Obstructive sleep apnea drug therapy: apnea–hypopnea index leaves us high and dry

Obstructive sleep apnea drug therapy: apnea–hypopnea index leaves us high and dry The past four decades of sleep apnea research have yielded tremendous insight into the pathophysiology of obstructive sleep apnea (OSA). Elegant research has substantiated that sleep state–dependent upper airway collapse obstructs ventilation, inducing intermittent reductions in oxygen, coincidental with increases in carbon dioxide, autonomic instability, and, typically, a brief arousal.1 We understand that upper airway collapse occurs, at least in part, because of reduced activity of upper airway dilator muscles in sleep, and we now understand more fully some of the sleep state–dependent alterations in neurotransmitters and modulators at the relevant motoneurons.2 Based on these advances, one would have anticipated 10–20 years ago that by now we would have one or more successful pharmacotherapies for OSA. The need for a pharmacotherapy is readily appreciable by most physicians and patients. OSA is an independent risk factor for myocardial infarction, stroke, hypertension, motor vehicle accidents, depression, and altered glucose metabolism.3–5 The mainstay therapy, positive airway pressure (PAP), while highly effective in palliating OSA, is a difficult therapy for many individuals; consequently, many patients have given up on PAP or use it for only a fraction of their sleep.6 Researchers have certainly tried to identify effective pharmacotherapies for OSA. There are, however, inherent hurdles unique to conducting drug trials for OSA. Subjects with OSA who are not being treated during a trial are at risk of motor vehicle accidents.5 Consequently, many trails exclude the most-at-risk sleepy subjects, which may alter the overall patient population by selecting out specific patients with OSA. Additionally, assessment of drug effect on OSA requires polysomnography or home respiratory studies, both of which are time consuming for the subjects and research teams and expensive for research trials. For these reasons, most OSA drug studies have tested the effects of one dose at one time point. This particular study design renders it impossible to distinguish a subset of true responders from night-to-night variability in the apnea–hypopnea index (AHI). To this day, this is true for most OSA drug trials. In this issue of SLEEP, Carley et al.7 report on the efficacy of a cannabimimetic therapy for OSA. The drug selected for study was dranabinol, a cannabinoid 1 and 2 receptor agonist. Its site of action for OSA is not known. The receptors are found throughout the brain including within sleep and wake nuclei and motoneuron and respiratory regions, and peripherally at the nodose ganglion. The investigators compared the effects of two doses and placebo, using three arms, so that only one condition was observed per participant. By administering the drug over 6 weeks before retesting, the study was able to assess longer-term tolerability and safety. Overall, the major finding of the study is mild reductions in the AHI (a reduction of two events per hour for low dose and four events per hour for high dose). Within the drug groups, there were some participants (approximately 15%) who seemed to have better responses for the AHI (defined by the authors as an “on drug” AHI < 15 and a 50% reduction). The responders tended to have higher rapid eye movement (REM) sleep AHIs at baseline, and in representative data for individual responders, responders tended to have larger reductions in their AHI in REM sleep. As noted above, the study design does not allow distinction of responders from variability in AHI. If these were also the individuals with less sleep fragmentation, improved nocturnal oxygen, or improved alertness, the collective findings would support that “responders” do exist for the drug. There were, however, group responses to secondary measures in the study. Despite the small overall effect in AHI, there was a strong beneficial effect on subjective sleepiness, as measured by the Epworth Sleepiness Scale, and interestingly six times as many participants receiving the higher drug dose responded that they were “extremely satisfied” with the therapy tested. Intriguingly, however, there was no effect on objective wakefulness, as measured by the maintenance of wakefulness test, or on sleep architecture. Specifically, there were just as many arousals per hour, no effect on total sleep time, percentages of time for each sleep stage, wake after sleep onset time, or in oxygen saturation data. Collectively, the results indicate that sleepiness in OSA, and possibly subjective well-being, may be effectively treated without necessarily correcting the AHI, without the use of a stimulant. Previous studies support a significant discordance between the AHI and sleepiness8—and it calls into question our continued use of the AHI as the primary end point. Suppose Carley et al. had gone further and shown not only a reduction in sleepiness, but also improved multiple sleep latency test and 24 hr blood pressure, without any relationship with the AHI? Would the AHI be as relevant? References 1. Dempsey JAet al.   Pathophysiology of sleep apnea. Physiol Rev . 2010; 90( 1): 47– 112. Google Scholar CrossRef Search ADS PubMed  2. Eastwood PRet al.   Obstructive sleep apnoea: from pathogenesis to treatment:current controversies and future directions. Respirology . 2010; 15( 4): 587– 595. Google Scholar CrossRef Search ADS PubMed  3. Javaheri Set al.   Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol . 2017; 69( 7): 841– 858. Google Scholar CrossRef Search ADS PubMed  4. Nagayoshi Met al.   Obstructive sleep apnea and incident type 2 diabetes. Sleep Med . 2016; 25: 156– 161. Google Scholar CrossRef Search ADS PubMed  5. Sassani Aet al.   Reducing motor-vehicle collisions, costs, and fatalities by treating obstructive sleep apnea syndrome. Sleep . 2004; 27( 3): 453– 458. Google Scholar CrossRef Search ADS PubMed  6. Weaver TEet al.   Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc . 2008; 5( 2): 173– 178. Google Scholar CrossRef Search ADS PubMed  7. Carley DWet al.   Pharmacotherapy of apnea by cannabimimetic enhancement, the PACE clinical trial: effects of dronabinol in obstructive sleep apnea. Sleep . 2017; 41( 1): zsx184. 8. Weaver EMet al.   Polysomnography indexes are discordant with quality of life, symptoms, and reaction times in sleep apnea patients. Otolaryngol Head Neck Surg . 2005; 132( 2): 255– 262. Google Scholar CrossRef Search ADS PubMed  © Sleep Research Society 2018. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png SLEEP Oxford University Press

Obstructive sleep apnea drug therapy: apnea–hypopnea index leaves us high and dry

SLEEP , Volume 41 (1) – Jan 1, 2018

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Publisher
Sleep Research Society
Copyright
© Sleep Research Society 2018. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.
ISSN
0161-8105
eISSN
1550-9109
D.O.I.
10.1093/sleep/zsy014
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Abstract

The past four decades of sleep apnea research have yielded tremendous insight into the pathophysiology of obstructive sleep apnea (OSA). Elegant research has substantiated that sleep state–dependent upper airway collapse obstructs ventilation, inducing intermittent reductions in oxygen, coincidental with increases in carbon dioxide, autonomic instability, and, typically, a brief arousal.1 We understand that upper airway collapse occurs, at least in part, because of reduced activity of upper airway dilator muscles in sleep, and we now understand more fully some of the sleep state–dependent alterations in neurotransmitters and modulators at the relevant motoneurons.2 Based on these advances, one would have anticipated 10–20 years ago that by now we would have one or more successful pharmacotherapies for OSA. The need for a pharmacotherapy is readily appreciable by most physicians and patients. OSA is an independent risk factor for myocardial infarction, stroke, hypertension, motor vehicle accidents, depression, and altered glucose metabolism.3–5 The mainstay therapy, positive airway pressure (PAP), while highly effective in palliating OSA, is a difficult therapy for many individuals; consequently, many patients have given up on PAP or use it for only a fraction of their sleep.6 Researchers have certainly tried to identify effective pharmacotherapies for OSA. There are, however, inherent hurdles unique to conducting drug trials for OSA. Subjects with OSA who are not being treated during a trial are at risk of motor vehicle accidents.5 Consequently, many trails exclude the most-at-risk sleepy subjects, which may alter the overall patient population by selecting out specific patients with OSA. Additionally, assessment of drug effect on OSA requires polysomnography or home respiratory studies, both of which are time consuming for the subjects and research teams and expensive for research trials. For these reasons, most OSA drug studies have tested the effects of one dose at one time point. This particular study design renders it impossible to distinguish a subset of true responders from night-to-night variability in the apnea–hypopnea index (AHI). To this day, this is true for most OSA drug trials. In this issue of SLEEP, Carley et al.7 report on the efficacy of a cannabimimetic therapy for OSA. The drug selected for study was dranabinol, a cannabinoid 1 and 2 receptor agonist. Its site of action for OSA is not known. The receptors are found throughout the brain including within sleep and wake nuclei and motoneuron and respiratory regions, and peripherally at the nodose ganglion. The investigators compared the effects of two doses and placebo, using three arms, so that only one condition was observed per participant. By administering the drug over 6 weeks before retesting, the study was able to assess longer-term tolerability and safety. Overall, the major finding of the study is mild reductions in the AHI (a reduction of two events per hour for low dose and four events per hour for high dose). Within the drug groups, there were some participants (approximately 15%) who seemed to have better responses for the AHI (defined by the authors as an “on drug” AHI < 15 and a 50% reduction). The responders tended to have higher rapid eye movement (REM) sleep AHIs at baseline, and in representative data for individual responders, responders tended to have larger reductions in their AHI in REM sleep. As noted above, the study design does not allow distinction of responders from variability in AHI. If these were also the individuals with less sleep fragmentation, improved nocturnal oxygen, or improved alertness, the collective findings would support that “responders” do exist for the drug. There were, however, group responses to secondary measures in the study. Despite the small overall effect in AHI, there was a strong beneficial effect on subjective sleepiness, as measured by the Epworth Sleepiness Scale, and interestingly six times as many participants receiving the higher drug dose responded that they were “extremely satisfied” with the therapy tested. Intriguingly, however, there was no effect on objective wakefulness, as measured by the maintenance of wakefulness test, or on sleep architecture. Specifically, there were just as many arousals per hour, no effect on total sleep time, percentages of time for each sleep stage, wake after sleep onset time, or in oxygen saturation data. Collectively, the results indicate that sleepiness in OSA, and possibly subjective well-being, may be effectively treated without necessarily correcting the AHI, without the use of a stimulant. Previous studies support a significant discordance between the AHI and sleepiness8—and it calls into question our continued use of the AHI as the primary end point. Suppose Carley et al. had gone further and shown not only a reduction in sleepiness, but also improved multiple sleep latency test and 24 hr blood pressure, without any relationship with the AHI? Would the AHI be as relevant? References 1. Dempsey JAet al.   Pathophysiology of sleep apnea. Physiol Rev . 2010; 90( 1): 47– 112. Google Scholar CrossRef Search ADS PubMed  2. Eastwood PRet al.   Obstructive sleep apnoea: from pathogenesis to treatment:current controversies and future directions. Respirology . 2010; 15( 4): 587– 595. Google Scholar CrossRef Search ADS PubMed  3. Javaheri Set al.   Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol . 2017; 69( 7): 841– 858. Google Scholar CrossRef Search ADS PubMed  4. Nagayoshi Met al.   Obstructive sleep apnea and incident type 2 diabetes. Sleep Med . 2016; 25: 156– 161. Google Scholar CrossRef Search ADS PubMed  5. Sassani Aet al.   Reducing motor-vehicle collisions, costs, and fatalities by treating obstructive sleep apnea syndrome. Sleep . 2004; 27( 3): 453– 458. Google Scholar CrossRef Search ADS PubMed  6. Weaver TEet al.   Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc . 2008; 5( 2): 173– 178. Google Scholar CrossRef Search ADS PubMed  7. Carley DWet al.   Pharmacotherapy of apnea by cannabimimetic enhancement, the PACE clinical trial: effects of dronabinol in obstructive sleep apnea. Sleep . 2017; 41( 1): zsx184. 8. Weaver EMet al.   Polysomnography indexes are discordant with quality of life, symptoms, and reaction times in sleep apnea patients. Otolaryngol Head Neck Surg . 2005; 132( 2): 255– 262. Google Scholar CrossRef Search ADS PubMed  © Sleep Research Society 2018. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

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Published: Jan 1, 2018

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