Efficacy of atomoxetine plus oxybutynin in the treatment of obstructive sleep apnea with moderate pharyngeal collapsibility

Paula K Schweitzer, James P Maynard, Paul E Wylie, Helene A Emsellem, Scott A Sands, Paula K Schweitzer, James P Maynard, Paul E Wylie, Helene A Emsellem, Scott A Sands

Abstract

Purpose: Preliminary studies have shown a significant decrease in severity of obstructive sleep apnea (OSA) with the use of a combination of atomoxetine and oxybutynin, with patients having moderate pharyngeal collapsibility during sleep more likely to respond. This study evaluated the efficacy and safety of AD036 (atomoxetine 80 mg and oxybutynin 5 mg) in the treatment of OSA.

Methods: This trial was a phase 2, randomized, placebo-controlled crossover study comparing AD036, atomoxetine 80 mg alone, and placebo during three home sleep studies, each separated by about 1 week. The trial included patients with OSA and moderate pharyngeal collapsibility as defined by a higher proportion of hypopneas to apneas and mild oxygen desaturation.

Results: Of 62 patients who were randomized, 60 were included in efficacy analyses. The apnea-hypopnea index (AHI) from a median (interquartile range) of 14.2 (5.4 to 22.3) events/h on placebo to 6.2 (2.8 to 13.6) with AD036 and 4.8 (1.4 to 11.6) with atomoxetine alone (p < .0001). Both drugs also decreased the oxygen desaturation index (ODI) and the hypoxic burden (p < .0001). AD036, but not atomoxetine alone, reduced the respiratory arousal index and improved ventilation at the respiratory arousal threshold (greater Vactive). There was a trend for total sleep time to be decreased more with atomoxetine alone than with AD036. The most common adverse event was insomnia (12% with AD036, 18% with atomoxetine).

Conclusion: AD036 significantly improved OSA severity in patients with moderate pharyngeal collapsibility. Atomoxetine may account for the majority of improvement in OSA severity, while the addition of oxybutynin may mitigate the disruptive effect of atomoxetine on sleep and further improve ventilation.

Trial registration: Clinical trial registered with www.

Clinicaltrials: gov (NCT04445688).

Keywords: AD036; Atomoxetine; OSA pharmacotherapy; Obstructive sleep apnea; Oxybutynin.

Conflict of interest statement

P Schweitzer has received consultancy fees from Apnimed, Inc. and Jazz Pharmaceuticals; her institution has received research funding from Apnimed, Inc., Avadel, Inspire Medical Systems, Jazz Pharmaceuticals, and Suven Life Sciences.

J Maynard reports no conflicts.

P Wylie reports no conflicts.

H. Emsellem has received research funding from Apnimed, Inc., Jazz Pharmaceuticals, Avadel, NLS, Philips, Suven, Vanda Pharmaceuticals, and Takeda. She has participated in advisory boards for Avadel, Harmony Biosciences, and Takeda.

S Sands has received consulting fees from Apnimed, Nox Medical, Merck, and Inspire, and received grant support from Apnimed, Prosomnus, and Dynaflex.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Consolidated Standards of Reporting Trials diagram of the clinical trial
Fig. 2
Fig. 2
Box plots of apnea–hypopnea index (AHI), oxygen desaturation index (ODI), and hypoxic burden (HB) on placebo, AD036, and atomoxetine. Black lines indicate medians; boxes indicate 25th and 75th percentiles

References

    1. Benjafield AV, Ayas NT, Eastwood PR, Heinzer R, Ip MSM, Morrell MJ, Nunez CM, Patel SR, Penzel T, Pépin JL, Peppard PE, Sinha S, Tufik S, Valentine K, Malhotra A. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med. 2019;8:687–698. doi: 10.1016/S2213-2600(19)30198-5.
    1. Gottlieb DJ, Punjabi NM. Diagnosis and management of obstructive sleep apnea: a Review. JAMA. 2020;14:1389–1400. doi: 10.1001/jama.2020.3514.
    1. Javaheri S, Barbe F, Campos-Rodriguez F, Dempsey JA, Khayat R, Javaheri S, Malhotra A, Martinez-Garcia MA, Mehra R, Pack AI, Polotsky VY, Redline S, Somers VK. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol. 2017;69(7):841–858. doi: 10.1016/j.jacc.2016.11.069.
    1. Patil SP, Ayappa IA, Caples SM, Kimoff RJ, Patel SR, Harrod CG. Treatment of adult obstructive sleep apnea with positive airway pressure: an American Academy of Sleep Medicine systematic review meta-analysis and GRADE assessment. J Clin Sleep Med. 2019;15(2):301–334. doi: 10.5664/jcsm.7638.
    1. Rotenberg BW, Murariu D, Pang KP. Trends in CPAP adherence over twenty years of data collection: a flattened curve. J Otolaryngol Head Neck Surg. 2016;45:43. doi: 10.1186/s40463-016-0156-0.
    1. Sawyer AM, Gooneratne NS, Marcus CL, Ofer D, Richards KC, Weaver TE. A systematic review of CPAP adherence across age groups: clinical and empiric insights for developing CPAP adherence interventions. Sleep Med Rev. 2011;15:343–356. doi: 10.1016/j.smrv.2011.01.003.
    1. Hedner J, Zou D. Drug therapy in obstructive sleep apnea. Sleep Med Clin. 2018;13(2):203–217. doi: 10.1016/j.jsmc.2018.03.004.
    1. Mason M, Welsh EJ, Smith I (2013) Drug therapy for obstructive sleep apnoea in adults. Cochrane Database Syst Rev (5):CD003002. 10.1002/14651858.CD003002.pub3.
    1. Osman AM, Carter SG, Carberry JC and Eckert DJ (2018) Obstructive sleep apnea: current perspectives. Nature and science of sleep 21–34. 10.2147/NSS.S124657.
    1. Taranto-Montemurro L, Messineo L, Wellman A. Targeting endotypic traits with medications for the pharmacological treatment of obstructive sleep apnea A review of the current literature. J Clin Med. 2019;8(11):1846. doi: 10.3390/jcm8111846.
    1. Taranto-Montemurro L, Messineo L, Sands SA, Azarbarzin A, Marques M, Edwards BA, Eckert DJ, White DP, Wellman A. The combination of atomoxetine and oxybutynin greatly reduces obstructive sleep apnea severity A randomized, placebo-controlled double-blind crossover trial. Am J Respir Crit Care Med. 2019;199:1267–1276. doi: 10.1164/rccm.201808-1493OC.
    1. Perger E, Montemurro LT, Rosa D, Vicini S, Marconi M, Zanotti L, Meriggi P, Azarbarzin A, Sands SA, Wellman A, Lombardi C, Parati G. Reboxetine plus oxybutynin for OSA treatment: a 1-week randomized, placebo-controlled, double-blind crossover trial. Chest. 2021;S0012–3692(21):03861–3867. doi: 10.1016/j.chest.2021.08.080.
    1. Lim R, Messineo L, Grunstein RR, Carberry JC, Eckert DJ. The noradrenergic agent reboxetine plus the antimuscarinic hyoscine butylbromide reduces sleep apnoea severity: a double-blind, placebo-controlled, randomised crossover trial. J Physiol. 2021;599(17):4183–4195. doi: 10.1113/JP281912.
    1. Chan E, Steenland HW, Liu H, Horner RL. Endogenous excitatory drive modulating respiratory muscle activity across sleep-wake states. Am J Respir Crit Care Med. 2006;174(11):1264–1273. doi: 10.1164/rccm.200605-597OC.
    1. Grace KP, Hughes SW, Horner RL. Identification of the mechanism mediating genioglossus muscle suppression in REM sleep. Am J Respir Crit Care Med. 2013;187(3):311–9. doi: 10.1164/rccm.201209-1654OC.
    1. Taranto-Montemurro L, Messineo L, Azarbarzin A, Vena D, Hess LB, Calianese NA, White DP, Wellman A, Sands SA. Effects of the combination of atomoxetine and oxybutynin on OSA endotypic traits. Chest. 2020;157(6):1626–1636. doi: 10.1016/j.chest.2020.01.012.
    1. Sands SA, Edwards BA, Terrill PI, Taranto-Montemurro L, Azarbarzin A, Marques M, Hess LB, White DP, Wellman A. Phenotyping pharyngeal pathophysiology using polysomnography in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2018;197:1187–1197. doi: 10.1164/rccm.201707-1435OC.
    1. Vena D, Taranto-Montemurro L, Azarbarzin A, Op de Beeck S, Marques M, Vanderveken OM, Edwards BA, Gell L, Calianese N, Hess LB, Radmand R, Hamilton GS, Joosten SA, Verbraecken J, Braem M, White DP, Redline S, Sands SA, Wellman A (2022) Clinical polysomnographic methods for estimating pharyngeal collapsibility in obstructive sleep apnea. Sleep zsac050. 10.1093/sleep/zsac050
    1. Berry RB, Quan SF, Abreu AR, et al; for the American Academy of Sleep Medicine (2020) The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Version 2.6. Darien, IL: American Academy of Sleep Medicine
    1. Azarbarzin A, Sands SA, Stone KL, Taranto-Montemurro L, Messineo L, Terrill PI, et al. The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the Osteoporotic Fractures in Men Study and the Sleep Heart Health Study. Eur Heart J. 2019;40:1149–1157. doi: 10.1093/eurheartj/ehy624.
    1. Amatoury J, Azarbarzin A, Younes M, Jordan AS, Wellman A, Eckert DJ. Arousal intensity is a distinct pathophysiological trait in obstructive sleep apnea. Sleep. 2016;39(12):2091–2100. doi: 10.5665/sleep.6304.
    1. Simpson D, Plosker GL. Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder. Drugs. 2004;64(2):205–222. doi: 10.2165/00003495-200464020-00005.
    1. Abramov Y, Sand PK. Oxybutynin for treatment of urge urinary incontinence and overactive bladder: an updated review. Expert Opin Pharmacother. 2004;5(11):2351–2359. doi: 10.1517/14656566.5.11.2351.
    1. Sangal RB, Sangal JM, Thorp K. Atomoxetine improves sleepiness and global severity of illness but not the respiratory disturbance index in mild to moderate obstructive sleep apnea with sleepiness. Sleep Med. 2008;9(5):506–510. doi: 10.1016/j.sleep.2007.07.013.
    1. Levendowski DJ, Zack N, Rao S, Wong K, Gendreau M, Kranzler J, Zavora T, Westbrook PR. Assessment of the test-retest reliability of laboratory polysomnography. Sleep Breath. 2009;13:163–167. doi: 10.1007/s11325-008-0214-6.
    1. Prasad B, Usmani S, Steffen AD, Van Dongen HP, Pack FM, Strakovsky I, Staley B, Dinges D, Maislin G, Pack AI, Weaver TE. Short-term variability in apnea-hypopnea index during extended home portable monitoring. J Clin Sleep Med. 2016;12(6):855–863. doi: 10.5664/jcsm.5886.
    1. Miettinen T, Myllymaa K, Westeren-Punnonen S, et al. Success rate and technical quality of home polysomnography with self-applicable electrode set in subjects with possible sleep bruxism. IEEE J Biomed Health Inform. 2018;22(4):1124–1132. doi: 10.1109/JBHI.2017.2741522.
    1. Messineo L, Carter SG, Taranto-Montemurro L, Chiang A, Vakulin A, Adams RJ, Carberry JC, Eckert DJ. Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: a randomized trial. Respirology. 2021;26(9):878–886. doi: 10.1111/resp.14110.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit