoreceptors consist of neurons or collections of neurons that detect changes primarily in the partial pressure of arterial oxygen and also carbon dioxide and pH. These chemoreceptors are located in the carotid bodies and the aortic bodies. What's important to realize, and was shown in a very elegant study in 2005 in CHEST, was that compared to acute opioid use, chronic opioid use produces a very different ventilatory control pattern. This was shown in methadone users that were on methadone treatment for more than two months. While they had a blunted hypercapnic ventilatory drive like acute opioid use, their hypoxic ventilatory drive was extremely augmented or increased, often doubled. This is in contrast to those with acute opioid use who have a decrease in the hypoxic ventilatory drive. This is important to note because this leads to heightened chemosensitivity and may contribute to increased loop gain or control loop gain. Finally, opioids suppress direct activity at central respiratory motor neurons. Opioids bind to mu receptors in the hypoglossal motor neuron and suppress the drive to the genioglossus muscles as well as other upper airway muscles. This could be particularly concerning in the setting of obstructive sleep apnea. Normally, when there is increased airway resistance, there is an increase in the phasic activity of the genioglossus muscle right before inspiration. When opioids are on board, this increased phasic activity is actually decreased. During sleep, the activity of these muscles decreases in everyone, but in those that have no opioids on board, upper airway patency is unchanged. In the setting of opioids, you can get obstruction of the upper airway and also rigidity of accessory muscles, such as the intercostal muscles and the abdominal muscles during sleep. In totality, when all these mechanisms apply together, you get a decrease in the tidal volume and respiratory rate with chronic opioid use. You also see a decline in the hypercapnic ventilatory response, but you see an increase in the hypoxic ventilatory response, mainly due to increased sensitivity of peripheral chemoreceptors, and that is from ongoing long-standing chronic hypoxia. You also see a decrease in the output of the hypoglossal nerve with decreased genoglossal activity and increase in upper airway resistance. The consequences of chronic opioid use were first described on sleep architecture and sleep disorder breathing in 2001 in this small pilot study. In 10 methadone patients on chronic methadone and nine age-matched, sex-matched, BMI-matched controls, the investigators looked at sleep disorder breathing and sleep architecture and compared between the methadone patients and the control group. What they found was that central sleep apnea, with central sleep apnea index greater than 5 or greater than 10, was only seen in the methadone patients. None of the controls had central sleep apnea. Methadone patients also had more subjective daytime sleepiness, and they had poor sleep architecture with lower sleep efficiency, less slow-wave sleep, less REM sleep, and more stage 2 sleep. So this was the first study that actually pointed to an issue with chronic opioid use and sleep, as well as sleep architecture. Since then, several studies have shown that chronic opioid use is associated with a wide spectrum of sleep disorder breathing, including central sleep apnea, hypoventilation, biased breathing, ataxic breathing, and obstructive events. Additionally, the rate or prevalence of sleep disorder breathing with chronic opioid use is extremely high, with most studies demonstrating a prevalence of 30 to 90 percent in patients with chronic opioids. Several patterns of opioid-associated sleep disorder breathing may be seen within one person within the same night. For example, somebody may have central sleep apnea events with apneas of at least 10 seconds, but also mixed with a background of ataxic breathing. So while a breathing pause or breathing apnea of 10 seconds would qualify as an apnea, there may be shorter pauses that don't meet criteria for sleep apnea, but may be ataxic or biased breathing in the background. In fact, ataxic breathing is commonly seen with opioid users, and the variability in interbreath interval has been shown to be cross-correlated with both the central apnea index and opioid plasma concentrations. So these two variables might be considered almost clinical markers for opioid-induced breathing irregularities. It's worth noting that like many other diseases in clinical medicine, the concept of phenotype and endotype is also emerging in sleep disorder breathing in the setting of chronic opioid use. Here, different phenotypes may actually signal different predominating causative mechanisms leading to variable manifestations of sleep disorder breathing across patients. For example, we know that hypoxia can reduce CO2 reserve and make a person more susceptible to apnea and breathing instability. But in certain individuals who have a very hypoxic ventilatory response or controller gain and reduce CO2 reserve, you may see periodic breathing in a mechanism similar to what you see with hypoxia at high altitude with cyclic central sleep apnea events. In other people who have a more narrow reserve, but not the same level of chemosensitivity or loop gain, you may see that a single breath may be enough to cause a central sleep apnea episode that lasts for a while. Finally, some people may have very blunted hypercapnic ventilatory responses, and they are prone to develop hypoventilation or hypercapnic central sleep apnea. So let's take a look at some pictures. Now, you all may be familiar with this top panel. This is central sleep apnea in heart failure, chain stokes, respiration. You see the apneic events here. There is breathing in between, which is crescendo, decrescendo in pattern. The bottom panel shows in a chronic opioid user. Again, you see apneas, but they are longer, and the breathing in between is shorter, and there is no crescendo, decrescendo pattern. Biot's breathing is characterized by cycles of deep breaths in which the amplitude of the tidal volume is fairly stable, but there are interspersed central apneas not reaching 10 seconds, but a variable shorter durations. With ataxic breathing, you see variability in the tidal volume and in the frequency, and again, there's interspersed unpredictable timings or pauses in breathing periods of apnea. This is in contrast to the slide that was just shown with Biot's breathing where the tidal volume is deeper and more stable. You can see different forms of different manifestations even within the same night. Here, you have a person who has some central apnea. You can see here there may be some ataxic breathing, and then you may have some episodes of obstructive apnea as well. While it would be great to talk about all these topics in depth, there's clearly not time, so we're going to focus on the two that we're most likely to see in clinical practice, which is central sleep apnea and obstructive sleep apnea. Let's start with central sleep apnea, and again, this is in chronic opioid use. One of the first groups that reported on the prevalence of central sleep apnea in chronic opioid use is the same group that originally described sleep disorder breathing and architecture in the original study from 2001 that I just shared with you. Here, they confirmed their findings 16 years later. They described central sleep apnea in methadone maintenance patients, 50, 25 men, and 20 women, and they matched them to 20 controls, age, sex, and BMI matched. They sought to look at the prevalence and pathogenesis of central sleep apnea. What they found was that, indeed, central sleep apnea was more common with chronic methadone use compared to the control group. In fact, 30% of their methadone patients had a central apnea index greater than 5, 20% greater than 10. None of the control group had a central apnea index greater than 1. The rates during REM were similar, but it was during non-REM when the differences in central sleep apnea were really seen. Interestingly, they found that the methadone blood concentrations in particular were the only significant variable that was associated with the central apnea index. So, interestingly, the prevalence numbers reported in this modest sample size of 50 methadone users has since been confirmed in multiple systematic reviews with thousands of patients. The meta-analyses from these reviews have, indeed, confirmed that the prevalence of central sleep apnea in chronic opioid users presenting primarily in sleep and pain clinic ranges from 20 to 33%. Given that high prevalence, it would be critical to be able to predict characteristics within these populations that are most likely to have central sleep apnea for early case identification. In 2007, this was one of the earliest studies that was published in JCSM that sought specifically to look at risk factors for central sleep apnea in chronic opioid users. This was a retrospective study with 60 patients on chronic opiates and 60 controls that were matched for age, sex, and body mass. What they found was, we're going to start here on the left side, that the overall apnea hypopnea index was higher in the opioid users at 44 per hour versus 33. Within the opioid group and after controlling for body mass index age, there was a dose response relationship between the morphine dose equivalent on the x-axis here and the apnea hypopnea index, including obstructive apneas, this middle line, central apneas, and hypopneas. These three are in non-REM. There was no difference during REM sleep. Interestingly, and not shown here, the oxygen saturation was lower in opioid users, both in wakefulness and in non-REM by 2%. They also showed that the body mass index was inversely related to apnea hypopnea severity in the opioid group. In the non-opioid group, it is what you would expect with a higher BMI. The rate ratio of apneas and hypopneas was higher compared to the group with the smallest BMI. This was exactly reverse in the opioid group. Central apneas accounted for the higher overall AHI seen in the opioid group. They also demonstrated that ataxic breathing was more prevalent in the opioid group versus the group not on opioids, significantly more. And it was also related to dose, with milliequivalent of morphine greater than 200 having an odds ratio of 15.4 for having ataxic breathing versus those on a lower dose of opioids. Hypnotics did not additionally increase the prevalence of sleep disorder breathing. The authors concluded that there's a dose-dependent relationship between chronic opioid use and the development of a peculiar pattern of respiration consisting of central sleep apneas and ataxic breathing. Since then, several studies have looked at the association between sleep disorder breathing and chronic opioid use. One of the most important studies has been OPS-SAFE, which was conducted at five university affiliated tertiary care pain clinics. This study was the largest prospective multicenter cohort investigating the risks of sleep disorder breathing in chronic opioid users. The study included adults age 18 and older that were taking opioid medications for chronic pain for at least three months with a stable dose for at least four weeks. People who had already been diagnosed with sleep disorder breathing were excluded. The primary objective of the study was to determine whether the stop bang questionnaire, the Epworth Malampati score, viral mental distance, resting daytime oxygen saturation, and the dose of opioids are predictive factors for moderate to severe sleep apnea in patients on opioids for chronic pain. The secondary objective was to identify predictive factors for central apnea index greater than five. The authors found a high prevalence of sleep apnea with 72% having obstructed sleep apnea and 20% having central sleep apnea. 8% were indeterminate. The predictive factors for moderate to severe sleep apnea in AHI over 15 in patients on chronic opioids were the stop bang score and daytime resting oxygen saturation. For the central apnea index, predictive factors included the dose of opioids and again the oxygen saturation resting daytime. I'd like to show you some of the data from the studies. So on the left, across the x-axis, we have the stop bang score. The y-axis is sleep apnea probability. And you can see as the stop bang score increases, the probability of sleep apnea increases as well. And the blue line is basically any sleep apnea over five. Green is moderate to severe sleep apnea and the red line is for 30. What they concluded is for each one unit increase in the stop bang score, the odds of moderate to severe sleep apnea increased by 70%. On the right is daytime oxygen saturation and the AHI as well as the central apnea index, so events per hour. Yellow is the central apnea index, blue is the AHI. Here you see across the x-axis three categories, those with an oxygen saturation less than 91%, those between 92% and 95%, and those between 96% and 100%. And you can see here that the odds of moderate to severe sleep apnea increased by 33% for each 1% decline in daytime oxygen saturation and the odds of central apnea index increased by 45%. Finally, they looked at the dose of opioid medication that the patient was on. This is morphine equivalent daily dosing. And what you see on the x-axis is increasing dose. Here, this is the odds ratio of having a central apnea index greater than five events per hour. For each 10 milligrams of increase in the dose, the odds of the central apnea index being greater than five increased by 3%. The authors concluded that since the stop bang questionnaire, the oxygen saturation and the dose are simple to use in clinical settings, the findings are useful clinically. This was a very important study that really has improved our understanding of who's at risk for sleep disorder and breathing in chronic opioid use. Now, I'd like to move to buprenorphine and naloxone because we've seen an increase in the use of these medications or this combined medication often referred to as suboxone in the setting of opioid detoxification. Buprenorphine is a semi-synthetic opioid, which is a partial mu agonist, and it has a very high receptor affinity, many times higher than morphine and a long dissociation half-life. It was approved in 2002 in the United States and is widely used for the treatment of opioid dependency and chronic pain. Now, it was thought that especially with the naloxone that this would be safer in terms of sleep disorder breathing. There is one study from 2013 by Farney et al that actually unfortunately did not show this. These were 70 patients recruited from an inpatient opioid detoxification center, and what you see here is that they had a significant number of these patients with sleep disorder breathing on buprenorphine, naloxone, ataxic breathing as well, and it was often moderate or severe. The central apnea index, which is not shown here, was also elevated, especially in women. So, we still have to be careful. These medications do not necessarily decrease or do not seem to decrease the prevalence of sleep disorder breathing in this population, and this has been confirmed by some case series as well. Now, I'd like to shift the focus to the association between obstructive sleep apnea and chronic opioid use and really focus on the relevance of sleep apnea, obstructive sleep apnea, and chronic opioid use. So, you remember the last mechanism, which is that opioids suppress direct activity at central respiratory motor neurons, specifically the hypoglossal motor neuron pool, which innervates the respiratory muscles and especially the genioglossus muscle. There does not seem to be clear consensus in the literature regarding the development of obstructive sleep apnea in patients who receive long-term opioid therapy. Several studies have demonstrated that there's a mixed picture with obstructive events and central events, and we actually just saw that in the OPS-AID study I presented. However, there are some recent systematic reviews with meta-analyses that seem to point to not having a strong association between chronic opioid use and obstructive events. The first systematic review and meta-analyses looked at 803 participants that had obstructive sleep apnea. 320 of them were on opioids or chronic opioid therapy, while 483 were not. They showed that the effect size for opioid use on the apnea hypopnea index in these people with obstructive sleep apnea was small at 0.25 events per hour. The effect size for central apneas was higher and was considered medium at 0.45. In 2020, another systematic review and meta-analysis that looked at almost 4,000 patients on chronic opioids versus those on no opioids, and included nine studies, showed that the prevalence of sleep disordered breathing on those on opioid therapy was not significantly different compared to those not on opioids, and they specifically looked at obstructive sleep apnea and central sleep apnea separately, and they found that there was no difference between these two groups with obstructive sleep apnea, central sleep apnea was higher with opioid use. And these were patients in both sleep clinics and pain clinics. More recently, in May 2021, this very interesting systematic review and meta-analysis was published in Sleep Medicine Reviews. They sought to answer three questions, but in fact answered two. The first question was, what is the effect of opioids on the presence and or severity of obstructive sleep apnea in adults? And second, does the use of opioids compared to no opioids affect treatment success with pap therapy in adults with obstructive sleep apnea? They included patients with an apnea hypopnea index of greater than five. There were 14 studies in total, and what they found was that the combined effect did not suggest a significant impact of opioids on the total apnea hypopnea index in adults with OSA. The total estimated mean difference was 1.47 when both observational and randomized controlled trials were considered together, and the analysis was done for both of them together. When they looked at randomized control trials only, the results were similar with an estimated mean difference of 2.05. They also found that there were higher failure rates observed in patients on CPAP for OSA. While the AHI was reduced by 17 to 30 events per hour, there were a significant number that actually did not normalize their AHI and continued to have central sleep apnea events or had emergent central sleep apnea events. When these patients were switched to bi-level spontaneous therapy, spontaneous time therapy, or ASV, the AHI normalized. One can explain some of these findings from a recent physiological study, which is a randomized control study published in European Respiratory Journal, which showed that morphine alters respiratory controls, so chemoreception, but not other key obstructive sleep apnea phenotypes, such as airway collapsibility, the frontal muscle responsiveness, and arousal threshold in individuals with moderate OSA. However, there were plenty of studies, as I showed you, that showed that obstructive sleep apnea is present, often with central sleep apnea, in those on chronic opioid therapy. One study in particular, by Dr. Guimanal, published in Lung in 2010, showed almost all patients on chronic opioid therapy had obstructive sleep apnea only. He suggested some mechanisms by which chronic opioids might make obstructive events more difficult. Opioid therapy may prolong obstructive hypopneas due to increase in inspiratory effort, sorry, decrease in inspiratory effort, that was described previously. You might get a prolongation of the exhalation phase with severe and persistent oxygen desaturations. And again, you might see emergence of central apneas with pap therapy, making it more difficult to treat. Now let's switch to therapeutic approaches, and there are four that I want to focus on. Opioid detoxification or reduction, positive airway pressure therapies, combined therapies, specifically oxygen plus pap therapy, and medications. In 2016, the CDC published guidelines for prescribing opioids. This came after seeing the opioid overdoses triple in the United States since 2000. Basically, the guidelines suggested to not use opioids for pain, if you have the choice, to consider non-opioid therapy. If opioid therapy must be used to consider immediate release formulations rather than sustained release, to use state prescription monitoring programs and services, and to not give opioids to patients with moderate or severe sleep disorder breathing whenever possible to minimize risk for opioid overdose. There are several case reports of complete reversal of sleep disorder breathing with opioid reductions. So whatever possible, we should consider stopping or at least reducing the dose of opioids. When that's not possible, pap therapy is definitely a consideration. But as I've already shown, CPAP therapy has variable success rate. Bi-level therapy in the S-mode, the spontaneous mode, often left patients with central events on a retrospective analysis. When an ST or spontaneous time backup rate was added, this did help with the apnea, hypopnea index normalization. These were all retrospective studies. Over the last decade, adapto-servo ventilation has been increasingly used. And I'm speaking specifically for central sleep apnea and obstructive sleep apnea in chronic opioid use, not in heart failure. These devices have breath-by-breath algorithms that analyze minute ventilation and then adjust pressure support and respiratory rate accordingly to meet a targeted minute ventilation. And most studies have demonstrated a marked reduction in the AHI and central apnea index in opioid patients. And these are some prospective studies. So this one was published in the Journal of Clinical Sleep Medicine by Dr. Java Harry. This was a prospective non-randomized study. There were 20 patients on chronic opioid therapy. 16 had central sleep apnea and four had OSA, but had emergent central sleep apnea on CPAP therapy. So the patients started off with a high AHI at 61 and a high central apnea index at 32 events per hour. They were all underwent CPAP titration. Of these 16, seven were found to have persistent sleep disorder and breathing with an AHI of 34 and a central apnea index of 21. They were converted to ASV right away. The second group of nine patients actually had went on, continued on CPAP therapy for another four weeks, thinking that this might reduce over time their central apnea index and their overall AHI. However, four weeks later, they had an average AHI of 33 with a central apnea index of 19, and they were all converted to ASV as well. And you can see here that ASV did a good job of reducing the AHI, normalizing the central apnea index, and the adherence was promising as well. Another study, also prospective, was published in Journal of Clinical Sleep Medicine that same year that looked at ASV compared to bi-level spontaneous time therapy. These were 18 patients, they were on bi-level therapy, but then they came into the study and they crossed over after two weeks. So their baseline AHI was 50. On ASV, the AHI was reduced to 2.5. The central apnea index went down from 13 to 4. With bi-level therapy, the AHI was 16.3, and the central apnea index also stayed elevated at 9.4. These were patients who were on opioid therapy for at least six months and had a central apnea index at baseline equal to 5. ASV normalized the respiratory parameters in 83%, whereas bi-level spontaneous time only normalized it in 33.3%. Additionally, on the morning after patient satisfaction questionnaire, more of the patients felt alert and awake with ASV. The authors concluded that compared to bi-level ST, the ASV suppressed all abnormal respiratory events, including obstructive central apneas, oxidation, oxygen desaturation, and respiratory-related arousal. So ASV has been promising in this setting of chronic opioid use. There is one study by Dr. Chaudhry that was published in 2012 that looked at the combination therapy of oxygen to pap therapy. This was a retrospective analysis. These were veterans with central sleep apnea on PSG. About 29% of them were on opioids. The protocol was to give CPAP therapy titrated upwards to 14 to start with. If they were not successful in eliminating the central events, oxygen at two liters per minute was given with a goal saturation of 93%. If central apneas persisted after 20 minutes of CPAP plus oxygen, then the patients were converted to bi-level pap with the oxygen continued. And what you see here, there were 47 patients total, is that they did a good job of reducing central apnea events and the AHI. 89% of the patients had an optimal response with this protocol where oxygen was used in addition to pap therapy. And you can see here, sometimes you might get something that looks like this, a CPAP titration night. This is a patient where we added oxygen, and you can see that things really stabilized with four liters of oxygen with the CPAP therapy. Something that's been very interesting is medications in treating sleep disordered breathing with chronic opioid juice. Now, naloxone you all might be familiar with. It is a new receptor antagonist. The problem with naloxone is that it is short lasting. The duration of effect is very short, and it lowers the efficacy of analgesia. It's associated with acute withdrawal symptoms, which consists of agitation, drug cravings, hypertension, tachycardia. Rarely people get violent when their opioid-induced sedation is reversed. There are also some other rare effects, side effects, or adverse effects that can be seen, including pulmonary edema, arrhythmias, and cardiac arrest. What's been more interesting, and you can find this in the review, is the use of non-opioid compounds for opioid-induced respiratory depression. There are about 39 or 40 of these compounds, but only four have been studied in humans. This includes BK channel blockers, N-methyl-D-aspartate receptor antagonists, and 4-aminofiridine. The one that has been sort of most interesting are the Ampakine class. This is a drug class that stimulates the AMPA receptors at the pre-Boxinger complex, and increases glutamate within the cell. And what this does is it increases respiratory rhythmogenesis, and also may facilitate hypoglossal motor output. There is a small study published in 2010 that showed that in 16 healthy men who received L-fentanyl, a derivative of fentanyl, had an improvement in respiratory rate, oxygen saturation, and hypercognitive response, which were all diminished due to the L-fentanyl. But here's something that is up for debate, and it's interesting, and it's food for thought. We know that chronic opioid use in and of itself is associated with adverse health outcomes, including cardiac outcomes. But what we don't know, whether central sleep apnea or sleep disorder breathing specifically in chronic opioid use is associated with adverse health outcomes. The data has not shown this yet. Additionally, we don't know the relevance of central sleep apnea in chronic opioid use. Does it prevent, or does it cause morbidity or mortality? The CERV-HF trial has taught us many important lessons. So, we know that when central sleep apnea events were eliminated with ASV in heart failure patients in CERV-HF, that the all-cause and cardiovascular mortality was significantly increased. Many experts have postulated that an explanation is that the central sleep apnea here actually serves as a compensatory mechanism with protective effects. So, we don't know if central sleep apnea in chronic opioid use is doing the same thing, whether it's trying to preserve or develop homeostasis for blood gases and the ongoing effects of the chronic opioid use. On the flip side, we know that there is a bi-directional association between sleep and pain. Pain disrupts sleeps, and sleep disturbances can exacerbate pain. Effective treatment of sleep disordered breathing may have beneficial impacts on reducing pain, because it's speculated that sleep fragmentation actually disrupts the pain inhibitory system, making patients with sleep apnea more hypoallergenic. And this might be reversed by treating the underlying sleep apnea. Therefore, it's unclear what is the right approach. What is the right approach? For now, the American Academy of Sleep Medicine position statement recommends appropriate screening and diagnostic testing for sleep disordered breathing in people with chronic opioid use. So, in summary, despite a decline in prescriptions, opioid-related deaths remain high. The respiratory effects of opioids are related to their inhibition of the respiratory drive at the pre-Botzinger complex, alterations in chemoreception, both centrally and peripherally. Remember that there is a decline in hypercapnic ventilatory response, but an increase in the hypoxic respiratory response or ventilatory response. There's suppression of respiratory motor neurons, especially the hypoglossal motor neuron pool. Opioids are associated with multiple types of sleep disordered breathing, including central sleep apnea, ataxic breathing, biased breathing, hypoventilation, and perhaps there are different phenotypes based on the predominating causative mechanism. The predictive factors for central sleep apnea and ataxic breathing seem to be the dose of opioid and daytime oxygen saturation levels. The literature on chronic opioid use and obstructive sleep apnea is mixed and evolving. Right now, the best treatment for sleep disordered breathing in the setting of chronic opioid use would be to stop or reduce the dose of opioid medication. ASV may end up being a better choice for opioid associated sleep disordered breathing compared to CPAP, and there are new medications on the horizon. So stay tuned. So with that, I'd like to thank you all, and I appreciate this opportunity to talk about chronic opioid use and sleep disordered breathing. Thank you. Thank you, Dr. Arora. Stay tuned for other upcoming webinars offered by the AASM on current sleep medicine.

chronic opioid use

sleep disordered breathing

respiratory depression

central sleep apnea

obstructive sleep apnea

prevalence of sleep disordered breathing

risk factors for central sleep apnea

treatment modalities

opioid detoxification