Abstract
Obstructive sleep apnoea (OSA) is common, causes considerable morbidity and probably contributes to mortality particularly through associated cardiovascular disease. The physical therapy of continuous positive airway pressure (CPAP) is extremely effective in the majority of patients but most patients would prefer an alternative. Intuitively, OSA should be amenable to pharmacotherapy. The upper airway of affected individuals can be narrowed but is patent during wakefulness. Collapse of the airway during sleep occurs when negative intra-luminal pressure generated by inspiratory effort exceeds the tone of the upper airway dilators. This mismatch may be in part due to respiratory drive instability but the state-dependent fall in drive to the airway dilator muscles is the biggest factor in most patients.
Various drugs have been investigated as treatment for OSA. Acetazolamide, theophylline, nicotine, opioid antagonists and medroxyprogesterone have been used to increase respiratory drive. Clonidine has been tested with the aim of reducing rapid eye movement sleep when OSA is often most severe. Variousantidepressants have been used to suppress rapid eye movement sleep and to preferentially activate the upper airway dilators. The drug trials have often been of poor design and none has included more than a few patients. Most of the drugs have been found to be ineffective and those that have worked for some patients (acetazolamide and protriptyline) have produced intolerable adverse effects.
There have been recent advances in the understanding of the neurotransmitters involved in the control of sleep and the upper airway motor neurones, offering the possibility of novel approaches to the drug treatment of OSA for those patients who cannot tolerate or do not benefit from CPAP. It seems likely that a better understanding of the mechanisms of OSA in individual patients and tailoring of drug therapy will be the way forward.
Similar content being viewed by others
References
Diagnostic Classification Steering Committee, Thorpy MJ. International classification of sleep disorders: diagnostic and coding manual. Rochester (MN): American Sleep Disorders Association, 1990
Davies RJ, Ali NJ, Stradling JR. Neck circumference and other clinical features in the diagnosis of the obstructive sleep apnoea syndrome. Thorax 1992; 47: 101–5
Flemons WW, Whitelaw WA, Brant R, et al. Likelihood ratios for a sleep apnoea clinical prediction rule. Am J Respir Crit Care Med 1994; 150: 1279–85
Remmers JE, Degroot WJ, Sauerland EK, et al. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978; 11: 931–8
Younes M, Ostrowski M, Thompson W, et al. Chemical control stability in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2001; 163: 829–39
Younes M. Contributions of upper airway mechanics and control mechanisms to severity of obstructive sleep apnea. Am J Respir Crit Care Med 2003; 168: 645–58
Friberg D. Heavy snorers' disease: a progressive local neuropathy. Acta Otolaryngol 1999; 119: 925–33
Issa FG, Sullivan CE. Alcohol, snoring and sleep apnea. J Neurol Neurosurg Psychiatry 1982; 45: 353–9
Young T, Palta M, Dempsey J, et al. The occurrence of sleep disordered breathing in middle aged adults. N Engl J Med 1993; 328: 1230–5
Stradling JR, Barbour C, Glennon J, et al. Prevalence of sleepiness and its relation to autonomic arousal and increased inspiratory effort in a community based population of men and women. J Sleep Res 2000; 9: 381–8
Olson LG, King MT, Hensley MJ, et al. A community study of snoring and sleep disordered breathing prevalence. Am J Respir Crit Care Med 1995; 152: 711–6
Bixler E, Vgontzas A, Ten Have T, et al. Prevalence of sleep disordered breathing in women. Am J Respir Crit Care Med 2001; 163: 608–13
Lacasse Y, Godbout C, Series F. Health-related quality of life in obstructive sleep apnoea. Eur Respir J 2002; 19: 499–503
Smith IE, Shneerson JM. Is the SF 36 sensitive to sleep disruption? A study in subjects with sleep apnoea. J Sleep Res 1995; 4: 183–8
Shahar E, Whitney CW, Redline S, et al. Sleep disordered breathing and cardiovascular disease. Am J Respir Crit Care Med 2001; 163: 19–25
Brooks D, Horner RL, Kozar LF, et al. Obstructive sleep apnea as a cause of systemic hypertension: evidence from a canine model. J Cin Invest 1997; 99: 106–9
Nieto FJ, Young TB, Lind BK, et al. Association of sleep disordered breathing, sleep apnea and hypertension in a large community based study: Sleep Heart Health Study. JAMA 2000; 283: 1829–36
Lavie P, Heret P, Hoffstein V. Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study. BMJ 2000; 320: 479–82
Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342: 1378–84
Juniper M, Hack MA, George CF, et al. Steering simulation performance in patients with obstructive sleep apnoea and matched control subjects. Eur Respir J 2000; 15: 590–5
George CFP. Reduction in motor vehicle collisions following treatment of sleep apnoea with nasal CPAP. Thorax 2001; 56: 508–12
Piper AJ, Sullivan CE. Effects of short-term NIPPV in the treatment of patients with severe obstructive sleep apnea and hypercapnia. Chest 1994; 105: 434–40
Smith I, Lasserson T, Wright J. Drug treatments for obstructive sleep apnoea (Cochrane Review). Available in The Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue 2. Oxford: Update Software, 2003
Sullivan CE, Issa FG, Berthon-Jones M. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981; I: 862–5
Jenkinson C, Davies RJO, Mullins R, et al. Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial. Lancet 1999; 353: 2100–5
McFadyen TA, Espie CA, McArdle N, et al. Controlled prospective trial of psychosocial function before and after continuous positive airway pressure therapy. Eur Respir J 2001; 18: 996–1002
Pepperell JC, Mullins B, Dow SR, et al. Ambulatory blood pressure following therapeutic and sub-therapeutic nasal continuous positive airway pressure for moderate to severe obstructive sleep apnoea: a randomised prospective parallel trial. Lancet 2002; 359: 204–10
Hoy CJ, Vennelle M, Kingshott RN, et al. Can intensive support improve continuous positive airway pressure use in patients with the sleep apnea/hypopnea syndrome? Am J Respir Crit Care Med 1999; 159: 1096–100
Loube-DI. Technologic advances in the treatment of obstructive sleep apnea syndrome. Chest 1999 Nov; 116: 1426–33
Wright J, White J. Continuous positive airways pressure for obstructive sleep apnoea (Cochrane Review). Available in The Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue 3. Oxford: Update Software, 1999
Guilleminault C, Philip P. Tiredness and somnolence despite initial treatment of obstructive sleep apnea syndrome (what to do when an OSAS patients stays hypersomnolent despite treatment). Sleep 1996; 19 Suppl. 9: S117–22
Stradling J. Handbook of sleep-related breathing disorders. Oxford: Oxford University Press, 1993
Cistuli P, Barnes D, Grunstein R, et al. Effect of short term hormone replacement in the treatment of obstructive sleep apnoea in post-menopausal women. Thorax 1994; 49: 699–702
St John WM, Bartlett D, Knuth KV, et al. Differential depression of hypoglossal nerve activity by alcohol: protection by pre-treatment with medroxyprogesterone acetate. Am Rev Respir Dis 1986; 133: 46–8
Block AJ, Wynne JW, Boysen PG, et al. Menopause, medroxyprogesterone and breathing during sleep. Am J Med 1981; 70: 506–10
Cook WR, Benich JJ, Wooten SA. Indices of severity of obstructive sleep apnea syndrome do not change during medroxyprogesterone acetate therapy. Chest 1989; 96: 262–6
Dexter DD, Dovre EJ. Obstructive sleep apnea due to endogenous testosterone production in a woman. Mayo Clin Proc 1998; 73: 246–8
Yee B, Liu PY, Yang Q, et al. A double blind, placebo controlled randomised crossover study of intramuscular testosterone esters onsleep in men over 60 years of age [abstract]. J Sleep Res 2002; 11 Suppl. 1: 254
Sandblom RE, Matsumoto AM, Schoene RB, et al. Obstructive sleep apnea syndrome induced by testosterone administration. N Engl J Med 1983; 308: 508–10
Luboshitzky R, Aviv A, Hefetz A, et al. Decreased pituitarygonadal secretion in men with obstructive sleep apnea. J Clin Endocrinol Metab 2002; 87: 3394–8
White DP, Zwillich CW, Pickett CK, et al. Central sleep apnoea: improvement with acetazolamide therapy. Arch Intern Med 1982; 142: 1816–9
Tojima H, Kunitomo F, Kimura H, et al. Effects of acetazolamide in patients with sleep apnoea syndrome. Thorax 1988; 43: 113–9
Whyte K, Gould G, Airlie A, et al. Role of protriptyline and acetazolamide in the sleep apnoea/hypopnoea syndrome. Sleep 1988; 11: 463–72
Brownell LGP, West P, Sweatman P, et al. Protriptyline in obstructive sleep apnea: a double blind trial. N Engl J Med 1982; 307: 1037–42
Stepanski E, Conway W, Young D, et al. A double blind trial of protriptyline in the treatment of sleep apnea syndrome. Henry Ford Hosp Med J 1988; 36: 5–8
Javaheri S, Evers JAM, Teppema LJ. Increase in ventilation caused by aminophylline in the absence of changes in ventral medullary extra cellular fluids, pH and carbon dioxide tension. Thorax 1989; 44: 121–5
Aubier M, Detroya A, Sampson M, et al. Aminophylline improves diaphragmatic contractility. N Engl J Med 1981; 305: 249–52
Mulloy E, McNicholas WT. Theophylline in obstructive sleep apnoea: a double blind evaluation. Chest 1992; 101: 753–7
Espinosa H, Antic R, Thornton AT, et al. The effects of aminophylline on the sleep and sleep-disordered breathing in patients with obstructive sleep apnea syndrome. Am Rev Respir Dis 1987; 136: 80–4
Saletu B, Oberndorfer S, Anderer P, et al. Efficiency of continuous positive airway pressure versus theophylline therapy in sleep apnea: comparative sleep laboratory studies on objective and subjective sleep and awakening quality. Neuropsychobiology 1999; 39: 151–9
Gislason T, Almqvist M, Boman G, et al. Increased CSF opioid activity in sleep apnea syndrome: regression after successful treatment. Chest 1989; 96: 250–4
Atkinson RL, Suratt PM, Wilhoit SC. Naloxone improves sleep apnea in obese humans. Int J Obes Relat Metab Disord 1985; 9: 233–9
Suratt PM, Wilhoit SC, Brown ED, et al. Effect of doxapram on obstructive sleep apnea. Bull Eur Physiopathol Respir 1986; 22: 127–31
Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002; 165: 1217–39
Shao XM, Feldman JL. Pharmacology of nicotinic receptors in preBötzinger complex that mediate modulation of respiratory pattern. J Neurophysiol 2002; 88: 1851–8
Gothe B, Strohl KP, Levin S, et al. Nicotine: a different approach to treatment of obstructive sleep apnea. Chest 1985; 87: 11–7
Davila DG, Hunt RD, Offord KP, et al. Acute effects of transdermal nicotine on sleep architecture, snoring, and sleepdisordered breathing in nonsmokers. Am J Respir Crit Care Med 1994; 150: 469–74
Kraiczi H, Hedner J, Peker Y, et al. Comparison of atenolol, amlodipine, enalapril, hydrochlorothiazide and losartan for antihypertensive treatment in obstructive sleep apnea. Am J Respir Crit Care Med 2000; 161: 1423–8
Weichler U, Kerres-Mayer B, Mayer J, et al. Influence of antihypertensive drug therapy on sleep pattern and sleep apnea activity. Cardiology 1991; 78: 124–30
Mayer J, Peter JH. First experience with cilazapril in the treatment of sleep apnoea-related hypertension. Drugs 1991; 41 Suppl. 1: 37–47
Grote L, Wutkewicz K, Knaack L, et al. Association between blood pressure reduction with antihypertensive treatment and sleep apnea activity. Am J Hypertens 2000; 13: 1280–7
Planes C, Foucher A, Leroy M, et al. Effect of celiprolol treatment in hypertensive patients with sleep apnea. Sleep 1999; 22: 507–13
Kammo O, Clarebarch P. Effects of clonidine and yohimbine on sleep in man: polygraphic study and EEG analysis by normalised slope descriptors. Electroencephalogr Clin Neurophysiol 1985; 60: 478–84
Issa F. Effect of clonidine in obstructive sleep apnoea. Am Rev Respir Dis 1992; 145: 465–9
Hudgel DW. Pharmacologic treatment of obstructive sleep apnea. J Lab Clin Med 1995; 126: 13–8
Bonora M, St John WM, Bledsoe TA. Differential elevation by protriptyline and depression by diazepam of upper airway respiratory motor activity. Am Rev Respir Dis 1985; 131: 41–5
Mezzanotte WS, Tangel DJ, White DP, et al. Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J Clin Invest 1992; 89: 1571–9
Horner RL. The neuropharmacology of upper airway motor control in the awake and asleep states: implications for obstructive sleep apnoea. Respir Res 2001; 2: 286–94
Chase MH, Soja PJ, Morales FR. Evidence that glycine mediates the post-synaptic potentials that inhibit lumbar motoneurons during the atonia of active sleep. J Neurosci 1989; 9: 743–51
Kubin L, Kimura H, Tojima H, et al. Suppression of hypoglossal motorneurons during the carbachol induced atonia of REM sleep is not caused by fast synaptic inhibition. Brain Res 1993; 611: 300–12
Kubin L, Tojima H, Davies RO, et al. Serotonergic excitatory drive to hypoglossal motorneurons in the decerabrate cat. Neurosci Lett 1992; 139: 243–8
Jacobs BL, Azmitia EC. Structure and function of the brain serotonin system. Physiol Rev 1992; 72: 165–229
Jelev A, Sood S, Liu H, et al. Microdialysis perfusion of 5-HT into the hypoglossal motor nucleus differentially modulates genioglossus activity across natural sleep-wake states in rats. J Physiol (Lond) 2001; 532: 467–81
Morin D, Monteau R, Hilaire G. Compared effects of serotonin on cervical and hypoglossal activities: an in-vitro study in the newborn rat. J Physiol (Lond) 1992; 451: 605–29
Veasey SC, Chachkes J, Fenik P, et al. The effects of ondansetron on sleep-disordered breathing in the English bulldog. Sleep 2001; 24: 155–60
Stradling J, Smith D, Radulovacki M, et al. Effect of ondansetron on moderate obstructive sleep apnoea, a single night, placebo-controlled trial. J Sleep Res 2003; 12: 169–70
Sunderram J, Parisi RA, Strobel RJ. Serotonergic stimulation of the genioglossus and the response to nasal continuous positive airway pressure. Am J Respir Crit Care Med 2000; 162: 925–9
Hanzel DA, Proia NG, Hudgel DW. Response of obstructive sleep apnea to fluoxetine and protriptyline. Chest 1991; 100: 416–21
Kraiczi H, Hedner J, Dahlof P, et al. Effect of serotonin uptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnea. Sleep 1999; 22: 61–7
Greenstone M. Doxapram for ventilatory failure due to exacerbations of chronic obstructive pulmonary disease. (Cochrane Review). Available in The Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue 2. Oxford: Update Software, 2003
Bellemare F. Bigland-Ritchie B. Central components of diaphragmatic fatigue assessed by phrenic nerve stimulation. J Appl Physiol 1987; 62: 1307–16
Jokic R, Klimaszewski A, Crossley M, et al. Positional treatment vs continuous positive airway pressure in patients with positional obstructive sleep apnoea syndrome. Chest 1999; 115: 771–81
Rubinstein I, Colapinto N, Rotstein LE, et al. Improvement in upper airway function after weight loss in patients with obstructive sleep apnoea. Am Rev Respir Dis 1988; 138: 1192–5
Sampol G, Munoz X, Sagales MT, et al. Long-term efficacy of dietary weight loss in sleep apnoea/hypopnoea syndrome. Eur Respir J 1998; 12: 1156–9
National Institute for Clinical Excellence. Guidance on the use of orlistat for the treatment of obesity in adults. Technology Appraisal Guidance no. 22, 2001 Mar [online]. Available from URL: http://www.nice.org.uk [Accessed 2003 Oct 10]
National Institute for Clinical Excellence. Guidance on the use of sibutramine for the treatment of obesity in adults. Technology Appraisal Guidance no. 31, 2001 Oct [online]. Available from URL: http://www.nice.org.uk [Accessed 2003 Oct 10]
Bray GA. Drug treatment of obesity. Rev Endocr Metab Disord 2001; 2: 403–18
Kapur VK, Koepsell TD, deMaine J, et al. Association of hypothyroidism and obstructive sleep apnea. Am J Respir Crit Care Med 1998; 158: 1379–83
Lin CC, Tsan KW, Chen PJ. The relationship between sleep apnea syndrome and hypothyroidism. Chest 1992; 102: 1663–7
Rajagopal KR, Abbrecht PH, Derderian SS, et al. Obstructive sleep apnea in hypothyroidism. Ann Intern Med 1984; 101: 491–4
Grunstein RR, Sullivan CE. Sleep apnea and hypothyroidism: mechanisms and management. Am J Med 1988; 85: 775–9
Skatrud J, Iber C, Ewart R, et al. Disordered breathing during sleep in hypothyroidism. Am Rev Respir Dis 1981; 124: 325–9
Mezon BJ, West P, MaClean JP, et al. Sleep apnea in acromegaly. Am J Med 1980; 69: 615–8
Hart TB, Radow SK, Blackard WG, et al. Sleep apnoea in active acromegaly. Arch Intern Med 1985; 145: 865–6
Perks WH, Horrocks PM, Cooper RA, et al. Sleep apnoea in acromegaly. BMJ 1980 Mar 29; 280: 894–7
Pack AI, Black JE, Schwartz JRL, et al. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnoea. Am J Respir Crit Care Med 2001; 164: 1675–81
Black JE, Douglas NJ, Earl CQ, et al. Efficacy and safety of modafinil as adjunctive therapy for excessive sleepiness associated with obstructive sleep apnea [abstract]. Sleep 2002; 25 Suppl. 1: A22
Kingshott RN, Vennelle M, Coleman EL, et al. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 2001; 163: 918–23
Pack AI. Should a pharmaceutical be approved for the broad indication of excessive sleepiness? Am J Respir Crit Care Med 2003; 167: 109–11
Acknowledgements
Dr Smith has received travel funds and honoraria for speaking at meetings sponsored by Cephalon UK.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Smith, I.E., Quinnell, T.G. Pharmacotherapies for Obstructive Sleep Apnoea. Drugs 64, 1385–1399 (2004). https://doi.org/10.2165/00003495-200464130-00001
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-200464130-00001