Impact of concomitant medications on obstructive sleep apnoea

Abstract

Obstructive sleep apnoea (OSA) is characterized by repeated episodes of apnoea and hypopnoea during sleep. Little is known about the potential impact of therapy drugs on the underlying respiratory disorder. Any influence should be taken into account and appropriate action taken, including drug withdrawal if necessary. Here, we review drugs in terms of their possible impact on OSA; drugs which (1) may worsen OSA; (2) are unlikely to have an impact on OSA; (3) those for which data are scarce or contradictory; and (4) drugs with a potentially improving effect. The level of evidence is ranked according to three grades: A – randomized controlled trials (RCTs) with high statistical power; B – RCTs with lower power, non‐randomized comparative studies and observational studies; C – retrospective studies and case reports. Our review enabled us to propose clinical recommendations. Briefly, agents worsening OSA or inducing weight gain, that must be avoided, are clearly identified. Drugs such as ‘Z drugs’ and sodium oxybate should be used with caution as the literature contains conflicting results. Finally, larger trials are needed to clarify the potential positive impact of certain drugs on OSA. In the meantime, some, such as diuretics or other antihypertensive medications, are helpful in reducing OSA‐associated cardiovascular morbidity.

Tables of Links

TARGETS
GPCRs 2	Enzymes 3	Other protein targets 5
Adrenoceptor	Acetylcholinesterase	TNF‐α
Angiotensin II receptor	Angiotensin‐converting enzyme
δ‐receptor (opioid receptor)	Carbonic anhydrase
Melatonin receptor	Transporters 4
μ‐receptor (opioid receptor)	H+/K+‐ATPases

LIGANDS
Acetazolamide	Flurazepam	Naltrexone	Salmeterol
Adalimumab	Furosemide	Nebivolol	Sodium oxybate
Atenolol	Gamma aminobutyric acid	Nicotine	Spironolactone
Baclofen	Infliximab	Ondansetron	Temazepam
Budesonide	Interleukin‐6	Paroxetine	Testosterone
Cilazapril	Isoflurane	Perindopril	Theophylline
Clonidine	Losartan	Phentermine	Topiramate
Desflurane	Medroxyprogesterone	Physostigmine	Triazolam
Donepezil	Metoprolol	Propofol	Valsartan
Enalapril	Mibefradil	Propranolol	Xylometazoline
Eszopiclone	Mirtazapine	Protriptyline	Zolpidem
Etanercept	Mometasone	Ramelteon	Zonisamide
Fentanyl	Morphine	Ramipril
Fluoxetine	Naloxone	Remifentanil

These Tables list key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2, 3, 4, 5.

Introduction

Obstructive sleep apnoea (OSA) is a common clinical condition characterized by repeated episodes of apnoea and hypopnoea during sleep 6. Pathophysiological mechanisms are manifold, including compromised pharyngeal anatomy (adipose tissue deposition, local inflammation, rostral fluid shift/oedema) 7, 8, 9, inadequacy of the upper airway muscles to stiffen/dilate the airway and maintain its patency in response to an increase in ventilatory drive 10, 11, and, finally, poor upper airway reflexes 12. The standard therapy of continuous positive airway pressure (CPAP) is efficient in improving OSA and in reducing its associated comorbidities, in compliant patients. Nevertheless, the impact of CPAP when assessed using cardiometabolic biomarkers remains unclear 13. However, patients often cannot tolerate CPAP, which can produce general discomfort or troublesome nasal symptoms (e.g. congestion, rhinorrhea), leading to poor adherence 14, 15. Thus, alternative options need to be developed and pharmacological therapies are an obvious approach. However, little is known about the possible influence of commonly used drugs on OSA. The aim of this review was to investigate this field, because any drug having a potential impact on OSA should be evaluated during the workup for OSA in any patient.

In this review we divide drugs into four categories, those which (1) may worsen OSA; (2) are unlikely to have an impact on OSA; (3) for which data are scarce or contradictory; and (4) drugs with a possible positive effect.

We searched the Medline database for all studies mentioning drugs [using International Nonproprietary Names (INN)] and looking at an effect on OSA. Nineteen Medical Subject Headings (MeSH) classes are referenced under ‘THERAPEUTIC USES’, covering the entire pharmacopoeia, such as ‘central nervous system (CNS) agents’ or ‘respiratory system agents’. Thus, we used the search equations: ‘each MeSH class’ AND ‘OSA’ to identify drug class of interest. Then, for each marketed drug, we used the search equations: ‘INN’ AND ‘apnoea/apnea’, ‘INN’ AND ‘OSA’ and ‘INN’ AND ‘sleep‐disordered breathing (SDB)’. Indeed, OSA is by far the most common form of SDB that regroups several chronic conditions in which partial or complete cessation of breathing occurs many times throughout the night, resulting in daytime sleepiness or fatigue that interferes with a person's ability to function and reduces quality of life. We repeated searches until no additional articles were found. No language or date filter was used. Thereby we consider this work as a systematic review. Inclusion criteria were: (i) clinical trial; (ii) evaluation of effect on variables measured by polysomnography (the reference examination for the OSA diagnosis) such as the apnoea‐hypopnoea index (AHI), oxygen desaturation index (ODI), respiratory disturbance index, minimum nocturnal oxygen saturation (SaO_2min) and time spent with an SaO₂ < 90%. The level of evidence was rated using three grades: A – randomized controlled trials (RCTs) (≥20 patients or 10 patients for a cross‐over design) and meta‐analyses of RCTs; B – RCTs (<20 patients), observational and non‐randomized comparative studies; and C – retrospective studies, case reports and comparative studies with biases. We discuss all grade A studies and all the relevant studies we found are included in the tables. Most of the studies we quote are referenced in the Pneumotox database, a website referencing literature of drug‐induced respiratory disease (available online at http://www.pneumotox.com/).

Drugs which may worsen OSA

Opioids 16, 17, 18, 19, 20, benzodiazepines 21, 22, 23, 24, 25, baclofen 26, 27, 28, testosterone 29, 30, 31, 32 and drugs inducing weight gain 33 are suspected to worsen sleep apnoea (Table 1).

Table 1.

Drugs that worsen sleep apnoea

Class	Considered mechanism	Molecules	Authors	Type of study	Outcomes	Level of evidence
Opioids and opiates	Mixed apnoea: obstructive (by increase in the upper airway collapse during sleep) and central (by depressant effect on respiratory drive)	Fentanyl	Ostermeier et al., 16	Series of cases	3 sudden respiratory arrests	C
		Morphine	Orlov et al., 17	Systematic review 5 studies of low‐quality evidence: 3 case reports and 2 retrospective chart reviews 121 patients	6 cardiorespiratory complications (3 deaths, 1 cardiorespiratory arrest, and 2 episodes of severe respiratory depression)	B
			Wang et al., 18	Small comparative study (before and after a single dose of 30 mg oral morphine) 10 mild‐to‐moderate OSA patients	Higher CO2 recruitment threshold and improvement in sleep time with SaO2 < 90%	B
		Methadone	Webster et al., 19	Observational study 140 chronic pain patients	Increased dosage of methadone associated with more severe sleep apnoea	B
		Remifentanil	Bernards et al., 20	RCT (remifentanil infusion vs saline infusion) 19 mild OSA	Number of central apnoeas increased Decrease in minimum SaO2	A
Benzodiazepines	Central apnoea: CNS depressants	Flurazepam	Cirignotta et al., 21	RCT crossover (20 mg zolpidem, 30 mg flurazepam and placebo for 1 night) 12 mild OSA patients	Increase in AHI but not significant Decrease in minimum SaO2	A
		Nitrazepam	Höijer et al., 22	RCT crossover (5 and 10 mg/night vs placebo for 3 nights) 11 OSA patients	No change in apnoea index or minimum SaO2	A
		Temazepam	Camacho and Morin, 1995 23	RCT (15–30 mg/day vs placebo for 8–10 weeks) 15 elderly patients with insomnia and mild OSA	No change in RDI	B
			Wang et al., 24	RCT crossover (10 mg vs placebo for 1 night) 20 OSA patients	No change in AHI and minimum SaO2	A
		Triazolam	Berry et al., 25	RCT crossover (0.25 mg vs placebo for 1 night) 12 severe OSA patients	Increase in AHI but not significant Decrease in minimum SaO2	A
Myorelaxants	Mixed apnoea	Baclofen	Finnimore et al., 26	RCT (25 mg/day of baclofen for 1 week) 10 mild OSA	No change in RDI	B
			Perogamvros et al., 27	Case report	Severe central sleep apnoea with an AHI of 81.6/h after introduction of baclofen, disappearance of the central apnoeas after withdrawal and reappearance after reintroduction	C
		Baclofen + diazepam	Ayas et al., 28	Observational study 197 persons with chronic spinal cord injury	Greatest risk of snoring occurred in patients treated with diazepam alone or baclofen + diazepam and with a BMI at or above the median	B
Male hormone	Obstructive apnoea: increase in upper airway collapsibility	Testosterone	Liu et al., 29	RCT (3 injections of im testosterone vs placebo) 17 men with no history of OSA	Increased AHI by >50% and prolonged duration of hypoxemia	A
			Schneider et al., 30	11 hypogonadal subjects both on and off testosterone‐replacement therapy	Increase in AHI	B
			Killick et al., 31	RCT (3 im injections of 1000 mg testosterone vs placebo, 18 weeks) 21 obese OSA men	Increase in sleep time with SaO2 < 90% at 6–7 weeks	A
		Flutamide	Stewart et al., 32	8 men with sleep apnoea, 1 week	No change in RDI or chemoresponsiveness to hypoxia and hypercapnia	B

AHI, apnoea hypopnoea index; BMI, body mass index; im, intramuscular; OSA, obstructive sleep apnoea; RCT, randomized controlled trial; RDI, respiratory disturbance index; SaO₂, oxygen saturation

Opioids and opiates

Opioids are known CNS respiratory depressants, but the mechanisms responsible for SDB are poorly understood. The opiate respiratory disturbances are mainly due to the activation of the μ‐ and δ‐subtypes of receptor and involve specific types of respiratory‐related neurons in the ventrolateral medulla (in particular the Pre‐Bötzinger Complex), regulating the respiratory rhythm. Synthetic opiates with affinity for either the μ‐ or the δ‐receptor subtype suppress all parameters of effective breathing. They depress rate and depth of respiration, induce chest and abdominal wall rigidity, reduce upper airway patency and blunt respiratory responsiveness to carbon dioxide and hypoxia 34. Sleep apnoea induced by opioids is characterized by a combination of obstructive apnoeas and central SDB. Some 75–85% of patients treated by opioids have at least mild sleep apnoea that is severe in 36–41% of cases 10, 11, depending on the dose 19. In an RCT that included 19 mild OSA patients, remifentanil for one night induced no change in AHI (the number of obstructive apnoeas decreased and the number of central apnoeas increased), a decrease in SaO_2min and an increase in the total arousal index 20. Opioids cause relaxation of the tongue and upper airway muscles, which may cause airway obstruction once the patient falls asleep 35, and the resulting weakness of upper airway muscles may exacerbate OSA. OSA patients receiving opioids such as morphine or fentanyl for chronic management of pain or other symptoms associated with chronic obstructive pulmonary disease or lung cancer may be at risk of adverse effects related to respiratory depression 36, 37. Long‐term opioid therapy seems to induce SDB by increasing the number of central apnoeas and decreasing the number of obstructive apnoeas 38.

Benzodiazepines

A Cochrane review has recently investigated the effects of hypnotic and sedative drugs (eszopiclone, zolpidem, flurazepam, temazepam, nitrazepam, triazolam, sodium oxybate and ramelteon) compared to placebo in OSA patients 12. That review revealed no worsening of OSA (a significant increase in AHI) with any of the studied drugs. However, flurazepam and triazolam significantly lowered nighttime SaO₂, whereas nitrazepam did not change AHI 22.

Myorelaxants

Baclofen is a centrally acting gamma aminobutyric acid B agonist prescribed as a muscle relaxant and antispasmodic agent. Despite its usage in the management of alcohol dependence, there is a growing caution concerning baclofen use. Baclofen provokes upper airway collapse during sleep worsening OSA and affecting central apnoeas or hypoventilation during sleep by depressing respiratory drive 26. Although the negative impact on sleep apnoea awaits further confirmation, it seems prudent to avoid baclofen in OSA patients.

Testosterone

The detrimental effect of testosterone on OSA is consistent with the higher prevalence of OSA in men than in women. In men with no history of sleep apnoea, testosterone increased AHI and prolonged hypoxemia time 29. Moreover, testosterone worsened SDB, increasing the time spent with an SaO₂ < 90% 31.

Drugs inducing weight gain

Obesity is the principal risk factor for OSA. About 70% of OSA patients are obese and 40% of the obese have sleep apnoea 39, 40. There is evidence that systemic inflammatory mediators associated with obesity and the localization of adipose tissue deposits may exacerbate pharyngeal mechanisms that mediate collapsibility and increase susceptibility to OSA 7, 8. Conversely, OSA may predispose the individual to weight gain 8, 41. Several medications (atypical antipsychotics in particular, antidepressants, anticonvulsants, antidiabetic drugs, antihistamines, β‐ and α‐adrenergic blockers) are associated with weight gain 33 that can induce or exacerbate OSA. Nevertheless, alternative drugs are available (Table 2). For example, weight increase was significantly greater in patients on long‐term paroxetine compared to those treated with fluoxetine or sertraline 42.

Table 2.

Drugs that produce weight gain and alternative agents (adapted from Kushner et al., 2014 33)

Category	Drugs that cause weight gain	Possible alternatives
Neuroleptics	Thioridazine, haloperidol, olanzapine, quetiapine, risperidone, clozapine	Ziprasidone, aripiprazole
Tricyclic antidepressants	Amitriptyline, nortriptyline, imipramine, doxepin	Protriptyline, bupropion, nefazodone
Monoamine oxidase inhibitors	Phenelzine
Selective serotonin reuptake inhibitors	Paroxetine	Fluoxetine, sertraline
Other antidepressants	Mirtazapine
Anticonvulsants	Valproate, carbamazepine, gabapentin	Topiramatea, lamotrigine, zonisamidea
Antidiabetic drugs	Insulin, sulfonylureas, thiazolidinediones	Acarbose, sitagliptin, saxagliptin, canagliflozin, dapagliflozin, pramlintide, exenatide, liraglutide, miglitol, metformin, orlistat
Antihistamines	Cyproheptadine	Inhalers, decongestants
β‐ and α‐adrenergic blockers	Propranolol, doxazosin	ACE inhibitorsb, calcium channel blockers
Steroid hormones	Contraceptives, glucocorticoids, progestational steroids	Barrier methods, nonsteroidal anti‐inflammatory agents

ACE, angiotensin‐converting enzyme

^aDrugs avoiding weight gain and improving OSA

^bDrugs avoiding weight gain but worsening OSA

Drugs with probably no impact on OSA

For some drugs there is no clear evidence of a positive or negative impact on OSA. This is often because there is only a small number of, or inconclusive, studies, despite mechanisms having been proposed (Table 3).

Table 3.

Drugs with no demonstrated impact on OSA

Class	Considered mechanism	Molecules	Authors	Type of study	Outcomes	Level of evidence
Antihypertensive drugs		Losartan	Kraiczi et al., 43	RCT (treatment in sequence of 6 weeks with two of the five agents (balanced incomplete block design)) 40 hypertensive OSA	No change in AHI	A
		Valsartan	Heitmann et al., 44	RCT (nebivolol 5 mg or valsartan 80 mg once daily) 31 hypertensive OSA	No change in AHI	A
		Atenolol Heitmann et al. Planès et al.	Kraiczi et al., 43	RCT 40 hypertensive OSA	No change in AHI	A
			Heitmann et al., 44	RCT 31 hypertensive OSA	No change in AHI	A
			Planès et al., 45	Comparative study: 2 treatment period of 21 days involving placebo followed by celiprolol (200 mg/day) 7 hypertensive patients OSA	No change in AHI	B
		Metoprolol	Mayer et al., 46	RCT (metoprolol 100 mg daily vs cilazapril 2.5 mg daily) 12 OSA	Reduced AHI in the 2 groups	B
		Clonidine	Issa, 1992 76	RCT (0.2 mg clonidine daily at bedtime for 10 days compared with 2 control and 2 placebo nights) 8 OSA men	No change in AHI	B
		Mibefradil	Heitmann et al., 47	RCT (mibefradil 50 mg or placebo orally for 8 days) 48 OSA	No change in AHI	A
Analeptic agent	Stimulates breathing by activating peripheral chemoreceptors	Almitrine	Mangin et al., 77	RCT (oral 200 mg dose) 9 OSA	No change in AHI	B
Nicotinic receptor agonists	Breathing stimulant, dilate the upper airway	Nicotine	Gothe et al., 48	8 OSA	Eliminate OSA during the first 2 h of sleep	C
			Davila et al., 49	RCT (placebo or active patch 11 mg over a 24‐h period) 20 nonsmoking subjects	No change in AHI	A
			Zevin et al., 50	RCT (2 doses of nicotine tooth patch 2 mg and 4 mg in a randomized order) 10 OSA	No change in AHI	B
Anaesthetic agents	Mixed apnoea: depression of the upper airway muscles, laryngospasm	Propofol, desflurane and remifentanil	Ahmad et al., 56	31 OSA patients and 9 non‐OSA patients	No difference in ODI, total hypoxemic episodes between OSA and non‐OSA groups	A
		Propofol vs isoflurane	Hendolin et al., 55	RCT (propofol‐nitrous oxide‐fentanyl or thiopentone‐isoflurane‐nitrous oxide‐fentanyl) 41 patients undergoing uvulopalatopharyngoplasty	Decrease in spontaneous breathing and O2 saturation in isoflurane group	A
		Propofol vs sevoflurane	Simons et al., 57	RCT (propofol vs sevoflurane) 12 healthy volunteers	Both anaesthetics increase upper airway collapsibility in a dose‐dependent manner with no difference at equivalent anaesthetic concentrations	B
		Fentanyl + propofol + cisatracurium and maintained by desflurane or isoflurane + remifentanil	Eikermann et al., 58	Observational prospective study 100 morbidly obese undergoing bariatric surgery: 36 OSA patients and 64 non‐OSA patients	Weight loss surgery represents a risk to desaturate during anaesthesia induction. A history of OSA does not increase this risk.	B
		Propofol, midazolam, fentanyl, ketamine and propofol	Iwama and Suzuki, 59	Case report	No adverse events	C
			Miller and Gerhardt, 60	Case report	No period of apnoea noted	C
		Fentanyl and midazolam	Cillo and Finn, 61	Retrospective review 15 patients undergoing uvuloplasty for snoring or mild OSA	No airway obstruction or respiratory distress (no change in SaO2)	B
		Ketamine	Brown, 62	Case report	Decrease in wheeze and airway pressure during mechanical ventilation	C
Melatonin‐related drugs		Ramelteon	Kryger et al., 63	RCT crossover (ramelteon 16 mg vs placebo for one night each with 5–12 days’ washout) 26 mild to moderate OSA patients	No significant change in AHI or in mean SaO2	A
			Gooneratne et al., 64	RCT (ramelteon 8 mg (n = 8) or placebo (n = 13) for 30 days) 21 OSA patients	No change in AHI	A
Antiemetic		Ondansetron	Stradling et al., 75	RCT (ondansetron 16 mg vs placebo) 10 OSA patients	No change in AHI	B

AHI, apnoea hypopnoea index; ODI, oxygen desaturation index; OSA, obstructive sleep apnoea; RCT, randomized controlled trial; RDI, respiratory disturbance index; SaO₂, oxygen saturation

Antihypertensive drugs

Angiotensin II receptor blockers

Angiotensin II receptor blockers seem to have a limited impact on OSA. In hypertensive OSA patients the use of valsartan or losartan had no effect on AHI 43, 44.

Beta‐blockers

Beta‐blockers seem to have variable effects on OSA 43, 44, 45, 46, possibly according to the selectivity of their action on adrenoceptor subtypes. Treatment with atenolol or nebivolol had no effect on AHI in hypertensive OSA patients 43, 44. One study (grade B) reported a reduction in AHI with metoprolol 46. We found no study that investigated the effects of propranolol on OSA, although the associated weight gain may exacerbate OSA (see section ‘Drugs inducing weight gain’ above) 33. Beta blocker safety is reassuring in light of their beneficial effect in coronary artery disease patients.

Calcium channel antagonists

The single RCT investigating the use of mibefradil in OSA reported no change in AHI 47.

Nicotine

Nicotine is a breathing stimulant that increases muscle activity and dilates the upper airway. The use of nicotine gum at bedtime was reported to prevent OSA in the first 2 h of sleep 48, although two subsequent RCTs concluded that nicotine had no effect on AHI 49, 50.

Anaesthetic agents

OSA has become a major concern for anaesthetists 51, 52. A systematic review highlighted adverse effects of the currently available anaesthetics and in patients with known OSA undergoing elective surgery 53, 54.

Propofol administered along with isoflurane decreased ODI in the immediate postoperative period 55. However, an RCT with propofol, desflurane, and remifentanil reported no change in ODI in OSA patients 56. There are few studies assessing the effect of anaesthesia on the patency of the upper airway in patients with OSA and they rarely compare agents; however, the impact is probably marginal 55, 56, 57, 58, 59, 60, 61, 62.

Melatonin‐related drugs

Two RCTs concluded that ramelteon, a melatonin receptor agonist used for the treatment of insomnia had no effect on the number of central, obstructive or mixed apnoea episodes in OSA patients 63, 64.

Drugs that induce weight loss

The effects of drugs that induce weight loss on OSA are summarized in Table 4. In particular, carbonic anhydrase inhibitors improve OSA by promoting ventilation via chemosensory mechanisms 65 and have an indirect effect on obese patients through weight loss. Many molecules for weight reduction are in development. Nevertheless, it should be remembered that pharmacological approaches to weight loss have a limited effect (10% weight loss is rarely achieved), a rebound effect when stopped (with subsequent weight gain) and serious safety concerns. Indeed, weight regulation is highly complex and involves numerous metabolic mechanisms. A pharmacological strategy alone probably has hardly any impact.

Table 4.

Drugs inducing weight loss

Class	Considered mechanism	Molecules	Authors	Type of study	Outcomes	Level of evidence
Antiepileptic drugs	Weight loss	Zonisamide	Eskandari et al., 68	RCT (zonisamide 300 mg/day (n = 16) or placebo (n = 16) or CPAP (n = 15) for 4 weeks) 47 overweight/obese patients with OSA	Decrease in AHI and oxygen saturation with zonisamide but CPAP treatment is superior	A
		Topiramate + phentermine	Winslow et al., 66	RCT (topiramate 92 mg/day and phentermine 15 mg/day (n = 22) or placebo (n = 23) for 28 weeks) 45 obese patients with moderate to severe OSA	Decrease weight and AHI with a significant correlation between these 2 changes	A
		Topiramate	Weber, 67	Case report (topiramate 100 mg/day) Moderate OSA	Decrease AHI of 70% without changes in body weight	C
Thyroid hormones	Weight loss	Thyroxine	Rajagopal et al., 72	Thyroxine replacement therapy 3–12 months 9 hypothyroid patients with OSA	Reduction in AHI No change in body weight	B
			Hira and Sibal, 73	Thyroxine, 3 months 20 hypothyroid patients (9 with OSA)	Resolution of OSA in 6 patients, partial improvement in 2 and no change in 1 patient	B
			Grunstein and Sullivan, 74	Thyroxine until euthyroid state achievement 8 hypothyroid patients with OSA	No change in AHI	B

AHI, apnoea hypopnoea index; CPAP, continuous positive airway pressure; OSA, obstructive sleep apnoea; RCT, randomized controlled trial

Antiepileptic drugs

In obese patients with moderate to severe OSA, a combination of topiramate and phentermine decreased AHI correlated to weight loss 66. Multifactorial causes, including weight loss, but also changes in serum bicarbonate concentration and pH, may account for the beneficial effects of topiramate on OSA 67. In overweight/obese OSA patients zonisamide decreased AHI and ODI, but was less effective than CPAP treatment 68.

Thyroid hormone

The weight loss induced by thyroid hormone replacement therapy 69 and the link between hypothyroidism and OSA 70, 71 would suggest that thyroid hormone can slightly improve OSA 72, 73, 74.

Other drugs

Ondansetron 75, clonidine 76 and almitrine 77 appear to induce no change in AHI, but larger studies are needed.

Drugs with an unresolved impact on OSA

Table 5 lists drugs whose impact on OSA needs to be clarified.

Table 5.

Drugs for which the impact on OSA needs to be clarified

Class	Considered mechanism	Molecules	Authors	Type of study	Outcomes	Level of evidence
‘Z’ drugs	CNS depressant	Eszopiclone	Eckert et al., 78	RCT (3 mg eszopiclone vs placebo for 1 night) 17 OSA	Decrease in AHI and increase in respiratory arousal threshold	B
			Rosenberg et al., 79	RCT (3 mg/night vs placebo during 2 nights) 22 OSA patients CPAP‐treated	No change in AHI or in arousal index	B
		Zolpidem	Cirignotta et al., 21	RCT crossover (single dose of 20 mg vs placebo) 12 mild OSA patients	No change in AHI Decrease in minimum SaO2	A
			Berry and Patel, 80	RCT crossover (10 mg vs placebo for 1 night) 16 severe OSA patients on CPAP ≥ 6 months	No change in AHI or minimum SaO2 A small decrease in the arousal index	A
Narcolepsy treatment	CNS depressant	Sodium oxybate (SXB)	George et al., 82	RCT crossover (9 g SXB or 9 g SXB/modafinil 200 mg or zolpidem 10 mg or placebo, for 4 nights) 42 OSA patients	No change in AHI or mean SaO2 Increase in central apnoeas	A
			George et al., 83	RCT crossover (4.5 g SXB or placebo, for 2 weeks) 48 OSA patients	Decrease in AHI No difference in mean SaO2, minimum SaO2 or central apnoea index	A
Opiate antagonists	Antagonize depressant effects of opioids	Naltrexone	Ferber et al., 84	RCT crossover (single dose of naltrexone 50 mg or placebo) 12 OSA patients	Decrease in AHI, number of hypoxic events, number of hypercapnic events	A
		Naloxone	Guilleminault and Hayes, 87	28 overweight men with OSA	No effect on the AHI, the duration of apnoeas or hypopnoeas, or associated oxygen desaturation	B
			Atkinson et al., 85	RCT (naloxone infusion vs saline control infusion on 2 separate nights) 10 obese OSA patients	Decrease in ODI	A
			Greenberg et al., 86	Naloxone 10 mg iv during a morning nap study 12 moderate to severe OSA patients	No change in AHI, but decrease in total sleep time, increase in awake periods and decreased in Stage I non‐REM sleep	B
Acromegaly treatment		Somatostatin analogue	Blanco Pérez et al., 88	17 patients with acromegaly (5 patients treated with somatostatin analogue)	No change in AHI	B
		Octreotide	Herrmann et al., 89	14 patients with acromegaly 6 months of treatment with octreotide acetate (Sandostatin LAR 10–30 mg every 4 weeks im).	Decrease in RDI	B
		Bromocriptine	Guilleminault et al., 87	28 overweight men with OSA	No change in AHI and ODI	B
Angiotensin‐converting enzyme (ACE) inhibitors	Obstructive apnoea: upper‐airway inflammation	Cilazapril	Grote et al., 91	RCT (cilazapril (2.5 mg/d) or placebo for 8 days) 54 OSA patients	Decrease in RDI and AHI during non‐REM sleep No change during REM sleep	A
		Enalapril	Cicolin et al., 92	Case report	Increase in AHI	C
Glutamate antagonist	Respiratory depressant	Sabeluzole	Hedner et al., 93	RCT crossover 13 OSA patients	Decrease in ODI, increased minimum SaO2 in a dose‐dependent manner, but did not improve OSA symptoms	A
Antidepressant drugs	Central respiratory stimulant and low increase in muscle tone	Paroxetine	Berry et al., 96	RCT crossover (paroxetine 40 mg or placebo four hours before bedtime) 8 OSA men	No change in AHI	B
			Kraiczi et al., 95	RCT crossover (paroxetine 20 mg daily or placebo, 2 treatment period of 6 weeks) 20 OSA men	Decrease in AHI only during non‐REM sleep vs no significant effect on hypopnoea indices	A
		Fluoxetine	Hanzel et al., 97	RCT (fluoxetine vs protriptyline) 12 OSA patients	Decreased number of apnoeas or hypopnoeas in non‐REM sleep	A
		Protriptyline	Brownell et al., 98	RCT crossover (2 weeks) 5 men	No change in apnoea duration and frequency Decrease in REM apnoea duration and similar improvement in oxygenation after 6 months of treatment	B
			Hanzel et al., 97	RCT (fluoxetine vs protriptyline) 12 OSA patients	Decreased the number of apnoeas or hypopnoeas in non‐REM sleep	A
			Whyte et al., 99	RCT (Protriptyline 20 mg daily vs placebo for 14 days) 10 OSA patients	No change in AHI	A
			Smith et al., 100	12 OSA patients (oral dose of 10 mg of protriptyline, increased by 5 mg every 2–3 weeks if no improvement in hypersomnolence, when symptomatic improvements are observed the dose is maintained for 1 month)	No change in the duration or frequency of SDB during non‐REM sleep but decrease in the amount of apnoea during SDB events	B
		Mirtazapine	Marshall et al., 101	2 RCTs: ‐ 20 patients: mirtazapine vs placebo 30 min prior to bedtime for 2 weeks at each dose (7.5, 15, 30, and/or 45 mg) ‐ 65 OSA patients: mirtazapine 15 mg or mirtazapine 15 mg + compound CD0012 or placebo for 4 weeks	No sleep apnoea improvement Weight gain greater with mirtazapine	A
			Carley et al., 102	RCT (3 consecutive 7‐day treatment periods, order of treatments randomized; (1) placebo, (2) 4.5 mg per day mirtazapine, and (3) 15 mg per day of mirtazapine orally 30 min before bedtime) 12 OSA patients	Decrease in AHI even if weight gain	B
			Castillo et al., 103	Case report 3 months, 15 mg of mirtazapine at bedtime	Decrease in AHI	C
		Trazodone	Eckert et al., 104	RCT (100 mg/night vs no treatment during 2 nights) 7 OSA patients with a low respiratory arousal threshold on CPAP	Increase in arousal threshold	B
TNF‐α antagonists	Anti‐inflammatory	Infliximab	Zamarron et al., 110	One case in a patient with rheumatoid arthritis and OSA One infusion of 3 mg kg-1	Increase in AHI Improvement of ESS	C
		Etanercept	Vgontzas et al., 106	RCT (3 weeks of placebo followed by 3 weeks of 25 mg twice a week of etanercept) 8 obese men with OSA	Decrease in AHI and sleepiness	B
			Taylor‐Gjevre et al., 111	Observational prospective study 1–4 months 10 RA patients with OSA	No change in AHI, ESS and arousals	B
		Adalimumab	Maari et al., 109	RCT 8 weeks (80 mg the first week followed by 40 mg for 7 weeks (n = 10) or placebo (n = 10)) 20 OSA patients with psoriasis	No change in AHI and ESS	A
Proton pump inhibitors	Acid exposure could cause oedema and inflammation in the upper airway	Esomeprazole	Friedman et al., 112	Prospective clinical trial (40 mg once daily for 2–6 months) 29 OSA patients	Decrease in AHI and ESS Increase in minimum SaO2	B
		Lansoprazole	Ermis et al., 113	Prospective clinical trial (30 mg twice daily for 3 months) 22 OSA patients	Decrease in AHI	B
			Eryılmaz et al., 114	Prospective clinical trial (30 mg twice daily for 3 months) 10 patients with mild or moderate OSA	No change in AHI	B
		Omeprazole	Senior et al., 115	Prospective clinical trial (once daily for 4 weeks) 10 OSA patients	Decrease in AHI and RDI	B
			Wasilewska et al., 118	Prospective clinical trial (1 mg/kg once daily for 4–8 weeks) 21 OSA children	Decrease in AHI	B
		Pantoprazole	Steward, 116	Prospective clinical trial (40 mg once daily for 3 months) 27 mild to moderate OSA patients	No change in AHI	B
		Rabeprazole	Orr et al., 117	Prospective clinical trial (20 mg twice a day for 2 months) 25 OSA patients with a gastroesophageal reflux disease	No change in AHI Improvement of ESS	B

AHI, apnoea hypopnoea index; CNS, central nervous system; CPAP, continuous positive airway pressure; ESS, Epworth sleepiness score; im, intramuscular; ODI, oxygen desaturation index; OSA, obstructive sleep apnoea; RCT, randomized controlled trial; RDI, respiratory disturbance index; SaO₂, oxygen saturation; SDB, sleep‐disordered breathing

‘Z’ drugs (eszopiclone and zolpidem)

‘Z’ drugs are a group of non‐benzodiazepine drugs with effects similar to benzodiazepines (gamma aminobutyric acid agonist), and most of whose names start with the letter ‘Z’. Surprisingly, some CNS depressants (sedatives and tranquilizers) such as ‘Z’ drugs might improve SDB by raising the low respiratory arousal threshold observed in OSA patients. While zolpidem did not change AHI, it significantly lowered SaO_2min 21, 78, 79, 80.

Sodium oxybate

Warnings have been issued about the possible development of SDB during long‐term treatment with sodium oxybate 81. Although an RCT that included OSA patients treated with sodium oxybate showed no change in AHI, an increase in central apnoeas and oxygen desaturations were observed 82. However, the same group reported that short‐term use (2 weeks) in OSA patients significantly decreased AHI without modifying mean SaO₂, SaO_2min or arousal index 83.

Opiate antagonists

As described above, opioids are respiratory depressants that can induce OSA, thus opiate antagonists should have the opposite effect. One crossover RCT in 12 OSA patients found a decrease in AHI following a single dose of naltrexone 84. Furthermore, another crossover RCT in OSA patients reported a decrease in ODI with naloxone 85. However, two other studies (grade B) reported no change in AHI 86, 87 after naloxone treatment of OSA patients.

Drugs used to treat acromegaly

Some studies report a high prevalence of OSA in patients with acromegaly. In theory, acromegaly treatments such as growth hormone could improve OSA by lowering the body mass index. However, these treatments seem to have no impact on OSA. Larger studies are needed as no grade A study exists 87, 88, 89.

Angiotensin‐converting enzyme inhibitors (ACEI)

ACEI may exacerbate OSA, particularly in patients who develop cough and/or symptoms of rhinopharyngeal inflammation or upper airway collapse 90. While cilazapril treatment did not modify AHI 91, a significant decrease in AHI was observed after withdrawal of ACEI (enalapril, perindopril or ramipril) in nine OSA patients presenting with coughs 92. These results suggest that ACEI can contribute to OSA, particularly in patients with adverse effects of the drugs such as cough and/or upper airway disorders. A therapeutic switch should be considered for such patients.

Sabeluzole

Hypoxaemia stimulates glutamate release in the CNS and is a characteristic of SDB. In turn, glutamate can elicit apnoea via its action on N‐methyl‐d‐aspartate (NMDA) receptors. Sabeluzole, a glutamate antagonist, decreased the ODI, and increased SaO_2min in a dose‐dependent manner 93. However, in a later study by the same group, no change in AHI or oxygen saturation was found after the administration of an NMDA receptor antagonist 94.

Antidepressant drugs

Paroxetine led to a decrease in AHI during NREM sleep, but not during REM sleep 95 and not change AHI in a grade B study 96. Fluoxetine and protriptyline seem to decrease AHI, but it is still controversial 97, 98, 99, 100.

In contrast, mirtazapine did not improve sleep apnoea 101. However, as mirtazapine causes weight gain, it can worsen OSA. Gain in weight had been reported with mirtazapine by Carley et al. 102, but they found a decrease in AHI as reported in a case report 103. Trazodone in a small RCT increased arousals 104.

TNF‐α antagonists

Inflammation is a mechanism shared by sleep apnoea, insulin resistance and visceral obesity, promoting atherosclerosis, cardiovascular diseases and premature death 105. Pro‐inflammatory cytokines, tumour necrosis factor‐α (TNF‐α) and interleukin‐6 are elevated in OSA and have been proposed as mediators of excessive daytime sleepiness and fatigue 106, 107. Numerous studies investigating the effect of anti‐inflammatory drugs on OSA have been reported, but the results are sometimes contradictory and the situation needs to be clarified. TNF‐α antagonists are prescribed for rheumatoid arthritis, inflammatory bowel diseases and psoriasis; and OSA is frequently found in patients with these inflammatory diseases 108, 109.

The only grade A RCT included OSA patients with psoriasis who were treated with adalimumab, but they showed no improvement in OSA 109. The effect of etanercept and infliximab are controversial 106, 110, 111; however, according to the available data 106, 109, etanercept and adalimumab should be preferred to infliximab for OSA patients.

Proton pump inhibitors

Only B grade studies have investigated the effect of proton pump inhibitors on OSA 112, 113, 114, 115, 116, 117, 118.

Drugs with a possible positive impact on OSA

Anti‐inflammatory drugs

Contrary to TNF‐α antagonists, overall, the data are in favour of the use of antileukotrienes and nasal corticosteroids in OSA patients (Table 6) unlike prednisone 119.

Table 6.

Drugs with a possible positive impact on OSA

Class	Considered mechanism	Molecules	Authors	Type of study	Outcomes	Level of evidence
Anti‐inflammatory drugs	Anti‐inflammatory	Montelukast	Goldbart et al., 120	RCT (montelukast or placebo for 12 weeks) 46 children	Decrease in AHI	A
		Fluticasone	Kiely et al., 122	RCT crossover (fluticasone vs placebo) 24 consecutive snorers with associated rhinitis	Decrease in AHI	A
			Brouillette et al., 121	RCT (fluticasone vs placebo) 25 children	Decrease in AHI	A
		Budesonide	Kheirandish‐Gozal and Gozal, 2008 123	RCT crossover (budesonide vs placebo, 6 weeks for each period) 62 children mild OSA	Decrease in AHI	A
			Mansfield et al., 124	Open trial 14 children	Decrease in AHI	C
		Mometasone	Acar et al., 125	RCT (mometasone + antihistamine vs mometasone + placebo vs placebo + antihistamine vs both placebo) 80 OSA patients with allergic rhinitis	Positive influence for all the study parameters (AHI, ESS, SaO2) Antihistamine did not alter the results	A
			Chan et al., 126	RCT (mometasone vs placebo) 50 children mild OSA	Decrease in AHI and ODI	A
		Prednisone	Berger et al., 119	Observational prospective study 17 patients with systemic diseases requiring steroids treatment for at least 3 months	Increase in AHI	B
Nasal decongestant	Upper airway decongestion		Braver and Block, 1994 128	RCT (nasal decongestant, best sleeping position or a combination of the two) 20 asymptomatic male snorers	No change in AHI with the decongestant alone	B
			Clarenbach et al., 127	RCT crossover (nasal xylometazoline or placebo for 1 week each) 12 OSA patients with chronic nasal congestion	Decrease in AHI	A
Topical soft tissue lubricant	Reduced surface tension in upper airways		Jokic et al., 129	RCT (lubricant treatment vs placebo) 10 OSA men	Decrease in AHI	B
			Morrell et al., 130	RCT crossover (surfactant or saline instillation) 7 + 7 OSA men	Decrease in AHI	A
Diuretics	Reduce the excess fluid collects in the lower extremities and redistributed rostrally to the neck on lying down overnight, which may increase upper airway collapsibility	Furosemide + spironolactone	Bucca et al., 131	Furosemide 20 mg, iv + spironolactone* 100 mg bid, iv, for 3 days 15 obese patients with severe OSA, hypertension and diastolic heart failure	Decrease in AHI	B
		Spironolactone	Gaddam et al., 132	Open label study (25 mg/day for 4 weeks and 50 mg/day for 4 more weeks) 12 patients with moderate–severe OSA and resistant hypertension	Decrease in AHI by almost 50%	B
		Acetazolamide	Edwards et al., 133	500 mg bid during for 7 days 13 OSA patients CPAP‐treated	Decrease non‐REM AHI	B
			Whyte et al., 1988 99	RCT (1000 mg/day or placebo for 14 days) 10 OSA patients	Decrease in AHI and ODI tended to decrease	B
			Tojima et al., 134	250 mg/day for 7–8 days 9 OSA patients	In 8 out of 9 patients apnoea index and total duration of apnoea decreased	C
			Edwards et al., 135	500 mg twice daily for 7 days 12 OSA patients CPAP‐treated	Acetazolamide increased resting ventilation and attenuated the hyperventilation following arousal	B
Beta‐2 agonists and other bronchodilators	Bronchodilators	Theophylline	Mulloy and McNicholas, 1992 136	RCT crossover (800 mg theophylline daily for 4 weeks) 12 OSA patients	Decrease in AHI	A
			Javaheri et al., 137	RCT crossover (theophylline or placebo orally twice daily for five days) 15 men with compensated heart failure with OSA	Decrease in AHI, central apnoea, and the duration of arterial oxyhaemoglobin desaturation	A
			Saletu et al., 139	CPAP with long‐acting vs theophylline (400 mg/day) 13 OSA men	Decrease in AHI and ODI	B
			Hein et al., 138	RCT crossover (theophylline vs placebo) 14 patients with mild OSA	Decrease in AHI	A
			Hu et al., 140	36 patients with chronic congestive heart failure who had mainly periodic breathing or Cheyne–Stokes respiration	Decrease in AHI	B
			Orth et al., 141	RCT 16 OSA patients CPAP‐treated	No change in AHI	B
		Aminophylline	Espinoza et al., 142	RCT crossover (aminophylline vs placebo for a single night) 10 OSA men	No change in AHI	A
		Salmeterol	Rasche et al., 143	RCT crossover (salmeterol vs placebo) 20 OSA patients	No change in AHI	A
Acetylcholinesterase inhibitors		Physostigmine	Hedner et al., 144	RCT crossover (physostigmine vs placebo infusion) 10 OSA men	Decrease in AHI and increase in SaO2	A
		Donepezil	Moraes et al., 145	RCT (donepezil vs placebo for 3 months) 23 OSA patients with mild‐to‐moderate Alzheimer disease	Decrease in AHI and increase in SaO2	A
			Sukys‐Claudino et al., 146 146	RCT (donepezil vs placebo for 4 weeks) 21 OSA men	Decrease in AHI	A
			Li et al., 147	RCT (donepezil vs placebo, single dose) 41 OSA	No difference in AHI	A
Female hormones		Estradiol	Manber et al., 149	RCT crossover (transdermal estradiol + oral micronized progesterone vs estradiol + placebo of progesterone) 6 postmenopausal women, diagnosed with mild–moderate SDB	Decrease in AHI with estradiol monotherapy	B
		Medroxyprogesterone	Polo‐Kantola et al., 148	RCT crossover (estrogen vs placebo, 3 months each) 62 healthy women	Decrease in the occurrence and frequency of sleep apnoea	A
			Cook et al., 153	RCT crossover (medroxyprogesterone vs placebo for 1 week) 10 OSA men	No change in sleep‐disordered breathing	A
			Block et al., 152	RCT (medroxyprogesterone vs placebo) 21 postmenopausal women	Maximum duration of apnoea was less the second night	A
			Strohl et al., 154	9 OSA adult ( medroxyprogesterone acetate, 60 to 120 mg/day)	Decrease in the number of obstructive apnoeas in 4 patients and cessation of therapy led to an overall increase in obstructive apnoeas in these subjects.	C
Anti‐Parkinson's medications		Dopaminergic agonists	Kaynak et al., 158	15 untreated patients with PD Dopaminergic drugs for 8 months	Decrease in AHI	B
		Benserazide/levodopa and cabergoline	Yoshida et al., 159	Case report	Decrease in AHI	C

AHI, apnoea hypopnoea index; ESS, Epworth sleepiness score; im, intramuscular; ODI, oxygen desaturation index; OSA, obstructive sleep apnoea; RCT, randomized controlled trial; RDI, respiratory disturbance index; SaO₂, oxygen saturation

Antileukotrienes

High levels of leukotrienes are found in the respiratory systems of children with OSA. An RCT found that montelukast, a leukotriene receptor antagonist, improved respiratory disturbance and decreased AHI in children 120.

Nasal corticosteroids

Increased resistance to nasal airflow can contribute to the obstruction of upper airways during sleep. Nasal corticosteroids may have a beneficial effect, particularly in patients with snoring or rhinitis and diagnosed or suspected OSA. Fluticasone nasal spray improves OSA in children 121 and has been shown to reduce the AHI in adults that is correlated with an improvement in nasal airflow resistance 122. In the same way, intranasal budesonide reduced the severity of OSA (improving SaO_2min and AHI) in children 123, 124. Finally, treatment with mometasone 125, 126 or the intranasal decongestant vasoconstrictor xylometazoline reduced AHI 127, whereas another nasal decongestant did not 129.

Topical soft tissue lubricant

These molecules seem to decrease AHI 129, 130.

Diuretics

Upper airway collapse caused by pharyngeal oedema can contribute to SDB, particularly in obese and hypertensive OSA patients. Indeed, during the day, due to gravity excess fluid collects in the lower extremities that is redistributed rostrally to the neck on lying down at night, and may increase upper airway collapsibility 9. To date, no grade A study has been carried out, but furosemide, spironolactone and acetazolamide seem to have a positive effect on OSA 99, 131, 132, 133, 134, 135. Acetazolamide resulted in a significantly reduced loop gain associated with a 51% improvement in AHI 133 and reduced OSA severity 99, 134, probably by reducing the sensitivity of the ventilatory control system. However, it does not reduce upper airway collapsibility or raise the arousal threshold. Nevertheless, acetazolamide increased resting ventilation and attenuated hyperventilation following arousal by ~2.5‐fold in OSA patients 135. This suggests an additional mechanism through which this drug contributes to improving OSA.

Beta‐2 agonists

Studies investigating bronchodilators used in asthma such as theophylline and salmeterol have given inconsistent results in OSA patients. Almost all studies with theophylline reported a decrease in AHI 136, 137, 138, 139, 140, 141, whereas no change was observed with aminophylline 142 or salmeterol 143.

Acetylcholinesterase inhibitors

While acetylcholinesterase inhibitors enhance cholinergic transmission, the mechanism affecting ventilation in OSA is unknown. The cholinergic system plays a role in the regulation of breathing during sleep and in reducing the collapsibility of upper airways. However, the improvement in oxygen saturation parameters is partly due to increased chemosensitivity, leading to respiratory instability and possibly to increased AHI in individuals with high loop gain. Physostigmine was found to reduce AHI (particularly during REM sleep) and increase SaO₂ 144. Donepezil decreased AHI 145, 146, but a single dose did not 147.

Female hormones

Oestrogen replacement therapy had no effect on partial airway obstruction, although it decreased the occurrence and frequency of sleep apnoea in women 148, 149. Women on hormone replacement therapy had a lower occurrence of SDB than untreated ones 150. The lower prevalence of OSA in women than in men and the increase in incidence during the menopausal period are in line with this beneficial effect 151. Medroxyprogesterone led to a small improvement in AHI in postmenopausal women with mild SDB 152. However, a later study found that while it increases ventilatory responses, it induces no change in AHI 153 contrary to cases reported by Strohl et al. 154.

Anti‐Parkinson's disease medications

The prevalence of OSA among patients with Parkinson's disease is still controversial. A meta‐analysis on 322 parkinsonian patients concluded that these patients have a lower risk of OSA compared to the general population 155. In contrast, recent studies showed increased prevalence of OSA in Parkinson's disease patients. Studies on drug‐naïve parkinsonian patients have shown that around 45% of patients had abnormal AHI and that OSA was frequent 156, 157. It seems that extrapyramidal involvement of the striated upper airway musculature may limit airflow and cause respiratory deficiency. However, anti‐Parkinson's drugs seem to decrease AHI 158, 159.

Treatment with medical gases

Carbon dioxide (CO₂) inhalation stabilizes arterial CO₂ levels and eliminates hypocapnia‐induced hypopnoea and periodic breathing 160. CO₂ stimulated upper airway inspiratory muscle tonic activity relative to chest wall inspiratory muscle activity and reduced apnoea time 161. A reduction in AHI was reported in OSA men, without change in the arousal index 162. Two case studies showed beneficial effects of CO₂ on OSA 163, 164. Supplemental oxygen (transtracheal or inhaled) reduced AHI, raised SaO_2min and improved subjective symptoms of sleepiness 38, 165, 166. However, while oxygen reduced central and mixed apnoeas, obstructive apnoea increased 167. Finally, oxygen therapy increased SaO_2min and reduced sleepiness in OSA patients, although their respiratory disturbance index was unchanged 168.

Conclusion

We found many studies evaluating the effects of pharmacological agents on OSA. As shown by Kohler et al. 169, there are some limitations to some of these studies. Those graded B or C (reported only in tables) have a lack of statistical power, including too few patients, with heterogeneity of the studied population. There is a lack of consensus on the best variable (AHI, ODI, SAO₂, sleepiness or other) for the classification of OSA severity, which renders it difficult to draw clear conclusions. This review clearly identified drugs exacerbating OSA that should be avoided (i.e. opiates, benzodiazepines, baclofen or drugs associated with weight gain), based on robust RCTs (grade A studies). Many other drugs for which different studies have given contradictory results (such as ‘Z drugs’ and sodium oxybate) need to be used with caution. Finally, larger trials are needed to clarify the potential of drugs with a possible positive impact on OSA: anti‐inflammatory drugs, diuretics or beta‐2 agonists. In the meantime, some, such as antihypertensive medications, are clearly useful for reducing the cardiovascular risk posed by OSA. Finally, further pharmacological analysis comparing drugs of the same class and indicating similarity and differences of their effects on OSA should be useful.

Competing Interests

There are no competing interests to declare.

We thank Dr Alison Foote (Grenoble Alps University Hospital) for critically reading and editing the manuscript.

Jullian‐Desayes, I. , Revol, B. , Chareyre, E. , Camus, P. , Villier, C. , Borel, J.‐C. , Pepin, J.‐L. , and Joyeux‐Faure, M. (2017) Impact of concomitant medications on obstructive sleep apnoea. Br J Clin Pharmacol, 83: 688–708. doi: 10.1111/bcp.13153.