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Study Objectives: Obstructive sleep apnea (OSA) is a highly prevalent disorder with serious health consequences but limited therapeutic options. For a subset of those with OSA, a key underlying mechanism is hypersensitive chemoreflex control of breathing. There is no approved therapy that targets this endotypic trait. Here we determine whether the P2X3 receptor antagonist gefapixant, which is predicted to attenuate hypersensitive carotid chemoreflexes, reduces OSA severity in patients with chemoreflex-dependent OSA., Methods: In a randomized placebo-controlled crossover study, 24 patients with moderate-to-severe OSA (aged 39-68 years, non-continuous positive airway pressure users) whose disorder was partially responsive to supplemental oxygen (chemoreflex-dependent OSA) were treated with gefapixant 180 mg (or placebo) administered as tablets taken orally before bedtime for 7 days and assessed via overnight polysomnography. The primary analysis examined whether gefapixant treatment resulted in a greater reduction in the apnea-hypopnea index from baseline than placebo., Results: Gefapixant did not lower the apnea-hypopnea index significantly more than placebo; the estimated ratio of the apnea-hypopnea index on gefapixant vs placebo was 0.92 (90% confidence interval: 0.73, 1.17). Notably, nocturnal hypoxemia was increased (ratio of total sleep time with saturated peripheral oxygen < 90% on gefapixant vs placebo = 2.08 [90% confidence interval: 1.53, 2.82]), consistent with reduced chemoreflex output. Commonly reported adverse events with gefapixant included ageusia, dysgeusia, oral hypoaesthesia, nausea, somnolence, and taste disorders., Conclusions: Gefapixant, while generally well tolerated, did not reduce OSA severity in patients with chemoreflex-dependent OSA. P2X3 receptor antagonism is unlikely to provide an avenue for therapeutic intervention in OSA., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Safety and Tolerability of Gefapixant (MK-7264) in Participants with Obstructive Sleep Apnea (MK-7264-039); URL: https://clinicaltrials.gov/study/NCT03882801; Identifier: NCT03882801., Citation: Robbins JA, Sands S, Maganti L, et al. Gefapixant as a P2X3 receptor antagonist treatment for obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med . 2024;20(12):1905-1913., (© 2024 American Academy of Sleep Medicine.)

Study Objectives: Randomized controlled trials have shown that combining norepinephrine reuptake inhibitors and antimuscarinics can ameliorate the severity of obstructive sleep apnea. This article explores whether the effectiveness and safety of combining norepinephrine reuptake inhibitors with antimuscarinic agents surpass monotherapy for treating obstructive sleep apnea., Methods: We searched randomized controlled trials including adult patients with obstructive sleep apnea who received combination therapy and monotherapy in 8 databases from inception until April 5, 2023 and evaluated the studies' quality and conducted a meta-analysis and systematic review. The primary outcome was the apnea-hypopnea index. Secondary outcome measures included loop gain, hypoxic burden, oxygen desaturation index, and ventilation at low ventilatory drive, among other indicators. We assessed the quality of the studies using Cochrane Methods criteria., Results: We identified 4 randomized controlled trials for systematic review and 2 for meta-analysis. The results of the meta-analysis showed that norepinephrine reuptake inhibitors combined with antimuscarinic agents in patients with obstructive sleep apnea prolonged total sleep time by a mean of 28.20 minutes [95% confidence interval (5.78, 50.61), P = .01] and increased sleep efficiency by 4.73% [95% confidence interval (0.50, 8.97), P = .03] compared with norepinephrine reuptake inhibitors alone. Other indices and adverse events were of no statistical significance. The systematic reviews revealed that norepinephrine reuptake inhibitors combined with antimuscarinics may be superior to monotherapy in improving apnea-hypopnea index and endotypic traits., Conclusions: This evaluation demonstrated the potential advantages of combining norepinephrine reuptake inhibitors plus antimuscarinics for treating OSA compared with norepinephrine reuptake inhibitors alone and revealed no statistically significant difference in drug safety., Citation: Wang J, Ye Y, Shang Z, et al. Effect of norepinephrine reuptake inhibitors combined with antimuscarinic agents vs monotherapy for OSA: a systematic review and meta-analysis. J Clin Sleep Med . 2024;20(8):1363-1372., (© 2024 American Academy of Sleep Medicine.)

Study Objectives: Despite the efficacy of positive airway pressure (PAP) for the treatment of obstructive sleep apnea, adherence remains challenging and negatively affects assessments of effectiveness. It is unclear whether low adherence is due to intolerance of PAP or whether this reflects overall adherence with medical therapy. We sought to correlate PAP use with medication adherence to determine whether poor adherence with PAP was specific to this treatment or represented global compliance with medical therapy., Methods: A total of 600 consecutive patients with obstructive sleep apnea were treated with PAP. Objective measures of PAP use were correlated with medication adherence. We included all chronically used medications, defined as medications used daily for at least 90 days prior to PAP initiation. Medication use was verified using an electronic health record. PAP adherence ("regular use") was defined as PAP use for ≥ 4 hours/night on ≥ 70% of nights. Medication adherence was defined as > 70% of pills taken as prescribed., Results: Complete records were available for 566 patients; 361 (63.8%) used chronic medications. The cohort was primarily men (90.3%, age 44.6 ± 10.2 years) with moderate obstructive sleep apnea (apnea-hypopnea index, 18.1 ± 13.9 events/h). In patients on chronic medications, PAP was used 55.8% of nights and 37.7% were regular users. Patients who were adherent with medications used PAP more hours/night (5.4 vs 4.6, P < .001) and were more likely to have regular PAP use compared with those nonadherent with medications ( P = .04)., Conclusions: Adherence with PAP correlated with adherence to chronic medications. Low PAP adherence may reflect an individual's global adherence to medical care. This association may lead to better identification of patients who benefit from targeted therapy to improve overall health care adherence., Citation: Lettieri MJ, Warren WA, Walter RJ, Lettieri CJ. Correlation between positive airway pressure and medication adherence: the healthy user effect. J Clin Sleep Med . 2024;20(7):1087-1092., (© 2024 American Academy of Sleep Medicine.)

Study Objectives: To evaluate the respiratory safety of lemborexant among adults and older adults with moderate to severe obstructive sleep apnea (OSA)., Methods: E2006-A001-113 (Study 113; NCT04647383) was a double-blind, two-period crossover, placebo-controlled study in adults (ages ≥ 45 to ≤ 90 years, n = 33) with moderate (apnea-hypopnea index [AHI] score ≥ 15 to < 30 events/h, n = 13) or severe (AHI ≥ 30 events/h, n = 20) OSA. Participants were randomized to lemborexant 10 mg (LEM10) or placebo (PBO) for two treatment periods of 8 nights with a ≥ 14-day washout period. AHI and peripheral oxygen saturation were evaluated after treatment on Day 1 (after a single dose) and Day 8 (after multiple doses)., Results: No significant differences in AHI were observed after single and multiple doses of LEM10 compared with PBO in participants with moderate to severe OSA (least-squares mean: single-dose LEM10, 41.7; PBO, 44.8; multiple-dose LEM10, 44.9; PBO, 45.7). In addition, there were no significant differences between treatments in peripheral oxygen saturation (least-squares mean: single-dose LEM10, 93.0; PBO, 93.1; multiple-dose LEM10, 93.1; PBO, 93.4). Further, there were no significant differences between treatments in percentage of total sleep time with peripheral oxygen saturation < 90%, < 85%, or < 80%. No significant differences were observed between treatments when AHI and peripheral oxygen saturation outcomes were analyzed by OSA severity. Altogether, 6/33 (18.2%) participants receiving LEM10, vs 3/33 (9.1%) PBO, reported treatment-emergent adverse events, mostly mild in severity., Conclusions: LEM10 demonstrated respiratory safety and was well tolerated with single-dose and multiple-dose administration in participants with moderate to severe OSA. This suggests that LEM may be a treatment option for patients with OSA and comorbid insomnia., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: A Study to Evaluate the Respiratory Safety of Lemborexant in Adult and Elderly Participants With Moderate to Severe Obstructive Sleep Apnea and in Adult and Elderly Participants With Moderate to Severe Chronic Obstructive Pulmonary Disease; URL: https://clinicaltrials.gov/ct2/show/NCT04647383; Identifier: NCT04647383., Citation: Cheng JY, Lorch D, Lowe AD, et al. A randomized, double-blind, placebo-controlled, crossover study of respiratory safety of lemborexant in moderate to severe obstructive sleep apnea. J Clin Sleep Med . 2024;20(1):57-65., (© 2024 American Academy of Sleep Medicine.)

Study Objectives: Intranasal administration of esketamine is Food and Drug Administration-approved for treatment-resistant depression. In a recent retrospective case series, we show that it has promise in reducing symptoms of posttraumatic stress disorder (PTSD) as well. Untreated obstructive sleep apnea (OSA) is prevalent among veterans with PTSD and has been shown to interfere with other PTSD treatments. In the current study, we examined whether OSA impacts esketamine's effectiveness in reducing symptoms of PTSD or depression., Methods: Participants were 60 veterans with a diagnosis of major depressive disorder and PTSD who received intranasal esketamine treatment at the San Diego Veterans Affairs (VA) Medical Center. We used growth-curve modeling to examine changes in depression and PTSD symptoms following esketamine treatments and, in the subset of individuals screened for OSA (n = 24, all prescribed positive airway pressure therapy), examined the impacts of OSA severity on these trajectories., Results: We first showed that both PTSD and depressive symptoms significantly decreased over the course of esketamine treatment. In the subset of veterans screened for OSA, individuals with lower OSA severity reported the greatest reduction in PTSD symptoms, while veterans with the most severe OSA reported the least reduction in PTSD symptoms. Depression response was not affected by severity of OSA in this analysis., Conclusions: Veterans with PTSD and depression tend to benefit from esketamine treatment, but OSA may interfere with esketamine effectiveness. Comorbid OSA should be assessed for and treated to maximize esketamine's benefits in PTSD., Citation: Titone MK, Hunt C, Bismark A, et al. The effect of obstructive sleep apnea severity on PTSD symptoms during the course of esketamine treatment: a retrospective clinical study. J Clin Sleep Med . 2023;19(12):2043-2051., (© 2023 American Academy of Sleep Medicine.)

Study Objectives: Children with Down syndrome (DS) are at very high risk for obstructive sleep apnea (OSA). Current OSA treatments have limited effectiveness in this population. We evaluated the effectiveness of atomoxetine and oxybutynin (ato-oxy) to treat OSA in children with Down syndrome., Methods: Children ages 6-7 years old with Down syndrome and OSA participated in a double-blind crossover clinical trial evaluating two dose regimens of ato-oxy. Participants received low-dose ato-oxy (0.5 mg/kg atomoxetine and 5 mg oxybutynin) and high-dose ato-oxy (1.2 mg/kg atomoxetine and 5 mg oxybutynin) for 1 month in random order. The primary study outcome was change in obstructive apnea-hypopnea index. Health-related quality of life as measured by the OSA-18 as well as changes in sleep architecture were secondary outcomes., Results: Fifteen participants qualified for randomization and 11 participants had complete data at all points. Baseline obstructive apnea-hypopnea index was 7.4 ± 3.7 (mean ± standard deviation), obstructive apnea-hypopnea index with low-dose ato-oxy was 3.6 ± 3.3 ( P = .001 vs baseline), and obstructive apnea-hypopnea index with high-dose ato-oxy was 3.9 ± 2.8 ( P = .003 vs baseline). No significant sleep architecture differences were present with ato-oxy. No significant difference in OSA-18 score was present. OSA-18 total score was 51 ± 19 at baseline, 45 ± 17 ( P = .09) at the end of 4 weeks of low-dose ato-oxy, and 45 ± 16 ( P = .37) at the end of high-dose ato-oxy therapy. The most common adverse effects were irritability and fatigue, and these were generally mild., Conclusions: Ato-oxy is a promising treatment for OSA in children with Down syndrome., Clinical Trial Registration: Registry: Clinicaltrials.gov; Name: Medications for Obstructive Sleep Apnea In Children With Down Syndrome (MOSAIC); URL: https://clinicaltrials.gov/ct2/show/NCT04115878; Identifier: NCT04115878., Citation: Combs D, Edgin J, Hsu C-H, et al. The combination of atomoxetine and oxybutynin for the treatment of obstructive sleep apnea in children with Down syndrome. J Clin Sleep Med . 2023;19(12):2065-2073., (© 2023 American Academy of Sleep Medicine.)

Study Objectives: Pharmacotherapy for obstructive sleep apnea (OSA) regained consideration after the discovery that atomoxetine and oxybutynin greatly reduced OSA severity. However, atomoxetine and oxybutynin reduced the arousal threshold and may therefore be poorly tolerated in patients with OSA and disturbed sleep. As a result, we tested the combination of atomoxetine plus 2 hypnotics in patients with OSA. The effects of atomoxetine plus: (1) trazodone (Ato-Trazo) and (2) lemborexant vs placebo on apnea-hypopnea index, hypoxic burden, arousal threshold, and total sleep time were assessed. Drug safety was also ascertained, together with the effect of the combinations on other OSA traits, self-reported sleep quality, and next-day alertness., Methods: Following a baseline study, 15 patients with mild-to-severe OSA with moderate upper airway collapsibility were administered Ato-Trazo, atomoxetine and lemborexant, and matching placebo according to a double-blind, randomized, crossover design. Apnea-hypopnea index and other objective outcomes were calculated from 3 clinical, in-laboratory polysomnograms., Results: Ato-Trazo significantly reduced apnea-hypopnea index from a median [interquartile range] of 18.2 [11.8 to 31.3] on placebo to 7.4 [5.4 to 16.1] events/h, P = .024, and hypoxic burden from 46.3 [25.1 to 88.3] on placebo to 18.7 [14.9 to 43.5], P = .003. This effect was likely driven by an increase in polysomnography-estimated pharyngeal muscle activity during the events ( P = .029). Atomoxetine and lemborexant had smaller statistically insignificant effects. Contrary to atomoxetine and oxybutynin, Ato-Trazo and atomoxetine and lemborexant did not reduce the arousal threshold. Both combinations had no effect on total sleep time but worsened self-reported sleep quality., Conclusions: Ato-Trazo has the potential to become a useful drug combination, however, longer trials are needed to determine the best dosage and the subgroup of patients who may benefit most from this combination., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Crossover Trial of AD182 and AD504 in Obstructive Sleep Apnea; URL: https://clinicaltrials.gov/ct2/show/NCT04645524; Identifier: NCT04645524., Citation: Corser B, Eves E, Warren-McCormick J, Rucosky G. Effects of atomoxetine plus a hypnotic on obstructive sleep apnea severity in patients with a moderately collapsible pharyngeal airway. J Clin Sleep Med . 2023;19(6):1035-1042., (© 2023 American Academy of Sleep Medicine.)

Study Objectives: This post hoc analysis characterized the weekly incidence and overall duration of common early-onset, treatment-emergent adverse events (TEAEs) during solriamfetol treatment., Methods: Participants (obstructive sleep apnea [OSA], n = 474; narcolepsy, n = 236) were randomized to 12 weeks of placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg. For common early-onset TEAEs (those occurring in ≥ 5% of participants in any solriamfetol dose group and with a higher incidence than that observed in placebo-treated participants during week 1), the incidence of new occurrence or change in severity over time was calculated for each subsequent study week. Data were analyzed separately for each study and summarized by placebo and combined solriamfetol groups., Results: Common early-onset TEAEs (at doses ≤ 150 mg; ie, approved doses) included headache (OSA, 5.1%; narcolepsy, 8.5%), nausea (OSA, 2.5%; narcolepsy, 4.2%), decreased appetite (OSA, 4.2%; narcolepsy, 5.9%), as well as anxiety (2.1%), insomnia (1.3%), and feeling jittery (3.0%) in OSA and dry mouth (4.2%) in narcolepsy. Incidence of common early-onset TEAEs was highest at week 1 and decreased over time. In OSA at doses ≤ 150 mg, headache, nausea, and feeling jittery had median durations ≤ 8 days, whereas decreased appetite, anxiety, and insomnia had longer durations. In narcolepsy at doses ≤ 150 mg, headache and nausea had median durations ≤ 8 days, whereas decreased appetite and dry mouth had longer durations. Most TEAEs were mild to moderate in severity., Conclusions: Common early-onset TEAEs with solriamfetol are limited in duration, with the majority subsiding during the first week of treatment., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in Narcolepsy; URL: https://clinicaltrials.gov/ct2/show/NCT02348593; Identifier: NCT02348593; and Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in OSA; URL: https://clinicaltrials.gov/ct2/show/NCT02348606; Identifier: NCT02348606., Citation: Rosenberg R, Thorpy MJ, Dauvilliers Y, et al. Incidence and duration of common early-onset adverse events in randomized controlled trials of solriamfetol for treatment of excessive daytime sleepiness in obstructive sleep apnea and narcolepsy. J Clin Sleep Med . 2022;18(1):235-244., (© 2022 American Academy of Sleep Medicine.)

Study Objectives: Excessive daytime sleepiness associated with obstructive sleep apnea affects 9%-22% of continuous positive airway pressure-treated patients. An indirect treatment comparison meta-analysis was performed to compare efficacy and safety of medications (solriamfetol, modafinil, and armodafinil) approved to treat excessive daytime sleepiness associated with obstructive sleep apnea., Methods: Efficacy and safety measures assessed in this indirect treatment comparison included Epworth Sleepiness Scale (ESS), 20-minute Maintenance of Wakefulness Test (MWT20), Clinical Global Impression of Change (CGI-C), Functional Outcomes of Sleep Questionnaire (FOSQ), and incidence of treatment-emergent adverse events (any, serious, or leading to discontinuation)., Results: A systematic literature review identified 6 parallel-arm, placebo-controlled randomized controlled trials that randomized 1,714 total participants to placebo, solriamfetol, modafinil, or armodafinil. In this indirect treatment comparison, all comparators were associated with greater improvements than placebo on the ESS, MWT20, and CGI-C after 4, 8, and 12 weeks of treatment. Relative to comparators and placebo at 12 weeks, solriamfetol at 150 mg or 300 mg had the highest probabilities of improvement in the ESS, MWT20, and CGI-C. Modafinil (200 or 400 mg) and solriamfetol (150 or 300 mg) were associated with greater improvement on the FOSQ than placebo at 12 weeks. Less than 2% of patients using placebo or comparators experienced serious or discontinuation-related treatment-emergent adverse events., Conclusions: The results of this indirect treatment comparison show 12 weeks of treatment with solriamfetol, modafinil, and armodafinil resulted in varying levels of improvement on the ESS, MWT20, and CGI-C and similar safety risks in participants with excessive daytime sleepiness associated with obstructive sleep apnea., Citation: Ronnebaum S, Bron M, Patel D, et al. Indirect treatment comparison of solriamfetol, modafinil, and armodafinil for excessive daytime sleepiness in obstructive sleep apnea. J Clin Sleep Med . 2021;17(12):2543-2555., (© 2021 American Academy of Sleep Medicine.)

None: Abnormalities of the upper airway anatomy are an underrecognized cause of obstructive sleep apnea. We present a unique case of a 51-year-old man with episodic sleep-maintenance insomnia and oromandibular dystonia requiring botulinum toxin injections of the temporalis and masseter muscles. He underwent multiple sleep studies and was found to have obstructive sleep apnea temporally associated with the severity of dystonia symptoms and dosing of botulinum toxin., (© 2020 American Academy of Sleep Medicine.)

Study Objectives: Children with Down syndrome (DS) have a high prevalence of obstructive sleep apnea (OSA). Anti-inflammatory medications have been shown to be an effective treatment for mild OSA in otherwise healthy children. However, the efficacy in children with DS and mild OSA has not been investigated. Our aim was to examine the polysomnographic changes of children with DS and mild OSA treated with medication., Methods: A retrospective chart review was performed in children with DS (< 18 years) and mild OSA (obstructive apnea-hypopnea index ≤ 5 events/h) diagnosed by polysomnography (PSG) between 2006 and 2018. Patients were included if they were treated with medications (intranasal corticosteroids and/or montelukast) or by observation with a duration of at least 3 months and had baseline and follow-up PSGs. Demographic data, comorbid diagnoses, and PSG data were collected and analyzed., Results: Forty-five children met inclusion criteria. In the medication group, 29 children were identified. The median age was 7.4 years (interquartile range [IQR] 4.9-9.3). In the observation group, 16 children were identified. The median age was 4.0 years (IQR 3.2-5.3). The median time from baseline to follow-up PSG was 14.0 months (IQR 10.0-22.9) for the medication group and 10.5 months (IQR 6.5-33.5) for the observation group. There were no significant changes in the median obstructive apnea-hypopnea index from the baseline to follow-up PSG in either the medication group (2.8 [IQR 2.2-3.6) versus 3.5 [IQR 1.4-4.8) events/h; P = .25) or the observation group (2.3 [IQR 1.3-3.1] versus 2.9 [IQR 1.9-6.8] events/h; P = .12). Similarly, there were no significant differences in apnea-hypopnea index, oxygen nadir or end-tidal carbon dioxide between the groups (P = .07-1)., Conclusions: In our cohort, medication therapy did not significantly improve polysomnographic measures in children with DS and mild OSA. Several factors such as hypotonia and relative macroglossia may explain the ineffectiveness of medical therapy for OSA in this population. Further prospective studies are necessary to confirm these results and to evaluate if a subgroup of DS children may benefit from medical therapy., (© 2020 American Academy of Sleep Medicine.)

Study Objectives: Patients with obstructive sleep apnea (OSA) have been shown to have high levels of inflammatory markers. Anti-inflammatory treatment with montelukast and intranasal steroids have demonstrated efficacy for mild OSA in children; this has not been fully evaluated in adults. This study investigated the response of mild OSA in adults to anti-inflammatory medical therapy., Methods: Adults aged ≥ 21 years with an apnea-hypopnea index (AHI) ≤ 15 events/h on polysomnography (PSG) were recruited to a prospective double-blind, randomized control trial. Patients were treated for 12 weeks with montelukast and fluticasone or placebo. All underwent a pretreatment and posttreatment PSG. Epworth Sleepiness Scale (ESS) score was obtained pretreatment and at 6 and 12 weeks posttreatment., Results: A total of 26 patients completed the study with 13 in each group. Mean age in the treatment and placebo groups were 58.3 ± 10.3 and 54.8 ± 14 years, respectively. There was no significant difference between groups reporting nasal congestion ( P = .186), rhinitis ( P = .666), or snoring ( P = .177). There was no difference in the pretreatment ESS score ( P = .077), body mass index ( P = .173), or AHI ( P = .535). The posttreatment PSG in the treatment group demonstrated a significant increase in total sleep time ( P = .02) and percent of stage R sleep ( P = .05). Neither group showed significant change in AHI. In patients in the treatment group, the 6- and 12-week follow-up ESS scores were not significantly different from pretreatment scores ( P = .37-.46)., Conclusions: Intranasal steroids and montelukast did not decrease AHI; however, total sleep time and percent of stage R sleep significantly increased. Self-reported improvement could be explained by observed changes in sleep parameters. Larger prospective studies could help elucidate the effects of medical therapy on adult patients with OSA., Clinical Trial Registration: Registry: ClinicalTrials.gov; Title: Montelukast and Nasa ICS for Treatment of Mild Obstructive Sleep Apnea in Adults; Identifier: NCT01089647; URL: https://clinicaltrials.gov/ct2/show/record/NCT01089647., (Copyright © 2019 American Academy of Sleep Medicine. All rights reserved.)

Abstract: The diagnosis and effective treatment of obstructive sleep apnea (OSA) in adults is an urgent health priority. Positive airway pressure (PAP) therapy remains the most effective treatment for OSA, although other treatment options continue to be explored. Limited evidence citing small pilot or proof of concept studies suggest that the synthetic medical cannabis extract dronabinol may improve respiratory stability and provide benefit to treat OSA. However, side effects such as somnolence related to treatment were reported in most patients, and the long-term effects on other sleep quality measures, tolerability, and safety are still unknown. Dronabinol is not approved by the United States Food and Drug Administration (FDA) for treatment of OSA, and medical cannabis and synthetic extracts other than dronabinol have not been studied in patients with OSA. The composition of cannabinoids within medical cannabis varies significantly and is not regulated. Synthetic medical cannabis may have differential effects, with variable efficacy and side effects in the treatment of OSA. Therefore, it is the position of the American Academy of Sleep Medicine (AASM) that medical cannabis and/or its synthetic extracts should not be used for the treatment of OSA due to unreliable delivery methods and insufficient evidence of effectiveness, tolerability, and safety. OSA should be excluded from the list of chronic medical conditions for state medical cannabis programs, and patients with OSA should discuss their treatment options with a licensed medical provider at an accredited sleep facility. Further research is needed to understand the functionality of medical cannabis extracts before recommending them as a treatment for OSA., (© 2018 American Academy of Sleep Medicine.)

Study Objectives: The carbonic anhydrase inhibitor acetazolamide (AZT) modulates blood pressure at high altitude and reduces sleep-disordered breathing in patients with obstructive sleep apnea (OSA). We aimed to investigate the treatment effect of AZT and in combination with continuous positive airway pressure (CPAP) on blood pressure in patients with hypertension and OSA., Methods: In a prospective, randomized, three-way crossover study, 13 male patients with hypertension and moderate to severe OSA (age 64 ± 7 years, body mass index 29 ± 4 kg/m 2 , and mean apnea-hypopnea index 37 ± 23 events/h) received AZT, CPAP, or AZT plus CPAP for 2-week periods. Antihypertensive medication was washed out. Office and 24-hour blood pressure, arterial stiffness, polygraphic sleep study data, and blood chemistry were compared., Results: AZT alone and AZT plus CPAP, but not CPAP alone, reduced office mean arterial pressure compared to baseline (-7 [95% CI -11 to -4], -7 [95% CI -11 to -4] and -1 [95% CI -5 to 4] mmHg, respectively; repeated- measures analysis of variance (RM-ANOVA; P = .015). Aortic systolic pressure and augmentation index, assessed by radial artery oscillatory tonometry, were unaffected by CPAP but decreased after AZT and AZT plus CPAP (RM-ANOVA P = .030 and .031, respectively). The apnea-hypopnea index was significantly reduced in all three treatment arms, most prominently by AZT plus CPAP (RM-ANOVA P = .003). The reduction of venous bicarbonate concentration following AZT was correlated with the change of apnea-hypopnea index ( r = 0.66, P = .013)., Conclusions: AZT reduced blood pressure, vascular stiffness, and sleep-disordered breathing in patients with OSA and comorbid hypertension. Carbonic anhydrase inhibition may constitute a potential target for drug therapy in patients with sleep apnea and comorbid hypertension., Clinical Trial Registration: Registry: ClinicalTrials.gov; Identifier: NCT02220803; Title: A Short Term Open, Randomized Cross-over Trial Exploring the Effect of Carbonic Anhydrase Inhibition by Acetazolamide on Sleep Apnea Associated Hypertension and Vascular Dysfunction; URL: https://clinicaltrials.gov/ct2/show/NCT02220803 and Registry: EU Clinical Trials Register; EudraCT Number: 2013-004866-33; Title: A short term open, randomized cross over trial exploring the effect of carbonic anhydrase inhibition by acetazolamide on sleep apnea associated hypertension; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004866-33., (© 2018 American Academy of Sleep Medicine.)

Study Objectives: We sought to determine whether non benzodiazepine sedative hypnotics (NBSH) reduce the occurrence of the low arousal threshold (LAT) phenotype., Methods: Consecutive patients with suspected obstructive sleep apnea (OSA) referred for polysomnography (PSG) had demographic and PSG data abstracted. LAT was estimated using PSG criteria. After adjusting for pretest probability (PTP) for OSA, we calculated the effect that premedication with NBSHs has on LAT prevalence., Results: Five hundred seventy-nine patients with a mean age and body mass index of 42.2 ± 10.1 y and 28.9 ± 4.5 kg/m 2 , respectively, had data available for analysis. Most patients (444, or 80.9%) had a LAT, and administering a NBSH (zolpidem or eszopiclone) on the same night as the PSG did not change LAT prevalence (NBSH: 339 (83.3%) versus no drug: 100 (80.6%); p = 0.50). Adjusting for PTP, neither administration of eszopiclone (odds ratio 0.80 (95% confidence interval: 0.33-2.0); 0.69) nor zolpidem (odds ratio 1.65 (95% confidence interval: 0.8-3.5); p = 0.19) reduced the odds that a patient had a LAT. NBSHs did not change the mean SpO 2 nadir, percentage hypopneas, or apnea-hypopnea index. There was no association between zolpidem or eszopiclone dosing and SpO 2 nadir (zolpidem: β = -0.69, p = 0.80; eszopiclone: β = -1.53, p = 0.68), percentage hypopneas (zolpidem: β = 2.2, p = 0.43; eszopiclone β = -6.2, p = 0.46), or apnea-hypopnea index (zolpidem: β = 3.1, p = 0.22; eszopiclone: β = 2.6, p = 0.39)., Conclusions: The LAT is common in our population and NBSH premedication does not alter its occurrence. Further studies are needed to determine how the LAT can be optimally managed to improve OSA treatment., (© 2017 American Academy of Sleep Medicine)

Study Objectives: To determine the effects of dronabinol on quantitative electroencephalogram (EEG) markers of the sleep process, including power distribution and ultradian cycling in 15 patients with obstructive sleep apnea (OSA)., Methods: EEG (C4-A1) relative power (% total) in the delta, theta, alpha, and sigma bands was quantified by fast Fourier transformation (FFT) over 28-second intervals. An activation ratio (AR = [alpha + sigma] / [delta + theta]) also was computed for each interval. To assess ultradian rhythms, the best-fitting cosine wave was determined for AR and each frequency band in each polysomnogram (PSG)., Results: Fifteen subjects were included in the analysis. Dronabinol was associated with significantly increased theta power (p = 0.002). During the first half of the night, dronabinol decreased sigma power (p = 0.03) and AR (p = 0.03), and increased theta power (p = 0.0006). At increasing dronabinol doses, ultradian rhythms accounted for a greater fraction of EEG power variance in the delta band (p = 0.04) and AR (p = 0.03). Females had higher amplitude ultradian rhythms than males (theta: p = 0.01; sigma: p = 0.01). Decreasing AHI was associated with increasing ultradian rhythm amplitudes (sigma: p < 0.001; AR: p = 0.02). At the end of treatment, lower relative power in the theta band (p = 0.02) and lower AHI (p = 0.05) correlated with a greater decrease in sleepiness from baseline., Conclusions: This exploratory study demonstrates that in individuals with OSA, dronabinol treatment may yield a shift in EEG power toward delta and theta frequencies and a strengthening of ultradian rhythms in the sleep EEG.

Study Objectives: This 12-month, open-label, flexible-dose study with an extension period evaluated the tolerability and efficacy of armodafinil in patients with excessive sleepiness associated with treated obstructive sleep apnea (OSA), shift work disorder (SWD), or narcolepsy., Methods: Armodafinil-naïve, adult patients with excessive sleepiness associated with treated OSA (n = 170), SWD (n = 108), or narcolepsy (n = 50) received armodafinil (100-250 mg) once daily (treated OSA or narcolepsy) or before night shifts (SWD). Patients with OSA were regular users of continuous positive airway pressure (CPAP) therapy. Efficacy measures included the Clinical Global Impression of Improvement (CGI-I) and the Epworth Sleepiness Scale (ESS)., Results: Across the diagnosis groups, the most commonly occurring adverse event was headache (14%-24%). Forty-three patients (13%) and 13 patients (4%) were withdrawn because of adverse events and insufficient efficacy, respectively. Armodafinil did not adversely affect CPAP therapy. At the final visit, 80% (95% CI: 74.1, 86.7) of patients with treated OSA and 84% (72.7, 94.8) of patients with narcolepsy were rated on the CGI-I as at least minimally improved with regard to overall clinical condition; 98% (95.2, 100.0) of patients with SWD were rated as improved with regard to sleepiness during night shifts, including the commute to and from work. Armodafinil improved ESS total scores in patients with treated OSA (mean [SD] [95% CI] change from baseline, -7.3 [5.6] [-8.39, -6.30]) and patients with narcolepsy (-4.7 [6.0] [-7.41, -1.93])., Conclusions: Armodafinil administered for 12 months or more was generally well tolerated and improved wakefulness in patients with excessive sleepiness associated with treated OSA, SWD, or narcolepsy. Armodafinil improved the overall clinical condition of patients with treated OSA or narcolepsy.

Study Objectives: Armodafinil is a wakefulness-promoting medication. Its efficacy and tolerability have been established in 12-week studies of patients with excessive sleepiness (ES) associated with treated obstructive sleep apnea (OSA), shift work disorder (SWD), or narcolepsy. This study evaluated the tolerability and efficacy of armodafinil for > or = 12 months., Methods: Patients with ES associated with treated OSA, SWD, or narcolepsy who completed one of four 12-week, double-blind studies were eligible for this multicenter, open-label study of > or = 12 months' duration of treatment with armodafinil (50 to 250 mg/day). Adverse events and other criteria of tolerability were monitored throughout the study. Efficacy assessments included the Clinical Global Impression of Change (CGI-C), Brief Fatigue Inventory (BFI), and Epworth Sleepiness Scale (ESS)., Results: Of 743 enrolled patients (474 with treated OSA, 113 with SWD, and 156 with narcolepsy), 57% of patients (420/743) completed 12 months or more of treatment. Discontinuations due to adverse events occurred in 13% of patients (95/743) during the initial 12-month period. Throughout the > or = 12-month study, adverse events were generally of mild-to-moderate intensity; headache (25% [180/731]), nasopharyngitis (17% [123/731]), and insomnia (14% [99/731]) were the most common. Modest increases were observed in vital sign measurements (blood pressure [3.6/2.3 mm Hg], heart rate [6.7 beats per minute]) across all patient groups; most of the changes occurred by month 3. Improvements from baseline in efficacy assessments started at month 1 and were maintained throughout the study., Conclusions: Armodafinil remained effective and was generally well tolerated. Increased monitoring of blood pressure may be appropriate in patients on armodafinil. Armodafinil represents an option for long-term treatment of patients with ES associated with treated OSA, SWD, or narcolepsy.

Objectives: To determine the effect of the drug combination domperidone and pseudoephedrine on nocturnal oximetry measurements and daytime sleepiness in patients with obstructive sleep apnea., Methods: We recruited patients with severe snoring and apneic episodes willing to undergo repeated nocturnal oximetry testing. Following baseline clinical history, Epworth Sleepiness Scale administration, and home overnight nocturnal oximetry, patients were started on weight-adjusted doses of domperidone and pseudoephedrine. Follow-up oximetry studies were performed at the patient's convenience. On the final visit, a repeat clinical history, Epworth score, and oximetry were obtained., Results: Seventeen of 23 patients noted disappearance of snoring and apneic episodes. Another 2 patients reported improvement in snoring and no apneic episodes. All but one patient had a decrease in Epworth scores (mean decrease 9.4 (95% CI, 6.8-12.1, p < 0.0001). Mean oxygen saturation (2.5; 95% Cl, 0.66-4.41, p = 0.008), percent time with oxygen saturation < 90% (14.8; 95% CI, 24.4 to 5.2, p = 0.003), and the 4% oxygen desaturation index (18.2; 95% CI, 27.3 to 9.1, p < 0.0001) improved significantly. No adverse effects of treatment were noted., Conclusions: The combination of domperidone and pseudoephedrine improved self reported snoring and sleepiness, and may have improved apneic episodes and sleep-related nocturnal oxygen desaturation in patients with obstructive sleep apnea provided the proportion of time spent asleep did not diminish. This drug combination warrants further study as a treatment for obstructive sleep apnea., Keywords: Obstructive sleep apnea; oximetry; sleepiness; domperidone; pseudoephedrine; pharmacotherapy; desaturation; treatment, Citation: Larrain A; Kapur VK; Gooley TA; Pope CE. Pharmacological treatment of obstructive sleep apnea with a combination of pseudoephedrine and domperidone.

Study Objectives: This study was designed to assess the effect of acid suppression on upper airway structure and function in patients with obstructive sleep apnea syndrome (OSAS) and gastroesophageal reflux disease (GERD)., Methods: This is a single-site within-subjects design. Twenty five patients with documented mild OSAS and objectively documented GERD via 24-hour pH measurement were included in the study. Patients were studied before and after 8 weeks of treatment with rabeprazole, 20 mg, twice a day. Subjects underwent laryngoscopy, polysomnography, and 24-hour pH monitoring. Subjective assessments of sleep obtained included the Pittsburg Sleep Quality Index and the Epworth Sleepiness Scale., Results: Posterior commissure edema was significantly reduced (p < 0.05), and the Reflux Finding Score was improved (p < 0.07). Objective and subjective sleep parameters were significantly improved, sleep-onset latency was significantly reduced (26.2 vs 11.2, p < 0.05), and sleep-related acid contact time was significantly reduced (8.0% vs 1.7% p < 0.001). There was no significant change in the apnea-hypopnea index., Conclusions: In patients with mild OSAS and documented GERD, acid suppression improves upper airway abnormalities, as well as objective and subjective measures of sleep quality. Aggressive treatment of GERD in patients with OSAS may be helpful in the overall treatment of this select patient population.

Study Objectives: Modafinil is a wake-promoting agent shown to improve wakefulness in patients with excessive sleepiness (hypersomnolence) associated with shift work sleep disorder, obstructive sleep apnea, or narcolepsy. Safety and tolerability data from 6 randomized, double-blind, placebo-controlled studies were combined to evaluate modafinil across these different patient populations., Methods: One thousand five hundred twenty-nine outpatients received modafinil 200, 300, or 400 mg or placebo once daily for up to 12 weeks. Assessments included recording of adverse events and effects of modafinil on blood pressure/heart rate, electrocardiogram intervals, polysomnography, and clinical laboratory parameters., Results: Two hundred seventy-three patients with shift work sleep disorder, 292 with obstructive sleep apnea, and 369 with narcolepsy received modafinil; 567 received placebo. Modafinil was well tolerated versus placebo, with headache (34% vs 23%, respectively), nausea (11% vs 3%), and infection (10% vs 12%) the most common adverse events. Adverse events were similar across all patient groups. Twenty-seven serious adverse events were reported (modafinil, n = 18; placebo, n = 9). In modafinil-treated patients, clinically significant increases in diastolic or systolic blood pressure were infrequent (n = 9 and n = 1, respectively, < 1% of patients). In the studies, 1 patient in the modafinil group and 1 in the placebo group had a clinically significant increase in heart rate. New clinically meaningful electrocardiogram abnormalities were rare with modafinil (n = 2) and placebo (n = 4). Clinically significant abnormalities in mean laboratory parameters were observed in fewer than 1% of modafinil-treated patients at final visit. Modafinil did not affect sleep architecture in any patient population according to polysomnography., Conclusions: Modafinil is well tolerated in the treatment of excessive sleepiness associated with disorders of sleep and wakefulness and does not affect cardiovascular or sleep parameters.

Background: Sedative medications may be inadvertently prescribed to patients with undiagnosed obstructive sleep apnea (OSA) and may worsen daytime sleepiness., Study Objectives: To determine whether patients with undiagnosed OSA were prescribed sedative medications and whether such prescriptions increased the risk for traffic accidents. A secondary objective was to determine physician characteristics associated with such prescription practices., Design: Retrospective chart review. Telephone interviews of patients and physicians., Intervention: None., Patients: One hundred fifty-one consecutive patients at a sleep laboratory., Results: Forty-one of 137 (30%) patients with undiagnosed OSA had received prescriptions for sedating medications. Regression analysis identified self-report of sleepiness while driving (p = .05) and prescription for risperidone as independent risk factors for motor vehicle accidents (p = .005), while prescription of any sedative (excluding risperidone) tended to be associated with accidents (p =.10). In patients with severe OSA, prescription of sedating medications was associated with a greater risk for motor vehicle accidents than those without such prescriptions (relative risk = 2.6; p = .04). In patients with prescription for sedating medications (n = 41), the apnea-hypopnea index was directly proportional to the risk for motor vehicle accidents (r2 = 0.26; p = .001) suggesting a 'dose effect' of severity of sleep-disordered breathing on risk for accidents. Physicians who did not usually treat patients with sleep disorders were more likely to prescribe sedatives to patients with undiagnosed OSA than were physicians with such expertise: neurologist, pulmonologist, or psychiatrist (52% vs 10%; relative risk = 5.2; p = .02), Conclusion: Prescription of sedating medications may increase the risk of road accidents in patients with undiagnosed severe OSA, and such prescription practices are less likely to occur in physicians with expertise in sleep medicine.

Study Objectives: An uncomfortable environment or continuous positive airway pressure (CPAP) intolerance may cause poor sleep efficiency during polysomnography and result in a poor-quality study. Unsatisfactory polysomnograms often must be repeated. Nonbenzodiazepine hypnotics may improve sleep efficiency without disruption of sleep architecture. We hypothesized that premedication with zolpidem improves polysomnogram quality and decreases the need to restudy., Methods: We retrospectively reviewed 200 consecutive polysomnograms. Zolpidem premedication was not standardized and was prescribed at the discretion of consulting sleep physicians, who were unaware of this study. We compared the quality of polysomnograms between patients who received zolpidem 10 mg prior to polysomnography and those who did not. A poor-quality polysomnogram was defined as having insufficient sleep time to allow for diagnosis, incomplete CPAP titration with a resulting apnea-hypopnea index > 10 on the highest level of CPAP achieved, or complete CPAP intolerance., Results: Of 200 records reviewed, 54 patients (27%) received zolpidem. Demographics did not differ between groups. Premedication with zolpidem resulted in improved sleep latency (11.8 +/- 9.5 minutes vs 26.0 +/- 19.9 minutes, p = .002) and sleep efficiency (89.5% +/- 5.6% vs 78.8 +/- 12.3, p < .0001). Zolpidem premedication resulted in significantly fewer studies meeting criteria for poor quality (7.4% vs 33.6%, p = .005). Of the 49 studies meeting criteria for poor quality, 21 were repeated using zolpidem, showing significant improvements in sleep latency (10.8 +/- 7.1 minutes vs 42.8 +/- 30.5 minutes, p = .0004) and sleep efficiency (89.5% +/- 4.9% vs 61.8% +/- 13.7%, p < .0001). No study repeated with zolpidem met criteria for poor quality., Conclusions: Pretreatment with zolpidem significantly improved polysomnographic quality and may decrease the need to repeat polysomnograms.