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Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine logoLink to Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine
. 2022 Feb 1;18(2):647–652. doi: 10.5664/jcsm.9730

Opioids and obstructive sleep apnea

Carla Freire 1,2, Luiz U Sennes 2, Vsevolod Y Polotsky 1,✉
PMCID: PMC8805010  PMID: 34672945

Abstract

Opioids are widely prescribed for pain management, and it is estimated that 40% of adults in the United States use prescription opioids every year. Opioid misuse leads to high mortality, with respiratory depression as the main cause of death. Animal and human studies indicate that opioid use may lead to sleep-disordered breathing. Opioids affect control of breathing and impair upper airway function, causing central apneas, upper airway obstruction, and hypoxemia during sleep. The presence of obstructive sleep apnea (OSA) increases the risk of opioid-induced respiratory depression. However, even if the relationship between opioids and central sleep apnea is firmly established, the question of whether opioids can aggravate OSA remains unanswered. While several reports have shown a high prevalence of OSA and nocturnal hypoxemia in patients receiving a high dose of opioids, other studies did not find a correlation between opioid use and obstructive events. These differences can be attributed to considerable interindividual variability, divergent effects of opioids on different phenotypic traits of OSA, and wide-ranging methodology. This review will discuss mechanistic insights into the effects of opioids on the upper airway and hypoglossal motor activity and the association of opioid use and obstructive sleep apnea.

Citation:

Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647–652.

Keywords: obstructive sleep apnea, opioids, hypoglossal nerve, respiratory physiology

INTRODUCTION

Opioids are frequently used to treat chronic and acute pain with a considerable increase in noncancer pain prescriptions in the last decades. Despite the efforts to reduce opioid prescriptions and minimize the effects of the opioid epidemic, the amount of prescribed opioids increased 3-fold since 1999, and 91.8 million Americans used prescription opioids in 2015.1,2 Mortality associated with opioids increased further during the coronavirus disease 2019 (COVID-19) pandemic.3 Respiratory depression is the main adverse effect of opioids, and comorbidities such as obesity and obstructive sleep apnea (OSA) increase the risk of opioid-induced respiratory depression (OIRD).4,5

Mu opioid receptors (MORs) play a pivotal role in OIRD. MORs are expressed in central and peripheral centers of the respiratory network, affecting rhythm generation and hypoxic and hypercapnic ventilatory responses. The ability to block pathways that are responsible for respiratory depression without affecting analgesia or inducing withdrawal symptoms is fundamental to mitigating morbidity and mortality related to opioids.6–8

Opioids are known to interfere with various aspects of sleep, which leads to altered sleep architecture and poor quality of sleep.9 Evidence from animal and human studies show that opioids are associated with central, obstructive, and hypoxemic events during sleep.9–13 Opioids may cause central sleep apnea (CSA) and ataxic breathing. CSA is characterized by impaired respiratory drive and breathing cessation without respiratory effort. CSA is present in approximately 20% of chronic opioid users; in individuals with chronic pain, CSA is more common in those who use opioids than in those who are not on opioid therapy.13–15

Opioids impair upper airway function. However, the mechanisms of this impairment and relationships between OSA and opioid use are unclear. This lack of clarity can be attributed to opposite effects of opioids on different phenotypic traits of OSA. Specifically, animal studies showed that opioids reduce upper airway muscle tone, which may increase pharyngeal collapsibility and exacerbate the disease.10,11,16–18 Opioids also decrease chemosensitivity, which may stabilize ventilation and alleviate OSA in patients with overly robust ventilatory responses to hypoxia/hypercapnia.19 An outcome of this tug of war will determine the effect of opioids on OSA in an individual patient.

TRANSLATIONAL SCIENCE AND MECHANISTIC INSIGHTS

The genioglossus muscle is critical to the maintenance of upper airway patency during sleep.20 Therefore, most efforts to study the pathophysiology of OSA have been focused on effects of opioids on genioglossus, the hypoglossal nerve, and hypoglossal motoneurons innervating this muscle. Several authors demonstrated that opioids suppress hypoglossal motoneuron activity in vitro and genioglossal muscle activity in vivo.10,11,16–18 However, it remains unclear if MORs are present in the hypoglossal nucleus (XIIN) and if opioids can act directly on hypoglossal motoneurons. Data on opioid receptor distribution in the brainstem is limited and methodology has been inconsistent. In murine models, most studies observed at least weak expression of MORs in the XIIN.21,22 A study in cats found expression of delta opioid receptors but not MORs,23 whereas in humans hypoglossal expression was not observed or could not be determined precisely.24,25

In vitro recordings demonstrated that local application of MOR agonist, the synthetic opioid peptide [d-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), to the XIIN reduced burst amplitude, area, and duration of hypoglossal inspiratory activity and decreased the frequency of miniature excitatory postsynaptic currents of hypoglossal motoneurons.10,17 Microdialysis of fentanyl to the XIIN suppressed genioglossal activity in anesthetized rats. Interestingly, administration of a muscarinic receptor antagonist did not affect the response, suggesting that this effect was not mediated by acetylcholine.11 These data were also confirmed by in vitro studies where a MOR agonist DAMGO decreased XII nerve inspiratory burst amplitude despite the addition of atropine.17

Non–rapid eye movement sleep recording in unanesthetized goats treated with DAMGO dialyzed into the hypoglossal nucleus showed the reduction of genioglossal muscle activity, whereas sleep recording in mice treated with intraperitoneal morphine revealed inspiratory flow limitation indicating upper airway obstruction.10,18 These findings are consistent with earlier reports suggesting that endogenous opioids modulate ventilatory response and might play a role in the pathophysiology of OSA in humans.26 However, attempts to block endogenous opioids and treat sleep apnea with naloxone yielded inconsistent results.27,28

What are potential mechanisms by which opioids may modulate upper airway patency? Microcircuits in the respiratory network are interconnected to act on the respiratory rhythm, and pattern generation regulating respiratory muscles and suppression of any population of respiratory neurons may impair upper airway patency. Lorier et al demonstrated that MORs modulate the activity of hypoglossal motoneurons both directly and indirectly via inputs from premotoneurons in the pre-Bötzinger region.17 Opioids may affect hypoglossal motoneurons presynaptically by inhibiting MORs on the raphe pallidus neurons, thus diminishing the glutamatergic input to the XII nucleus.29 The Kölliker-Fuse nucleus, which projects to the hypoglossal nucleus and regulates upper airway patency, was identified as one of the key centers associated with OIRD,30,31 but the effect of opioids at this site on hypoglossal motoneuron activity has not been investigated. Opioid-induced hypoglossal motoneuron dysfunction and upper airway obstruction may be reversed by ampakines, modulators of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) glutamatergic receptors.17,32

In addition, opioids decrease afferent input to hypoglossal motoneurons via opioid-induced sedation and suppression of chemoreception, which may lead to upper airway dysfunction.33 Biologicals and pharmaceuticals augmenting hypercapnic and hypoxic sensitivity, such as the adipocyte-derived hormone leptin, reverse opioid-induced suppression of hypoglossal neuron activity and relieve upper airway obstruction acting presynaptically.10,17 Thus, emerging evidence from animal studies suggests that opioids affect the activity of hypoglossal motoneurons via multiple mechanisms, which may aggravate OSA. Figure 1 summarizes the potential mechanisms by which opioids modulate upper airway function.

Figure 1. Putative mechanisms by which opioids affect activity of the hypoglossal motoneurons.

Figure 1

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REM = rapid eye movement, XIIN = hypoglossal nucleus.

HUMAN STUDIES AND CLINICAL CONSIDERATIONS

Acute effects

Acute effects of opioids on OSA are particularly relevant for perioperative management of pain. OSA increases risk of perioperative respiratory depression and postoperative cardiopulmonary complications.34,35 Case reports and medicolegal literature suggest that OSA is associated with a risk of respiratory arrest induced by opioids.36,37 In an attempt to minimize adverse effects and reduce the volume of opioid prescriptions, anesthesiologists have been studying the benefits and state-of-the art approaches to opioid free anesthesia.38 A systematic review determined that most anesthetic agents cause some degree of airway collapse and opioids are associated with upper airway obstruction and depression of upper airway reflexes.39 Children with history of hypoxemia due to OSA have increased sensitivity to opioids and increased risk of respiratory depression postoperatively.40

However, studies in larger cohorts failed to find an association between OSA and perioperative mortality.41 This lack of association could be attributed to a combination of factors. Anesthesia and surgery became extremely safe due to the advances of anesthetic drugs and noninvasive minimal surgery. Over the last decade anesthesiologists became increasingly aware of a potential risk imposed by OSA42 and employ relatively sensitive questionnaires, to detect undiagnosed OSA.43 Observations made in many patients with untreated OSA are required to establish an effect on mortality, and, fortunately, remarkable progress achieved by anesthesiologists and surgeons makes these observations impossible. Nevertheless, surrogate markers suggest a significant impact of severe OSA on surgical outcomes. A prospective study of 1,218 undergoing major surgery showed that severe untreated OSA was associated with a significant increase in rates of postoperative cardiovascular events, and post-hoc analyses established a strong association with cardiac death, with a hazard ratio of 13.66.44 In contrast, mild and moderate OSA did not have an effect.

The lack of an impact of mild-moderate OSA postoperatively was reported in a smaller prospective observational study. Polysomnography was performed before and after surgery in 38 patients with OSA (median apnea-hypopnea index of 18 events/h) and 20 patients without OSA who received either balanced anesthesia without opioids or postoperative narcotics. Both groups had an increase in apnea-hypopnea index, but there was no significant difference between the groups. Other factors such as disrupted sleep architecture, methodological differences between the sleep studies, oxygen therapy, surgical stress, and other medications might have confounded the results.45

There are only a few randomized controlled trials investigating the effects of opioids on patients with OSA. In patients with moderate apnea, remifentanil increased the number of central apneas and decreased the number of obstructive apneas, with significant reduction in oxygen saturation levels. The decrease in obstructive apneas was attributed to the disruption of sleep architecture with marked decrease in rapid eye movement sleep.46 Wang et al reported that the variability in ventilatory responses after a 30-mg dose of morphine is related to the variability in plasma morphine levels. Paradoxically, higher plasma morphine concentrations and a decrease in ventilatory chemosensitivity directly correlated with improvement of the time with oxygen saturation below 90% (T90).47 Rowsell et al treated patients with 40 mg of controlled release morphine and showed a large interindividual variability in levels of respiratory depression in the absence of change in mean apnea-hypopnea index and T90. The investigators reported that opioid receptor mu 1 (OPRM1) gene polymorphisms might influence the response to opioids during sleep. OSA worsened in patients with the A/A OPRM1 phenotype and improved with the A/G OPRM1 phenotype.48 Martins et al studied the effects of 40 mg of controlled release morphine on different OSA phenotypical traits. The investigators showed a reduction in hypercapnic ventilatory response but no change in arousal threshold or upper airway collapsibility. Morphine blunted the genioglossus response to hypercapnia.49

In patients with over robust chemoreflex, the low arousal threshold in response to stimulation of chemo- and mechanoreceptors leads to respiratory instability exacerbating OSA. Opioids blunt the hypercapnic and hypoxic ventilatory responses and, in this patient population, opioids stabilize breathing and increase the arousal threshold, which may alleviate OSA.50 Overall, acute effects of opioids on OSA are complex and may vary depending on the dose, and individual patient characteristics, especially chemoreflex and the arousal threshold.

Chronic effects

Increasing trends in prescription of high doses of opioids (>200 mg morphine equivalent daily doses [MEDD]) have been observed in Canada and United Kingdom.51,52 Between 2000 and 2010, more than 200-mg MEDD have been prescribed for noncancer pain in approximately 8% of primary care patients in the United Kingdom.52 Sleep-disordered breathing has been examined in patients with opioid use disorder on maintenance therapy with methadone or buprenorphine. However, these reports are inconsistent due to variability in medications and MEDD. In addition, sleep-disordered breathing is rarely considered as an adverse event.53 Patients treated for opioid dependency with buprenorphine and methadone develop central sleep apnea and blunted hypoxic and hypercapnic responses.9,54 A systematic review focused on central sleep apnea identified a relationship between MEDD and severity of sleep-disordered breathing.55 Discontinuation of opioids was related to a reversal of central sleep apnea.55

Evidence on the relationship between chronic opioid use and OSA is scarce. Recent systematic reviews and meta-analysis found fewer than 15 studies addressing relationships between OSA and opioid therapy, none of which was a randomized clinical trial with OSA as the main outcome.15,56 There was no significant association between opioid use and severity of OSA.56 Other investigators reported that OSA was present in more than one third of patients with chronic use of opioids,57,58 but there was no control group and the prevalence in the general population was extrapolated from a study with different methodology.59 Another study showed that OSA was twice as common as CSA in a subgroup of patients treated with methadone who had self-reported sleep complaints. It is not clear if the diagnosis of OSA was independently related to the use of methadone or if it was dependent on other factors, such as body mass index.58

Overall, given the high prevalence of opioid use disorder and basic research findings suggesting the direct effect of opioids on upper airway patency, future well-structured clinical studies are needed to evaluate causal relationships between chronic opioid use and OSA.

POSITIVE AIRWAY PRESSURE TREATMENT

In this section we will review current evidence on benefits of positive airway pressure (PAP) therapy in patients with OSA and comorbid opioid use disorder.

In an acute perioperative setting, surgical patients with OSA on continuous positive airway pressure therapy (CPAP) had better postoperative outcomes than untreated OSA patients. The use of CPAP also reduced postoperative respiratory complications in patients without OSA.35 Overall, studies suggest a positive effect of positive pressure, but since complications are rare, most studies have been underpowered. There are relative and absolute contraindications to PAP therapy depending on the surgical procedure, and with some procedures, patients have a high risk of developing OSA, such as bariatric surgery, transsphenoidal pituitary surgery in patients with Cushing and acromegaly, and upper airway surgeries to improve upper airway patency. However, initial clinical suspicion that PAP may induce anastomotic leaks post–bariatric surgery was not confirmed and current evidence suggests that PAP therapy is safe in these patients.35 If PAP is contraindicated, an individual approach is recommended, minimizing opioid prescription and considering respiratory monitoring and therapies such as oral devices, positional therapy, and even tracheostomy as alternatives.60

Current recommendations in opioid users suggest the use of the lowest possible dose, avoiding doses higher than 200 mg MEDD, and consideration of drug interactions that may suppress breathing during sleep. Guilleminault et al demonstrated that, in chronic opioid users, CPAP therapy resolved mixed and obstructive apneas but led to the emergence of central apneas. The use of bilevel PAP with back-up rate abolished central apneas, improved oxygen saturation, and resolved sleep-related symptoms.61 Shapiro et al compared CPAP vs adaptive servo-ventilation (ASV) therapy in patients with chronic pain prescribed more than 100 MEDD (average 390 ± 338 MEDD). CPAP improved OSA but did not normalize apnea-hypopnea index, central apneas, or hypoxia. ASV significantly improved respiratory variables compared to CPAP, and sustained results after 3 months of ASV home treatment have been observed.62 Thus, bilevel PAP and ASV treatment of OSA should be considered in patients on chronic opioid therapy or with opioid use disorder. Of note, ASV should be avoided in patients with concomitant heart failure.63 Although this treatments was proven effective, a recent study that evaluated a cohort of patients with chronic pain on opioid therapy demonstrated that over 50% of the patients diagnosed with OSA were not compliant, whereas those who were prescribed PAP therapy had a 55% adherence rate.64

CONCLUSIONS

Animal studies suggest that opioids inhibit hypoglossal motoneuron and genioglossal muscle activity and induce upper airway obstruction, ie, OSA, but mechanisms are insufficiently understood. While there is a consensus that opioids cause central sleep apnea, the effects of opioids on OSA in clinical studies are not uniform and depend on the disease phenotype. Large clinical studies addressing the role of phenotypic traits, such as upper airway muscle response to pharyngeal obstruction, chemoreflex, and the arousal threshold, may identify the patients with OSA at risk of OIRD.

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. Work for this study was supported by the US National Institutes of Health (grants: R01HL 128970, R01HL 138932, R61 HL156240, U18 DA052301) and the São Paulo Research Foundation (FAPESP; grant 2018/08758-3). C.F. and V.Y.P. have a patent pending (Leptin Prevents Opiate-induced Respiratory Depression). L.U.S. report no conflicts of interest.

ACKNOWLEDGMENTS

Author contributions: C.F., V.Y.P., and L.U.S. wrote the manuscript.

ABBREVIATIONS

ASV

adaptive servo-ventilation

CPAP

continuous positive airway pressure therapy

CSA

central sleep apnea

MEDD

morphine equivalent daily doses

MOR

mu opioid receptor

OIRD

opioid-induced respiratory depression

OSA

obstructive sleep apnea

PAP

positive airway pressure

XIIN

hypoglossal nucleus

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