Chronic Opioid Use and Central Sleep Apnea: A Review of the Prevalence, Mechanisms, and Perioperative Considerations : Anesthesia & Analgesia

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Patient Safety: Review Article

Chronic Opioid Use and Central Sleep Apnea

A Review of the Prevalence, Mechanisms, and Perioperative Considerations

Correa, Denis MBBS, MD*; Farney, Robert J. MD; Chung, Frances MBBS, FRCPC*; Prasad, Arun MBBS, FRCA, FRCPC*; Lam, David BMSc*; Wong, Jean MD, FRCPC*

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Anesthesia & Analgesia 120(6):p 1273-1285, June 2015. | DOI: 10.1213/ANE.0000000000000672
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Opioids are the cornerstone for managing moderate to severe acute postoperative pain. The potential for acute respiratory suppression and death caused by opioids is well known; however, the relationship between sleep and opioid toxicity has only recently been described.–8 Opioids are associated with various sleep-induced respiratory disturbances such as central sleep apnea (CSA),1,2,4–7 other types of abnormal breathing patterns,1–3,8 and hypoxemia.1–3,5,8

Most studies in the anesthesiology literature have assessed the impact of acute parenteral opioid administration on metrics such as respiratory rate and ventilatory response to hypoxia or hypercapnia in normal healthy subjects and in the awake state.9–11

However, many patients taking chronic opioids may suffer from significant unrecognized central and obstructive sleep-disordered breathing (SDB) that may result in increased morbidity and mortality.12–14 Of special concern is the possibility of fatal complications in patients undergoing outpatient surgery or who are discharged after a short hospital stay and are receiving acute or increased opioids without oxygen therapy or monitoring. Satisfactory arterial oxygen saturation while breathing room air, having a normal respiratory rate, and the absence of subjective respiratory symptoms while awake provide no assurance that a lethal respiratory abnormality will not occur once the patient goes to sleep at home. Information regarding the perioperative management of patients with SDB associated with chronic opioids is limited.

The objectives of this review are to define the clinical manifestations of SDB associated with chronic opioid therapy, especially CSA, and to highlight the prevalence, mechanisms, risk factors, and perioperative management. Other sleep-induced respiratory disturbances, such as obstructive sleep apnea (OSA) syndrome and obesity hypoventilation syndrome, and the cardiotoxicity of opioids will not be reviewed in this paper.


We searched Medline (1983 to July 2014), Medline In-Process and other nonindexed citations (July 2014), EMBASE (1983 to July 2014), Cochrane Central Registry of Controlled Trial, Cochrane Database of Systematic Reviews (2005 to July 2014), and PubMed basic search (1983 to July 2014) for relevant English language articles using key terms: “central sleep apnea” and “opioids” (literature search terms available as Supplemental Digital Content 1,

Inclusion and Exclusion Criteria

For inclusion, studies had to fulfill the following criteria: (a) original published article, (b) adult population, (c) polysomnography-confirmed opioid-related CSA, and (d) report the prevalence, risk factors for CSA, and the treatment. Central Apnea Index (CAI) ≥5 events/h was considered significant. Studies on patients with OSA, cancer, or other medical conditions and pediatric patients were excluded.

Data Extraction

Abstracts and full texts of those potentially eligible were assessed by 2 reviewers (DC and JW) independently, and any disagreement was resolved by consensus. The following data were extracted: author, year of publication, country, study design, sample size, prevalence, age, sex, body mass index (BMI), type of opioids, dose, morphine equivalent daily dose (MEDD), comedications and sleep parameters, and modalities of positive airway pressure (PAP) used to treat central apnea.


The search strategy identified 633 studies (Fig. 1). After excluding irrelevant studies, 8 studies comprising 560 subjects were selected (Table 1).

Table 1:
Study Design, Demographics, and Prevalence of Sleep-Disordered Breathing
Figure 1:
Literature search strategy. OSA = obstructive sleep apnea; PAP = positive airway pressure; CSA = central sleep apnea.

Sleep-Disordered Breathing

A spectrum of respiratory disturbances was observed consisting of obstructive apneas, central apneas, hypopneas (sometimes grouped with obstructive apneas), hypoxemia, and ataxic or irregular breathing patterns (Table 2). As expected, the cohort specifically referred for evaluation of sleep apnea was found to have the highest prevalence of SDB and most severe sleep apnea (mean AHI 43.5 ± 35.2).3 Nevertheless, the overall prevalence of SDB (AHI ≥5/h) in all other studies was also high (range 42%–85%) mean of 70%, and severity was in the moderate category (AHI ≥15 to <30/h). The relative distribution of central versus obstructive apnea prevalence is difficult to determine. Two reports suggest the prevalence of OSA is much lower than CSA (10% vs 60% and 8% vs 30%, respectively).1,8 The prevalence of CSA in 7 of 8 studies was much higher than would be expected compared with the general population (mean 24%, range 14%–60%). One study3 was excluded because of an unreported prevalence. Hypoxemia was found consistently (5 of 8 studies),1–3,5,8 but the lack of uniform methodology precludes precise characterization for this variable. Ataxic breathing patterns were described or quantified in only 2 reports,3,8 but irregular breathing was also reported in another study.2

Table 2:
Opioid Medications and Respiratory Parameters

Type of Opioids and Dosages

All opioid dosages except for those of buprenorphine were converted to MEDD15 (Appendix 1). A direct relationship between the MEDD of opioids and the development and severity of SDB or CSA was reported in 5 studies (Table 2).1,3–5,7 MEDD of 200 mg/d or higher was associated with an increased severity of CSA and ataxic breathing.3 Ataxic breathing was present in 92% patients on MEDD >200 mg/d, and 61% patients with MEDD <200 mg/d. Each 100 mg MEDD increased the rate of apneas by 14.4% and central apneas by 29.2%.3 Each 100 mg MEDD was expected to increase (CAI) by 2.8 events/h versus patients not taking opioids.7 Wang et al.2 found that the blood methadone concentration was related to the degree of CAI (P = 0.008) but accounted for only 12% of the variance.

Concurrent Medications/Substances and Additive Risk for Developing CSA

The possible interactions between the most common drugs and SDB or CSA are shown in (Table 3). The concurrent administration of benzodiazepines was associated with the severity of CSA in one retrospective study.4 One prospective study of 50 subjects enrolled in methadone maintenance treatment, reported a 30% prevalence of CSA, and described an aggravating effect of antidepressants in relation to the severity of CSA.2 An interaction between cigarette smoking5–7or use of cannabis1,2,6 was not found, and no study specifically assessed the effect of alcohol or sleep deprivation on the occurrence of CSA.

Table 3:
Correlation of Opioid Dose and Concurrent Medications with Sleep-Disordered Breathing


BMI was inversely related to the severity of CSA in one study.3 Patients taking opioids with the lowest weight category (BMI 16–28 kg/m2) had a 42% increase in rate of apneas and hypopneas (P < 0.001) compared with the patients with higher BMI (32 kg/m2). In contrast, for patients not taking opioids, a lower BMI 16–28 kg/m2 was associated with a 47% reduction in the rate of apneas and hypopneas.3


Our survey of the literature reveals that: (1) the prevalence of SDB in all reported groups being treated with chronic opioids, even partial μ-agonists, is very high (from 42% to 85% of subjects); (2) both obstructive and central apneas are present, although the breathing patterns with central apnea are distinctive; (3) the varied clinical presentation confounds identification of patients at increased risk; (4) no clinical tool is available to diagnose CSA; and (5) the optimal therapy has not been established. We found that there are relatively few studies and many uncontrolled variables (i.e., heterogeneous study populations, types and doses of opioids, and methodology differences). Despite these limitations, we conclude that anesthesia providers need to be more aware of the potential for serious adverse respiratory effects of opioid therapy, specifically during sleep after surgery. Importantly, the risk continues beyond the first few hours after anesthesia and may persist for days or after discharge, for as long as opioids are used.

Definition and Mechanism of CSA

Both sleep and opioids reduce respiratory drive, as shown by decreased ventilatory response to hypoxia and hypercapnia.9,16,17 It is important to understand that when overall respiratory drive from the ventrolateral medulla is decreased, reduced efferent output to spinal motoneurons activity decreases intercostals and diaphragmatic activation of the respiratory bellows (decreases alveolar ventilation). At the same time, decreased respiratory drive also reduces efferent output to cranial motoneurons responsible for maintaining upper airway patency (increases upper airway resistance). Accordingly, any factor that reduces respiratory drive tends to promote hypoventilation, central apneas, and increased upper airway collapsibility. Obstructive apneas/hypopneas develop when decreased respiratory drive to the upper airway dilating muscles is reduced disproportionately compared to the lower respiratory muscles generating negative pressure during inspiration. Central apneas develop when respiratory drive is reduced to the respiratory pump muscles, although occult upper airway closure may be present.18 Because both obstructive and central events arise from reduced respiratory drive, the differentiation of these disturbances is often difficult.

According to current criteria for scoring respiratory events during sleep, an apnea is defined by ≥90% reduction from baseline of airflow signal for ≥10 seconds using an oronasal thermal sensor.19 If there is evidence of effort with the use of respiratory inductive plethysmography, then the apnea is scored as obstructive. If there is no evidence of effort, then the apnea is scored as central. A hypopnea can be defined by using a nasal air pressure transducer to detect airflow as a ≥30% reduction of the peak signal excursion for ≥10 seconds associated with either a ≥3% oxygen desaturation or an arousal (recommended) or a ≥4% oxygen desaturation from preevent baseline (acceptable) according to the American Academy of Sleep Medicine.19 The Obstructive Apnea Index (OAI), CAI, and Hypopnea Index (HI) are calculated as total number of obstructive apneas, central apneas, or hypopneas/total sleep time.

Unlike OSA,20–22 there are no standardized diagnostic criteria for central sleep apnea syndrome with characteristic clinical presentation, established prevalence, or standard therapy. A common definition of CSA is a CAI ≥5/h with ≥50% of the AHI comprising pure central events.23–25 In contrast to OSA syndrome, which is a relatively homogeneous entity, CSA is a manifestation of diverse medical conditions, each with a specific pathogenesis (e.g., heart failure, central nervous system diseases, chronic opioid use, etc). In all cases of central apnea, the defining feature is simultaneous absent airflow and effort lasting 10 seconds; however, the morphology of the respiratory patterns recorded by polysomnography is highly variable, depending on the pathogenesis.

Central apneas can be seen in patients with hypercapnia, but more commonly associated with variable degrees of respiratory drive with transient arousals, hyperventilation, and hypocapnia. Apneas occur when the degree of hypocapnia is reduced below the apneic threshold. The brainstem pattern generator may be intrinsically normal, but periodic breathing with central apneas develops because of the phase delay of afferent signaling or circulatory delay (e.g., congestive heart failure). The typical pattern in these cases is usually Cheyne-Stokes respiration with a gradual crescendo/decrescendo pattern (Fig. 2). In other cases (e.g., secondary to acromegaly), the pattern generator is also normal, except that the gap between the apneic threshold and prevailing cerebral spinal fluid CO2 levels is narrow. In these cases, the cycle interval is short, and there is no gradual change in the tidal volume (Fig. 3).

Figure 2:
Cheyne-Stokes breathing with central apneas. Characterized by crescendo–decrescendo pattern of airflow and effort. SpO2 = oxygen saturation.
Figure 3:
Idiopathic central sleep apnea. Breathing pattern is characterized by apneas of similar duration without overt evidence of respiratory effort and invariably terminated by 3–4 breath. SpO2 = oxygen saturation.

All commercially available narcotics inhibit μ-opioid receptors distributed on respiratory neurons throughout the central and peripheral nervous system.26 Some of the most important opioid-sensitive areas include (1) pre-Bötzinger complex, the principal kernel responsible for generating inspiration and for central chemoreception of CO2; (2) glomus cells of the carotid body, responsible for breath-by-breath control by providing rapid feedback from the periphery to the central nervous system regarding O2, CO2, H+, and K+; (3) bulbospinal inspiratory and expiratory premotor neurons that project to the phrenic, intercostal, and abdominal motoneurons; and (4) the hypoglossal motor nucleus necessary for maintaining upper airway patency during sleep.27–31 As a result, opioids have the potential of affecting all aspects of respiration, including breathing frequency, tidal volume, rhythm, upper airway patency, chemosensitivity to CO2 and O2, arousal response to hypoxia and hypercapnia, inspiratory load, cough reflex, and chest and abdominal wall compliance.

The clinical manifestations of SDB associated with chronic opioid exposure are seen in 3 domains: (1) fundamental breathing pattern (ataxia or irregular versus regular); (2) breathing interruptions (apneas and hypopneas); and (3) gas exchange (hypoxia and hypercapnia).8 Any of these abnormalities may occur in isolation, or all 3 may be present. The toxicity and manifestation of opioids will depend on whether opioids are used acutely in opioid-naïve subjects or chronically in opioid-dependent patients, the class of μ-opioid (highly potent and short acting, such as fentanyl versus opium derived, such as oxycodone), sex, age, other drugs, comorbidities, and especially the sleep–wake state.

The acute effects of opioids on ventilation (hypoventilation secondary to reduced ventilatory drive) should be distinguished from chronic effects (periodic breathing). Hypoxic/hypercapnic respiratory failure due to decreased respiratory drive and hypoventilation is most characteristic of acute toxicity, although hypoxemia is often seen chronically.1–3,5,8 Obstructive apneas may occur with opioids because of their direct inhibitory effect on genioglossus muscle activity31 in addition to their effect on central hypoglossal motor pool and depression of protective arousal responses,32particularly in those with other risk factors; however, central apneas are far more typical in most series. Central apneas due to opioids may occur with several morphologies: highly irregular intervals with underlying ataxic breathing or periodic appearing with clusters of breathing (Figs. 4 and 5)

Figure 4:
Opioid-induced ataxic and cluster breathing. The respiratory pattern is characterized by a highly irregular rhythm, varying in rate and amplitude as originally described by M.C. Biot. There are a few scattered central apneas with a “cluster” pattern. SpO2 = oxygen saturation.
Figure 5:
Central apneas with predominantly cluster pattern.There are persistent central apneas but the underlying rhythm is more irregular and variable than idiopathic central apneas. SpO2 = oxygen saturation.

Conversely, long-term opioid use involves peripheral chemoreceptors in addition to its central effects. The mechanism underlying periodic breathing or central apnea patterns during sleep is unclear. Santiago found that the hypercapnic ventilatory response (HCVR) and hypoxic ventilatory response (HVR) both decreased initially after beginning methadone, but after 5 months the HCVR returned to normal and the HVR remained low.33 In a cohort of stable long-term methadone maintenance patients, Teichtahl et al.34 found that the HCVR was reduced but the HVR was increased, which is a recipe for ventilatory instability. These circumstances could result in ventilatory overshoot with arousals, relative hypocapnia, and central apneas.

The irregular, ataxic, underlying breathing pattern often found suggests that the brainstem pattern generators are inherently dysfunctional and may not be responsive to negative-feedback loop signals, as in Cheyne-Stokes respiration or idiopathic CSA, in which periodicity is a prominent feature (Figs. 2 and 3). Mellen et al.35 attributed the irregular breathing pattern to “quantal slowing” due to the differential effects of opioids on the opioid-sensitive pre-Bötzinger complex and the opioid-insensitive preinspiratory neurons. Of particular concern in the perioperative period is that opioids may disable normal protective arousal mechanisms in response to hypoxemia that commonly occurs postoperatively, especially in obese patients who may also have OSA or chronic hypoventilation. The presence of an ataxic underlying breathing pattern in the presence of hypoxemia may also be a warning sign of impending respiratory failure.36,37

Prevalence of CSA

In contrast to OSA syndrome, in which the overall prevalence has been established by multiple large epidemiologic studies, there are no corresponding data for CSA because central apneas are manifestations of multiple disease processes. Assessment of the prevalence of opioid-induced respiratory effects during sleep, in particular, is inherently more complicated because opioids are associated with diverse respiratory abnormalities that often overlap owing to their unique pathophysiology: central apneas, obstructive apneas, hypopneas, ataxic breathing patterns, and hypoxemia. We found that obstructive apneas occurred, but, when compared with control populations, the overall prevalence of SDB was increased in the opioid patients owing to the additional presence of CSA. Unfortunately, reliable determination of the prevalence of opioid-induced CSA is confounded by the following limitations: (1) the biases and diversity of the small populations studied. For example, subjects with numerous comorbidities were recruited from detoxification programs or chronic pain clinics, or patients were referred for the evaluation of OSA who happened to be receiving opioids; (2) only 4 of the 8 studies were entirely prospective; (3) various classes and doses of opioids were used, frequently with different timing of administration; (4) numerous other drugs that may affect respiratory control were used simultaneously; (5) baseline polysomnography (PSG) was not available for comparison; (6) the application of standard scoring criteria for central apneas is often made difficult because of an underlying irregular breathing pattern or when the patient is receiving positive airway pressure (PAP) such as adaptive servoventilation; and (7) hypopneas, which occasionally may be quite prolonged and associated with severe hypoxemia because of a blunted arousal response, may be the most common respiratory event, but these are not usually differentiated as central or obstructive. Moreover, other opioid effects, such as hypoxemia and ataxic breathing, were either not described or not quantified in any detail. Our review suggests a mean prevalence of CSA related to opioid therapy of 24%, although the reported range is wide (14.1%–60%). The reason for the wide range was unclear, because it did not seem to be accounted for by any obvious differences in the populations studied.

Risk Factors for Opioid-Associated CSA

Well-known risk factors for OSA have been identified from large epidemiologic surveys to formulate clinical prediction models such as the STOP-Bang questionnaire.38–41 None of the current screening instruments or known risk factors have been validated or useful for identifying patients with SDB related to chronic opioid use. Consequently, the tendency to readily suspect OSA in the tired, obese, hypertensive male who snores only serves to misdirect and underdiagnose severe and potentially lethal opioid-induced CSA and hypoxemia in other demographics, such as the nonobese female. At least some patients have OSA with typical risk factors that may prompt investigation, but the chronic use of opioids likely exacerbates SDB and increases the risk of developing more complex sleep apnea that is difficult to treat, particularly with standard continuous positive airway pressure (CPAP) therapy. Only 2 variables seem to be somewhat helpful: (1) dose of opioid and (2) low or normal BMI.

A positive correlation between either oral dose or plasma level was found in 5 of 8 studies.1–4,7 Numerous factors may explain the lack of tight or consistent correlation between opioid dose and effects on respiration during sleep. These include uncertainty about actual amounts of drugs ingested, timing of measurements in the case of blood levels, individual susceptibility due to μ-receptor polymorphism, pharmacokinetics related to body weight, and interactions with concurrent drugs.

It is reasonable to suspect that the use of various drugs in conjunction with opioids should increase the probability of developing CSA. Benzodiazepine/hypnotics depress central nervous system activity and blunt the arousal or ventilatory response to hypoxia and hypercapnia during sleep,42,43 and benzodiazepines may worsen or precipitate SDB in patients with pulmonary and cardiac disease44 and prolong the methadone effect by possibly inhibiting the metabolism of methadone.45 Interestingly, only one study found that benzodiazepines had any additive effect.4 This is not only counterintuitive but is also at variance with standard admonitions. There are insufficient data regarding alcohol and other commonly used substances in these populations that could conceivably increase risk, such as cannabis, tobacco smoke, muscle relaxants, and gabapentin.

Antidepressants appear to act in synergy with methadone to further reduce already blunted HCVR.2 Wang et al.2 reported that 4 of 7 patients (57%) receiving antidepressants had CAI >10/h; however, 4 studies showed that there was no interaction,4,6–8 and there was no information in the other 3 reports.1,3,5 The effect of concurrent medications and chronic opioid-associated CSA was assessed in each of the studies,1–6,8 with the exception of the report by Jungquist et al.,7 and no relationship was observed. The synergy between opioids and sleep deprivation, as might occur in the perioperative environment, also seems plausible and relevant; however, none of the studies has addressed this point. It is almost impossible to exclude concurrent use of various medications as risk factors. Therefore, until more definitive studies can be performed, it would be prudent to avoid potentially exacerbating medications.

The relationship with nonobese status is particularly interesting and has not been thoroughly investigated. The increase in central apneas in patients with lower BMI may be because the dosage was prescribed according to general guideline with a dose range and not as a milligram per kilogram basis. It is possible that patients with smaller BMIs may have a relative overdose versus patients with higher BMIs because of a difference in effect site concentration based on differences in pharmacokinetics.

Do Patients with Opioid-Associated CSA Have Higher Morbidity and Mortality?

The effect of opioid-associated CSA on morbidity and mortality has not been well characterized because long-term studies are not available. The current practice of chronic pain management is to use multiple analgesic medications at reduced doses to take advantage of their synergetic effect; however, there are no data to indicate whether this practice alters the risk of ataxic breathing, sleep apnea, or unanticipated death during sleep. Ideally, polysomnography should be performed if symptoms are observed. Whether the treatment of opioid-associated CSA prevents sleep-related mortality is unclear.

Therapy for Opioid-Associated CSA

Management of patients with opioid-related CSA is extremely challenging.25 Practice parameters with an evidence-based literature review of therapy for CSA was recently published46; however, there are no consensus guidelines that define indications and therapy for opioid-related breathing disorders. The main options available include: withdrawal of opioids,47,48 reducing opioid dose, selecting an opioid that may have less toxicity (e.g., buprenorphine in lieu of methadone),49–51 greater use of non-opioid analgesics, supplemental oxygen, pharmacologic therapy (e.g., acetazolamide, theophylline, carbon dioxide), positional therapy,52 avoidance of potentially aggravating concurrent drugs, and PAP. It is extremely important to identify and treat those with OSA and those who are using chronic opioids because there may be substantial interactions (e.g., increased upper airway resistance, hypoxemia, and blunted ventilatory and arousal responses). For the perioperative period, the 2 major therapeutic modalities are oxygen and PAP.


The effectiveness of oxygen for OSA53 and in the treatment of certain types of CSA, primarily Cheyne-Stokes breathing associated with heart failure, has been reviewed.46 However, the role of oxygen therapy for hypoxemia or CSA specifically related to opioids has not been established. Of note, nonapneic hypoxemia can occur during wakefulness in patients without cardiopulmonary disease and who are receiving chronic opioids with and without sleep apnea.3,5,54 More than 10% of patients on chronic opioids demonstrated resting awake and asleep hypoxemia without apnea.5 In a case series report by Farney et al.,55 oxygen supplementation corrected hypoxemia; however, Biots/ataxic breathing persisted. Despite the beneficial effects on arterial oxygen saturation, patients using opioids chronically already have a reduced arousal/ventilatory response hypercarbia. Therefore, oxygen therapy could potentiate hypoventilation or prolong central apneas/hypopneas. Conversely, opioids can stabilize breathing if the arousal threshold is low and respiratory controller gain is high associated with pain, so that oxygen therapy is unlikely to cause respiratory suppression. Unfortunately, these phenotypes may be indistinguishable based on anatomy or the specific opioid being used. We are unaware of any study in which the effect of oxygen on central apneas or ataxic breathing has been systematically assessed. Accordingly, oxygen therapy to treat hypoxemia due to opioids (with or without central apneas) appears prudent; however, patients need to be monitored very closely in the perioperative period because of multiple, potentially interactive factors. Adjunctive oxygen, in particular, may be necessary, in addition to PAP therapy, for optimal resolution of CSA and hypoxemia due to opioids.56

PAP Therapy

There are 4 PAP modalities: (1) continuous positive airway pressure (CPAP); (2) bilevel positive airway pressure (BPAP); (3) automatic self-adjusting positive airway pressure (APAP); and (4) servo-controlled ventilation (ASV or BPAP adapt). (See Table 4 for detailed comparison.) Except for servo-controlled ventilation, practice parameters have been published for all of these modalities for therapy of OSA and CSA not associated with chronic opioid use.57–59

Table 4:
Positive Airway Pressure Therapy

Continuous Positive Airway Pressure

CPAP devices maintain a CPAP with adjustable flow generated by fan-driven or turbine systems to stent the upper airway open and to increase functional residual capacity. A pressure adjusted to abolish flow limitation is prescribed. CPAP can be autotitrated or fixed. In either case, the pressure is adjusted to abolish flow limitation and is thus several cm H2O higher than closing pressure, which is the pressure at which the airway closes completely. Furthermore, the pressure is not determined by PSG. It can be determined during PSG, but can also be determined under other circumstances, such as autotitration at home. Patients with sleep apnea related to opioids often have obstructive events, providing a logical basis for use of CPAP. Five retrospective studies60–64 (Table 4) showed that CPAP therapy does not eliminate or may even increase central apneas.60–63 The use of opioids does not preclude a favorable response to CPAP, but adjunctive oxygen or alternative PAP modalities will be required in most cases.

Bilevel Positive Airway Pressure

These devices permit independent adjustment of inspiratory positive airway pressure and expiratory positive airway pressure to target the obstructive and central SDB events. There are different modes of BPAP: Spontaneous (S Mode), Timed (T Mode), and Spontaneous/Timed Mode (ST Mode). In BPAP-ST Mode, a “backup” rate is also set to ensure that patients still receive a minimal number of breaths per minute if they fail to breathe spontaneously. BPAP (S or ST Mode) alone, or with a backup rate and/or oxygen, was effective for treating CSA unresponsive to CPAP62,65,66 (Table 4). A recent systematic review also reported the effectiveness of BPAP in eliminating CSA in 62% and ASV in 58% of patients taking chronic opioids.67

Servo-Controlled Ventilation

Adaptive servoventilation is a relatively new approach in treating CSA, mainly in patients with congestive heart failure or complex apnea related to overtitration with CPAP. Based on an internal algorithm and a moving window sampling of the patient’s minute ventilation, ASV uses a preset or autotitrating end-expiratory pressure to eliminate any obstructive apneas or hypopneas, and it generates variable inspiratory pressure support (usually in the range of 3–10 cm H2O) on a breath-by-breath basis above the expiratory pressure to regulate ventilation to prevent hypocapnic-induced central apneas. Pressure support increases as ventilation wanes and decreases as it waxes. ASV appears to successfully treat CSA associated with chronic opioid use unresponsive to CPAP60,61,63,66 (Table 4).

Perioperative Management

Unlike OSA, the perioperative risk due to CSA syndromes is unknown. Diagnostic studies for CSA are not standard, and the possibility of opioid-induced SDB, such as CSA, may not even be considered.

Based on our review, none of the usual risk factors for OSA has been useful for screening patients for opioid-induced CSA. However, the following factors should raise concern: (1) the clinical context identified in these studies (i.e., patients receiving methadone or buprenorphine for opioid addiction, patients being treated for chronic pain, and patients who have risk factors or diagnosis of OSA and are also receiving chronic opioids); (2) any patient being treated with an MEDD ≥ 200 mg/d; and (3) patients with low or normal BMI. Although methadone has been most widely implicated, virtually any opioid appears capable of inducing sleep apnea and other respiratory disturbances. In these cases, early awareness can lead to timely recognition and treatment. Patients with underlying CSA may be at increased risk for worsening of CSA when opioids are used for pain relief at night.26–28 Acute ingestion of an extra dose of opioids at night can result in the precipitation of CSA in patients using chronic opioids who were not previously diagnosed with SDB.68

Perioperative management using a multimodal approach with combinations of non-opioid analgesics69–71 requires careful planning to minimize the need for opioids. Preoperative sedative and hypnotic medications should be used with extreme caution, because these medications may worsen CSA/hypoxemia in some patients. Non-opioid analgesics,72–84 regional anesthesia techniques and epidural or peripheral nerve catheters, perioperative infusions of lidocaine, and local anesthetic infiltration can decrease the postoperative requirement of opioids.85–88

Improved postoperative monitoring is a key to reducing the risk of central apnea. Patient-specific, anesthetic, and surgical factors determine the requirements for postoperative monitoring. Central apnea patients undergoing major surgery who require postoperative opioid should be monitored with continuous oximetry and respiratory rate at night, because there may be an increased risk of worsening of CSA when opioids are used for pain relief in the evening.26–28 Recurrent respiratory events in the postanesthesia care unit, including apnea for ≥10 seconds, bradypnea of <9 breaths/min, pain-sedation mismatch, or desaturation to <90%, can be used to identify patients at high risk of postoperative respiratory complications.89 Macintyre et al.90 proposed that sedation level is a more reliable sign of opioid-induced respiratory depression than respiratory rate, because multiple reports suggest that opioid-induced ventilatory impairment is not always accompanied by a decrease in respiratory rate. Thus, sedation scoring systems should be used postoperatively to recognize opioid-induced ventilatory impairment, so that appropriate interventions are triggered.90 CPAP may not be effective, and BPAP with a backup rate may be useful in treating the central apneic episodes and hypercapnia. If patients with opioid-associated CSA are on PAP before the surgery, PAP should be resumed as soon as possible postoperatively.


The prevalence of SDB in all populations receiving chronic opioids is high (42%–85%), and the prevalence of CSA is much higher than in the general population (24%). The respiratory patterns associated with opioids are distinctive, and severe nonapneic hypoxemia can be observed. The usual risk factors seen in patients with OSA are not reliably predictive in patients with opioid-related SDB, and therapy with CPAP is often ineffective. The possibility of CSA and other disturbances should be considered in any person being treated with chronic opioids, especially if the MEDD ≥ 200 mg/d. The risk appears to be greater in nonobese persons but is not clearly increased by concurrent benzodiazepines. There are many limitations to the published studies, and the clinical outcomes of patients with documented CSA due to opioids are not known. Evidence-based research on the perioperative management of patients with opioid-associated CSA is also lacking. Surgical patients with opioid-associated CSA may be more vulnerable to sedation, anesthesia, and analgesics. Supplemental oxygen should be used to treat hypoxemia; however, higher levels of monitoring are needed in patients with opioid-induced SDB because of reduced arousal and ventilatory responses to hypoxemia/hypercapnia. When CPAP is ineffective, adaptive servoventilation or BPAP support with a backup rate is often adequate. Precautions, including screening, diagnosis and treatment of unrecognized CSA, use of multimodal, opioid-sparing analgesic regimens, and increased postoperative monitoring should be taken in these patients. There is a need for further prospective studies on the perioperative risks and management of these patients.

Appendix 1

Calculation of Morphine Equivalents

Opioids were converted to oral morphine equivalent daily dose (mg) by multiplying the daily dose of opioids by the designated multiplier for each type of opioid given in the following Appendix table.

No title available.


Name: Denis Correa, MBBS, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Denis Correa approved the final manuscript.

Name: Robert J. Farney, MD.

Contribution: This author helped write the manuscript.

Attestation: Robert J. Farney approved the final manuscript.

Name: Frances Chung, MBBS, FRCPC.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Frances Chung approved the final manuscript.

Name: Arun Prasad, MBBS, FRCA, FRCPC.

Contribution: This author helped write the manuscript.

Attestation: Arun Prasad approved the final manuscript.

Name: David Lam, BMSc.

Contribution: This author helped analyze the data.

Attestation: David Lam approved the final manuscript.

Name: Jean Wong, MD, FRCPC.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Jean Wong approved the final manuscript.

This manuscript was handled by: David Hillman, MD.


The authors thank Marina Englesakis, BA (Hons) MLIS, Information Specialist, Surgical Divisions, Neuroscience & Medical Education, Health Sciences Library, University Health Network, Toronto, ON, Canada, for her assistance with the literature search.


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