Data extracted included study ID, study year, study type, method of OSA identification, exposure definition, diagnosis of outcome (eg, perioperative outcomes and complications), patient characteristics, as well as the type of surgery and intervention. To assess the overall quality of evidence, the original intent was to utilize the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach including quantitative and qualitative analysis.9 However, given the large heterogeneity of studies and lack of high-quality trials, quantitative meta-analysis and a comprehensive conventional GRADE analysis were not feasible. Nevertheless, the risk of bias for every study in relation to the outcome of interest was assessed, and the Oxford level of evidence was reported.10 Methods of OSA identification within studies are presented in Tables 1 and 2.
POSTOPERATIVE RESPIRATORY COMPLICATIONS
OIRD is a serious concern, particularly in patients with OSA. In this context, Esclamado et al14 were among the first to suggest an opioid dose-dependent increase in postoperative, particularly respiratory, complications in OSA (Table 1). In a retrospective analysis of PSG-tested patients undergoing surgery for OSA, patients with postoperative complications, had significantly lower nocturnal nadir oxyhemoglobin saturations (SpO2 66% vs 79%) and higher apnea/hypopnea indices (AHI of 75 vs 57 events per hour of sleep) preoperatively and had received greater amounts of opioids intraoperatively. These data, therefore, indicated that greater OSA severity and increased intraoperative opioid use may present drivers of respiratory complications.14
Blake et al12 suggested a potentially greater detrimental impact of opioids in patients with OSA, which was established by body mass index, medical history, upper airway, and physical examination,51 compared to controls. Patients at OSA risk experienced significantly more postoperative obstructive apneas and hypopneas, more severe hypoxemia, and a higher percentage of sleep duration at SpO2 levels <90%.12
While perioperative morphine dose predicted central apneas regardless of OSA status, patients at OSA risk experienced hypoxemia of significantly greater severity, predominantly due to obstructive respiratory events.
An association between oxyhemoglobin desaturation and opioid use was also reported by Bolden et al13 in unadjusted data. Odds for postoperative hypoxia were increased by >10-fold in patients with OSA identified by PSG and medical history when using intravenous or oral opioids compared to patients not treated with opioids (P < .001, respectively). Although opioids depress respiration in the general population and with common postoperative hypoxemia,52 it is worth noting that desaturation in this analysis was not reliably prevented by continuous positive airway pressure (CPAP) therapy.13
In contrast, Khanna et al17 found that OSA determined by STOP-BANG did not predict hypoxemia during recovery from noncardiac surgery. Although in the obese population with a high OSA prevalence, the occurrence of postoperative oxyhemoglobin desaturation and other respiratory complications after opioid consumption is common, studies focusing on obesity could not establish OSA as an independent driver of postoperative hypoxemia in this setting.11,25,53 While these reports may be affected by the wide use of CPAP treatment, possibly diminishing increased respiratory risk,53 comorbidities associated with OSA, such as obesity and diabetes, are potential confounders when it comes to the occurrence of postoperative complications.54
A recent large-scale population-based analysis of >107,000 ICD-9 code-identified patients with OSA undergoing orthopedic surgery showed that increased perioperative opioid prescription was associated with greater odds for gastrointestinal complications, prolonged length of stay, and increased cost, while no effect for myocardial infarction, thromboembolic complications, or renal failure was observed.20 In patients with increased opioid dose, however, reduced odds for pulmonary complications were observed, which was potentially indicative of higher use of preventive measures and surveillance in patients with OSA receiving higher opioid levels.20 More insight was provided in a separate analysis by the same investigators, presenting findings in the general surgical population of the same dataset.55 When comparing the occurrence of respiratory and other types of postoperative complications between patients with and without OSA, the incidence of pulmonary (2.49% vs 1.83%), cardiac (2.81% vs 0.23%), gastrointestinal (0.45% vs 0.33%), renal (3.47% vs 1.83%), and thromboembolic (0.41% vs 0.33%) complications was significantly higher in patients with OSA versus those without OSA at similar opioid dose levels.17,53 In sum, these data indicate a higher perioperative complication risk in OSA, while the higher prevalence of respiratory complications at baseline may not per se further increase within conventional opioid dose limits. The contribution of other factors besides sheer opioid dosage, such as OSA severity and opioid sensitivity, is also indicated in studies reporting that a significant amount of life-threatening or fatal events occurs at relatively low opioid consumption.18,21,23
In this context, a number of retrospective observational analyses have studied the occurrence of life-threatening anesthesia-related respiratory events in association with perioperative opioid analgesia and the presence of OSA. OSA is typically identified by patient records and ICD-9 codes in these studies.
Using naloxone as a surrogate marker for severe OIRD, 2 matched control studies by Weingarten et al24,26 demonstrated that the postoperative requirement for naloxone was significantly associated with OSA and higher opioid use. This finding was supported by Etches,15 who showed that in patient-controlled analgesia (PCA) with morphine, postoperative severe respiratory depression with rescue naloxone requirement occurred in 0.5% of cases, while OSA was reported as a driver. Melamed et al19 also found that severe postoperative respiratory failure with ICU requirement after elective orthopedic surgery was associated with higher intraoperative opioid utilization and established OSA as an independent risk factor after multivariable analysis.
Ramachandran et al21 demonstrated that the odds for life-threatening respiratory failure during postoperative parenteral opioid analgesia, including unresponsiveness, hypoxic or apneic conditions requiring naloxone, endotracheal intubation, or cardiopulmonary resuscitation, were increased by >15-fold in patients with OSA, while a similar complications risk was also observed in patients with postoperative acute renal failure. Moreover, OSA was a prevalent factor among fatalities during concurrent opioid therapy. Among cases of critical respiratory complications, the utilized opioid dose was low, while a tendency for higher pain scores was found. These observations may support the notion of increased opioid sensitivity in OSA,1,44 possibly lowering the threshold for OIRD in a subset of patients. Ramachandran et al22 recently corroborated their previous findings in a new analysis by showing that high OSA risk, assessed by the Perioperative Sleep Apnea Prediction (PSAP) score, was significantly associated with the requirement for postoperative endotracheal intubation.
Focusing specifically on postoperative death or near-death events in patients with OSA, Subramani et al23 recently analyzed 60 case reports.23 Besides factors including undiagnosed or untreated OSA and lack of monitoring, opioids and sedatives were among the risk factors for postoperative death or near-death events in OSA. Furthermore, consistent with Ramachandran et al,21 the majority of affected patients had consumed typical or less than typical doses of opioids, suggesting increased opioid sensitivity as a possible mechanism.1,7
A closed claims analysis by Lee et al18 identified 92 cases of postoperative OIRD in the National Anesthesia Closed Claims Project database. Consistent with previous studies, most complications occurred within 24 hours postoperatively,19,21 the majority resulting in severe brain damage or death, while 97% of the cases were deemed preventable. Of all identified OIRD claims, 25% were related to OSA. PCA and neuraxial analgesia were the most common modes of opioid analgesia, while no claims were associated with peripheral nerve blocks or catheters. About 50% of the cases received opioids by using >1 modality. Thus, nearly 50% had a continuous background opioid infusion in addition to PCA, while excessive opioid dosages were administered in only a minority of cases (16%).18 Perioperative respiratory complications directly related to OSA are also increasingly recognized in the legal arena, as shown by Fouladpour et al16 in cases of adverse postoperative outcome that resulted in lawsuits. More than half of the cases occurred in an unmonitored setting, and in 38% of cases opioids played a role. These cases were most likely to be associated with death as the outcome.16
In summary, these studies support the heightened level of concern regarding perioperative opioid consumption in patients with OSA (Table 1). Evidence indicates a particularly increased risk within the first 24 hours of opioid utilization, while notably, life-threatening OIRD may not only occur in excessive or high opioid utilization. This finding suggests a potential impact of other additional contributors, such as OSA severity and possibly altered opioid sensitivity and pain perception.1 In the absence of high-quality randomized evidence to robustly verify this notion, adequate postoperative monitoring in OSA during opioid therapy initiation could possibly prevent life-threatening OIRD.
POSTOPERATIVE SLEEP ARCHITECTURE AND SLEEP-DISORDERED BREATHING
Patients with OSA are known to postoperatively experience a significant deterioration in sleep architecture and sleep-disordered breathing, which is sustained for about 7 days and reaches its peak severity on postoperative night 3.43 These postoperative changes reflected in decreased sleep efficiency and increased AHI can also occur in the general population but at a lower incidence and with blunted severity.43 The exact underlying pathophysiology has not been established so far56,57; however, potential drivers may include postoperative rebound of nocturnal rapid eye movement sleep (REM), OSA severity, and perioperative complications.56
Given the postoperative risk resulting from deteriorations in sleep architecture and sleep-related breathing, Chung et al28 investigated possible causes by enrolling 376 elective surgery patients to undergo pre- and postoperative PSG.43 Results revealed a modest but significant association between cumulative 72-hour opioid dose and the severity of postoperative AHI. Moreover, increased postoperative central apnea index was associated with general versus regional anesthesia and male sex, suggesting an impact of general anesthesia drugs. The finding of an opioid dose-dependent impact on postoperative AHI is consistent with Blake et al,12 who found that opioid dose predicted postoperative central apneas in patients with and without OSA. OSA-related postoperative exacerbation of sleep-disordered breathing may therefore present a detrimental risk, potentially augmented by opioid effects in a dose-dependent manner.28
Based on the concern of opioid-related worsening of sleep-related respiratory insufficiency in OSA, Bernards et al27 conducted a nonsurgical, randomized placebo-controlled study among 19 PSG-confirmed patients with OSA. Patients received an additional sleep study during randomization to either saline or remifentanil infusion. Similar to Chung et al,28 significant changes in sleep architecture as a result of opioid use were revealed. Remifentanil markedly increased stage 1 sleep, decreased REM sleep, increased arousals from sleep, and decreased sleep efficiency. Moreover, remifentanil conferred an increase in the incidence of central apneas, while reducing the number of OSAs, probably through reduced REM sleep. Moreover, arterial oxyhemoglobin saturation was also significantly lower in OSA patients with remifentanil infusion.
Overall, because OSA was worsened during remifentanil infusion, results indicated that the primary risk may perhaps arise from central rather than obstructive apnea, which may render ineffective attempts to eliminate OIRD using CPAP therapy.27 Notably, about 15% of CPAP-naïve patients with OSA develop central apneas (complex apnea) with the initiation of CPAP treatment.27,58 Despite the small sample size, Bernards et al27 provide largely lacking high-quality evidence on the impact of opioids in OSA.27,59
Wang et al29 presented contrasting findings among 10 mild to moderate patients with OSA undergoing PSG before and after experimental administration of a single oral dose of 30 mg controlled- release morphine. Morphine plasma concentrations, although highly variable among subjects, were positively associated with CO2 ventilatory recruitment threshold (ie, the level of CO2 required to reinstate rhythmic breathing after hyperventilation-induced hypocapnia, when rebreathing of CO2 is initiated) and, paradoxically, negatively associated with the fraction of sleep time spent at SpO2 <90% (ie, morphine administration, in this context, decreased hypoxemia during sleep), compared to baseline. These results would suggest that, rather than worsening sleep-disordered breathing, a single oral dose of morphine could paradoxically improve oxygenation through modulating chemoreflexes in OSA. However, these findings are limited by the factors of large (30-fold) interindividual variability in morphine plasma concentrations, small sample size, limited OSA severity, and use of oral, controlled-release morphine (Table 1).60
PAIN PERCEPTION AND OPIOID ANALGESIC POTENCY IN OSA
Inherent features of OSA, including recurrent hypoxia and chronic sleep fragmentation, have been suggested to interact with pain processing and sensitivity to opioid analgesia.7,40,61 Both chronic recurrent hypoxia and sleep disruption appear to enhance sensitivity to pain, while hypoxia may also potentiate opioid analgesic effects (Table 2).1
The idea of changes in pain and opioid sensitivity was originally sparked in pediatric patients with OSA. In 2 independent analyses, Brown et al40,41 found that children with preoperative recurrent hypoxemia (nocturnal nadir SpO2 <85%) required half the dose of morphine postoperatively compared to children who were less or not hypoxemic (SpO2 ≥85%). This finding was consistent in children living at high altitudes under chronic sustained hypoxia.62 Based on earlier animal experiments, these observations were attributed to upregulation of central opioid receptors triggered by recurrent hypoxia,63,64 while 2 other pediatric prospective studies could not confirm these findings.47,48 Sadhasivam et al47 suggested that African American versus Caucasian children with OSA presented with more pain requiring a higher dose of morphine for postoperative analgesia, while Sanders et al48 also reported higher postoperative morphine use in children with OSA.
In adult patients with OSA, Doufas et al44 applied an experimental pain paradigm and found that nocturnal hypoxemia potentiated the analgesic effect of a µ-opioid agonist. Furthermore, lower nocturnal nadir SpO2 and insulin-like growth factor binding protein-1, a serum marker of hypoxia,65 predicted increased sensitivity to opioid analgesia, while the augmented potency of opioid analgesic effect was also predicted by serum levels of proinflammatory mediators.44 This finding suggests the involvement of inflammatory activity,44,66 which appears particularly important given that OSA represents a chronic inflammatory condition with intermittent hypoxia as a causal protagonist. Moreover, inflammatory mediators associated with these processes, such as interleukin-6, interleukin-1, and tumor necrosis factor-α, have been shown to confer both hyperalgesia67 and increased analgesic opioid potency.44 Although apparently contradictory at the surface, evidence suggests that these developments are not mutually exclusive.1,50
In a large retrospective analysis of prospectively collected data (Cleveland Family Study), Doufas et al45 demonstrated that intermittent hypoxia was significantly associated with increased pain in patients with OSA; these findings were independent of sleep fragmentation and systemic inflammation, as measured by PSG and serum cytokines.45 More specifically, a decrease in the nocturnal nadir SpO2 from 92% to 75% approximately doubled the odds for reporting pain in patients with OSA, rendering recurrent hypoxemia a potential risk marker for enhanced pain behavior. However, Turan et al50 showed that opioid consumption after bariatric surgery was significantly reduced in OSA patients with longer sleeping periods and nocturnal intermittent hypoxia.50
Chronic Sleep Fragmentation
Next to hypoxia, chronic sleep fragmentation has been implicated in enhancing pain behavior, as shown in patients with insomnia due to temporomandibular joint disorder and patients with primary insomnia who demonstrated hyperalgesia.49,68 In contrast, patients with OSA with temporomandibular joint disorder presented with hypoalgesia to experimental pain.49 Evidence from burn patients also supports an interaction between insomnia and pain, demonstrating that in hospitalized patients, insomnia symptoms and poor sleep quality were linked to higher pain intensity during the day.69,70 Consistent with these findings, Khalid et al46 showed that CPAP treatment, which improved ventilation and sleep continuity, reduced pain sensitivity in patients with OSA.
Ultimately, enhanced pain perception and augmented opioid potency modulated by intermittent hypoxia7,45,66 could be critical in the perioperative care of patients with OSA, as suggested by numerous investigators, including Brown et al.41,42,57 This group reported an association between preoperative hypoxemia severity and respiratory complications in pediatric patients with OSA.42 Accordingly, adopting a precautionary line of practice, the American Society of Anesthesiologists (ASA) has encouraged adjusting opioid dosing in pediatric patients who demonstrate hypoxemia.5
Therefore, the apparently poor association between AHI and hypoxia severity71 may indicate that AHI as a measure of OSA severity may not be optimal for the estimation of perioperative risk in adults,6 possibly rendering SpO2 a more accurate measure for perioperative risk stratification.1
In conclusion, evidence supporting changes in pain and opioid sensitivity7,11,40,41,44,46,47,49,50,72 imply that opioid and analgesic requirements could be substantially lower in patients with OSA. Therefore, careful titration of opioid analgesia and postoperative monitoring tailored to the individual risk profile seems prudent. More research, however, is needed to robustly establish drivers of pain and opioid sensitivity in OSA.
NEURAXIAL OPIOID ADMINISTRATION IN OSA
Evidence on the impact and safety of neuraxial opioid administration in patients with OSA is rather scarce and heterogeneous, while the differential role of either spinal or epidural opioid administration remains unstudied (Table 1).
In a systematic review including 5 studies, Orlov et al31 estimated an incidence of 4.1% for cardiorespiratory complications in surgical patients with OSA undergoing neuraxial anesthesia with opioids. However, the authors emphasized significant limitations related to this estimate, based on heterogeneity, imprecision, and lack of information on concomitant medications.31,73–77
Only a few other studies have investigated the safety of neuraxial opioid administration in the context of OSA.30,32,33 One randomized trial found that increased neuraxial opioid administration by intraoperative morphine loading did not improve postoperative analgesia but rather delayed ambulation and recovery in bariatric surgery.33 Others showed that in parturients receiving intrathecal morphine for cesarean delivery, OSA diagnosis by Berlin questionnaire and obesity were independently associated with increased odds for a SpO2 <90%.30 In contrast, among patients with joint arthroplasty receiving a multimodal pain regimen, including neuraxial anesthesia, no correlation was found between OSA (identified by patient records and screening questionnaires) and pulmonary complications after intrathecal morphine analgesia, potentially indicating a benefit of multimodal analgesia.32
Overall, as suggested by the ASA, a potentially greater risk for neuraxial OIRD in patients with OSA should be considered, with special attention given to signs of adverse effects after opioid administration.78 Preventive measures of OIRD after neuraxial opioid administration include careful decisions regarding opioid dose, type, and administration modality, such as single-injection neuraxial or continuous epidural opioids versus parenteral opioids, neuraxial fentanyl or sufentanil administration versus morphine, or continuous neuraxial opioids versus parenteral opioids. In any case, patients receiving neuraxial opioids should be continuously monitored for adequacy of ventilation (eg, respiratory rate, depth of respiration), oxygenation (eg, pulse oximetry when appropriate), and level of consciousness.78
POSTOPERATIVE MONITORING TO PREVENT OIRD
Postoperative monitoring may allow for early detection of potentially dangerous or even fatal events. It may also enable risk stratification of patients with OSA in need of extended care.79,80
Besides the effect of opioids and sedatives on upper airway muscle tone and ventilation responsiveness, lack of monitoring has been found to be a risk factor or cause for critical life-threatening and fatal postoperative outcome in OSA.18,21,23 Particularly, patients with OSA with a high arousal threshold appear to be susceptible to OIRD and respiratory arrest in an unmonitored environment.23,81 Postoperative complications directly related to OSA are also increasingly recognized in the legal arena, with inadequate monitoring deemed causative in a significant proportion.16,54,82
Postoperative patients with confirmed or suspected OSA may, according to some reports, be admitted to a fully monitored care environment with continuous ventilatory and cardiac surveillance.83,84 The ASA recommends continuous pulse oximetry monitoring and supplemental oxygen use after discharge from the recovery room in patients at increased risk of respiratory compromise from OSA until baseline oxygen saturation can be maintained at room air.5,85 This can be facilitated in critical care units, in stepdown units, or on routine hospital wards by telemetry and observation.5,86 The ASA guidelines also recommend nonsupine positioning during recovery and the consideration of CPAP or noninvasive positive pressure ventilation in severe airway obstruction.5 Monitoring recommendations, however, are independent of CPAP use, given the uncertainty of compliance.86 Other critical factors in the context of reducing the postoperative risk for OIRD include the avoidance of premature extubation87 and repeated assessment of sedation levels.18 While continuous monitoring in OSA is strongly supported,13,84 population-based data indicate limited implementation of postoperative oximetry and supplemental oxygen therapy on a national level.88 This could reflect the scarcity of institutional policies,89,90 challenges in clinical feasibility, and resource availability, as well as lack of evidence on the efficacy of costly monitoring interventions. For instance, despite the conventional use of pulse oximetry, a significant body of evidence supports the use of capnography, measuring end-tidal carbon dioxide partial pressure as a more accurate and sensitive indicator for respiratory depression.84,91 Nevertheless, postoperative capnography use is relatively rare given the advanced training requirement for accurate interpretation in the absence of a secured airway.82,92 New technologies, such as a recently presented impedance-based, noninvasive respiratory volume monitor with accurate real-time measurement of postoperative ventilation parameters could emerge as clinically feasible for OIRD prevention in OSA.93 Overall, health care institutions aim to avoid patient harm with appropriate utilization of resources. While prevention of complications through monitoring may be less costly per patient compared to complication management, it should be noted that current preoperative OSA screening tools have high false-positive rates, potentially promoting the waste of resources as systems allocate funds to enhanced monitoring and treatment of patients truly at increased risk for OSA-related complications.82 Moreover, poor specificity of monitoring alarms can lead to hazardous alarm fatigue, labor burden, and patient unrest.82 Therefore, further research is critical to allow accurate risk stratification of suspected or verified patients with OSA at genuine postoperative risk and to provide evidence-based guidance on the optimal level and duration of individual monitoring requirements.23,82,84 Nevertheless, the risk of postoperative opioid use35 must be carefully weighed against the benefits of pain relief on an individual basis.5,84,94
OPIOID DOSE REDUCTION IN OSA
Opioid effects in patients with OSA have also been indirectly demonstrated by studies reporting outcomes in patients randomized to opioid dose-reducing interventions (Table 1).
Abdelmageed et al34 randomized 39 PSG-confirmed patients with OSA undergoing uvulopalatopharyngoplasty to dexmedetomidine versus placebo in addition to postoperative intravenous morphine titration and subsequent PCA. Patients with dexmedetomidine required 53% less morphine in the first 24 hours, expressed significantly lower pain scores, and experienced a longer time to first analgesic request. Concurrent with opioid dose reduction, dexmedetomidine use caused a significantly lower incidence of oxyhemoglobin desaturation and bradypnea. While supporting the use of dexmedetomidine,95–97 these findings, in particular, indicate an opioid dose-dependent detrimental outcome on respiration in patients with OSA.34
An association between opioid use and impaired respiratory function was also demonstrated by Blake et al,35 who randomized 62 clinically assessed patients with OSA to standard morphine PCA versus an opioid-sparing protocol, showing that postoperative morphine dose was significantly associated with central apnea respiratory events.
In the context of avoiding opioids for postoperative analgesia, Lee et al36 showed that randomization to ketorolac versus oral mefenamic acid/intramuscular meperidine conferred noninferior postoperative wound pain alleviation and physical activity, as well as patient satisfaction in PSG-confirmed patients with OSA.36
PAIN MANAGEMENT AFTER UVULOPALATOPHARYNGOPLASTY IN OSA
In the context of increasing perioperative safety in OSA, surgical interventions of uvulopalatopharyngoplasty, which are associated with significant postoperative pain, have proven suitable for the study of opioid effects in OSA. However, they are not without the caveat of dealing with an anatomically and functionally impaired airway inherent to the surgical intervention.39,98
Thus, butorphanol, a synthetic opioid-agonist-antagonist with 5-fold greater analgesic potency and a lower incidence of postoperative nausea and vomiting than morphine due to its antagonistic effect, has recently gained interest in uvulopalatopharyngoplasty.99,100 Butorphanol can be administered intravenously, intramuscularly, or intranasally for moderate to severe pain, while it appears to lack OIRD due to its ceiling effect on respiration.101
Yang et al39 recently found that in elderly PSG-verified patients with OSA randomized to 4 different modalities of preemptive opioid analgesia, including intranasal or intravenous butorphanol, intranasal fentanyl, and placebo (intravenous saline), all tested interventions decreased pain, opioid requirement, and postanesthesia care unit stay. Intranasal butorphanol, however, was superior to all other interventions with regard to reducing pain and opioid consumption and decreasing postoperative cognitive dysfunction. Reasons could include higher bioavailability of nasal butorphanol and potentially the impact of reduced opioid utilization on cognitive function.102
Advantages of intranasal butorphanol, compared to other conventional opioid analgesic modes, have also been suggested by others when studying patients with OSA undergoing uvulopalatopharyngoplasty (Table 1).36–38,103
This systematic review demonstrates the existence of a growing body of evidence addressing opioid effects in patients with OSA while supporting a heightened level of concern regarding the occurrence of OIRD and serious adverse outcome in the postoperative setting.
While there is a lack of high-quality randomized evidence on the effect of acute opioid analgesia in OSA,29 the current body of evidence is largely based on relatively heterogeneous observational studies, including case-control analyses and case reports.76,104 Given the nature of this health care matter, most studies are burdened by high risk of bias and heterogeneity due to the involvement of multiple unaccounted drugs, the presence of various perioperative potentially confounding interventions within a cohort (ie, CPAP), and differences in OSA assessment, severity, and related comorbidities. Inconsistencies are also prevalent between studies, based on differences in comparators and outcome definitions, while evidence involving direct comparisons between patients with and without OSA is generally rare. These factors reflect the complexities of study design and interpretation in this subject matter and impede robust conventional analysis to provide precise quantitative estimates of effect for important patient outcomes. Furthermore, the general tendency of underreporting of adverse events in the medical literature poses a significant limitation in observational analyses, bearing the risk for systematic underestimation or overestimation of true effects when trying to establish accurate risk estimates.105–107
Despite these limitations, a growing body of evidence consistently supports a detrimental impact of opioids in patients with OSA, thus raising the level of concern for the occurrence of life-threatening OIRD in the perioperative setting even at the administration of typical or lower opioid dose levels.
The intrinsic ability of opioids to suppress central respiratory drive and induce a monotonous respiratory pattern clearly provides the grounds for concern for exaggerated respiratory compromise in OSA.108 Although OSA implies vulnerability to the potent respiratory depressant effects of opioids, which are known to depress pharyngeal muscle activity and promote airway collapse leading up to airway obstruction, hypoxemia, and even death due to asphyxia,40,78,109–111 the effect of opioids may be determined by underlying OSA phenotypes expressed in each particular patient (ie, airway muscle responsiveness, ventilatory control and chemoreflexes responsiveness, and arousal threshold).112–114
The initial 24 hours after opioid administration appear to be the most critical,18,19,21 rendering patients most receptive to respiratory insufficiency during this period.21,115 The postoperative period is marked by changes in sleep architecture, increased pain severity, and high analgesic requirement, resulting in worsening of sleep-disordered breathing. Opioids may play a significant role in the postoperative worsening of OSA.27,28,109
Other noteworthy implications relate to potential increase in pain perception due to chronic sleep fragmentation and enhanced opioid sensitivity possibly due to upregulation of opioid receptors by recurrent hypoxia.41,64 Thus, changes in drug response may predispose patients with OSA to a higher risk of OIRD without overdosing.78,116 Death from opioids often occurs during sleep when breathing is primarily regulated by autonomic neurochemical control.117 Due to potential changes in pain and opioid sensitivity, the severity of OSA may be a factor of greater importance besides opioid dose.22
In conclusion, while more research is needed, retrospective analyses suggest that opioid-related serious adverse events may be largely preventable with a more cautious approach to opioid use. This includes the utilization of multimodal analgesia to reduce opioid requirement, caution, or avoidance of concurrent administration of sedatives and opioids by multiple pathways (eg, PCA plus background infusion). Moreover, adequate monitoring of ventilation, repeated assessment of sedation levels, and early response to emerging events present critical measures in the context of reducing postoperative risk in patients with OSA.5,18,19
The authors express special thanks to the following participants in alphabetical order for their significant contribution in the systematic literature search and the process of full-text extraction:
Marina Englesakis, Library and Information Services, University Health Network, University of Toronto, Toronto, ON, Canada;
Rie Goto, Kim Barrett Memorial Library, Hospital for Special Surgery, New York, NY;
Bridget Jivanelli, Kim Barrett Memorial Library, Hospital for Special Surgery, New York, NY.
Name: Crispiana Cozowicz, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Conflicts of Interest: None.
Name: Frances Chung, MBBS, FRCPC.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Conflicts of Interest: F. Chung received research grants from Ontario Ministry of Health and Long-Term Care Innovation Fund, University Health Network Foundation, ResMed Foundation, Acacia Pharma and Medtronics Inc. STOP-Bang tool: proprietary to University Health Network, royalties from Up-To-Date.
Name: Anthony G. Doufas, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Conflicts of Interest: None.
Name: Mahesh Nagappa, MD.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Conflicts of Interest: None.
Name: Stavros G. Memtsoudis, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Conflicts of Interest: S. G. Memtsoudis is a director on the boards of the American Society of Regional Anesthesia and Pain Medicine (ASRA) and the Society of Anesthesia and Sleep Medicine (SASM). He is a 1-time consultant for Sandoz Inc and the holder US Patent Multicatheter Infusion System. US-2017-0361063. He is the owner of SGM Consulting, LLC and co-owner of FC Monmouth, LLC. None of the above relations influenced the conduct of the present study.
This manuscript was handled by: David Hillman, MD.
1. Lam KK, Kunder S, Wong J, Doufas AG, Chung F. Obstructive sleep apnea, pain, and opioids: is the riddle solved? Curr Opin Anaesthesiol. 2016;29:134–140.
2. Kaw R, Chung F, Pasupuleti V, Mehta J, Gay PC, Hernandez AV. Meta-analysis of the association between obstructive sleep apnoea and postoperative outcome. Br J Anaesth. 2012;109:897–906.
3. Chung F, Memtsoudis S, Krishna Ramachandran S, et al. Society of anesthesia and sleep medicine guideline on preoperative screening and assessment of patients with obstructive sleep apnea. Anesth Analg. 2016;123:452–473.
4. Opperer M, Cozowicz C, Bugada D, et al. Does obstructive sleep apnea influence perioperative outcome? A qualitative systematic review for the Society of Anesthesia and Sleep Medicine Task Force on Preoperative Preparation of Patients With Sleep-Disordered Breathing. Anesth Analg. 2016;122:1321–1334.
5. Gross JB, Apfelbaum JL, Caplan RA, et al. Practice guidelines for the perioperative management of patients with obstructive sleep apnea an updated report by the American Society of Anesthesiologists Task Force on Perioperative Management of Patients with Obstructive Sleep Apnea. Anesthesiology. 2014;120:268–286.
6. Gross JB, Bachenberg KL, Benumof JL, et al.; American Society of Anesthesiologists Task Force on Perioperative Management. Practice guidelines for the perioperative management of patients with obstructive sleep apnea: a report by the American Society of Anesthesiologists Task Force on Perioperative Management of patients with obstructive sleep apnea. Anesthesiology. 2006;104:1081–1093.
7. Doufas A. Obstructive sleep apnea, pain, and opioid analgesia in the postoperative patient. Curr Anesthesiol Rep. 2014;4:1–9.
8. Innovation VH. Covidence systematic review software. Melbourne, Australia. Available at: https://www.covidence.org
. Accessed June 2, 2018.
9. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383–394.
10. Group OLoEW. The Oxford 2011 Levels of Evidence. Oxford Centre for Evidence-Based Medicine. Available at: www.cebm.net/index.aspx?o=5653
. Accessed June 2, 2018.
11. Ahmad S, Nagle A, McCarthy RJ, Fitzgerald PC, Sullivan JT, Prystowsky J. Postoperative hypoxemia in morbidly obese patients with and without obstructive sleep apnea undergoing laparoscopic bariatric surgery. Anesth Analg. 2008;107:138–143.
12. Blake DW, Chia PH, Donnan G, Williams DL. Preoperative assessment for obstructive sleep apnoea and the prediction of postoperative respiratory obstruction and hypoxaemia. Anaesth Intensive Care. 2008;36:379–384.
13. Bolden N, Smith CE, Auckley D, Makarski J, Avula R. Perioperative complications during use of an obstructive sleep apnea protocol following surgery and anesthesia. Anesth Analg. 2007;105:1869–1870.
14. Esclamado RM, Glenn MG, McCulloch TM, Cummings CW. Perioperative complications and risk factors in the surgical treatment of obstructive sleep apnea syndrome. Laryngoscope. 1989;99:1125–1129.
15. Etches RC. Respiratory depression associated with patient-controlled analgesia: a review of eight cases. Can J Anaesth. 1994;41:125–132.
16. Fouladpour N, Jesudoss R, Bolden N, Shaman Z, Auckley D. Perioperative complications in obstructive sleep apnea patients undergoing surgery: a review of the legal literature. Anesth Analg. 2016;122:145–151.
17. Khanna AK, Sessler DI, Sun Z, et al. Using the STOP-BANG questionnaire to predict hypoxaemia in patients recovering from noncardiac surgery: a prospective cohort analysis. Br J Anaesth. 2016;116:632–640.
18. Lee LA, Caplan RA, Stephens LS, et al. Postoperative opioid-induced respiratory depression: a closed claims analysis. Anesthesiology. 2015;122:659–665.
19. Melamed R, Boland LL, Normington JP, et al. Postoperative respiratory failure necessitating transfer to the intensive care unit in orthopedic surgery patients: risk factors, costs, and outcomes. Perioper Med (Lond). 2016;5:19.
20. Mörwald EE, Olson A, Cozowicz C, Poeran J, Mazumdar M, Memtsoudis SG. Association of opioid prescription and perioperative complications in obstructive sleep apnea patients undergoing total joint arthroplasties. Sleep Breath. 2018;22:115–121.
21. Ramachandran SK, Haider N, Saran KA, et al. Life-threatening critical respiratory events: a retrospective study of postoperative patients found unresponsive during analgesic therapy. J Clin Anesth. 2011;23:207–213.
22. Ramachandran SK, Pandit J, Devine S, Thompson A, Shanks A. Postoperative respiratory complications in patients at risk for obstructive sleep apnea: a single-institution cohort study. Anesth Analg. 2017;125:272–279.
23. Subramani Y, Nagappa M, Wong J, Patra J, Chung F. Death or near-death in patients with obstructive sleep apnoea: a compendium of case reports of critical complications. Br J Anaesth. 2017;119:885–899.
24. Weingarten TN, Herasevich V, McGlinch MC, et al. Predictors of delayed postoperative respiratory depression assessed from naloxone administration. Anesth Analg. 2015;121:422–429.
25. Weingarten TN, Hawkins NM, Beam WB, et al. Factors associated with prolonged anesthesia recovery following laparoscopic bariatric surgery: a retrospective analysis. Obes Surg. 2015;25:1024–1030.
26. Weingarten TN, Chong EY, Schroeder DR, Sprung J. Predictors and outcomes following naloxone administration during phase I anesthesia recovery. J Anesth. 2016;30:116–122.
27. Bernards CM, Knowlton SL, Schmidt DF, et al. Respiratory and sleep effects of remifentanil in volunteers with moderate obstructive sleep apnea. Anesthesiology. 2009;110:41–49.
28. Chung F, Liao P, Elsaid H, Shapiro CM, Kang W. Factors associated with postoperative exacerbation of sleep-disordered breathing. Anesthesiology. 2014;120:299–311.
29. Wang D, Somogyi AA, Yee BJ, et al. The effects of a single mild dose of morphine on chemoreflexes and breathing in obstructive sleep apnea. Respir Physiol Neurobiol. 2013;185:526–532.
30. Ladha KS, Kato R, Tsen LC, Bateman BT, Okutomi T. A prospective study of post-cesarean delivery hypoxia after spinal anesthesia with intrathecal morphine 150 μg. Int J Obstet Anesth. 2017;32:48–53.
31. Orlov D, Ankichetty S, Chung F, Brull R. Cardiorespiratory complications of neuraxial opioids in patients with obstructive sleep apnea: a systematic review. J Clin Anesth. 2013;25:591–599.
32. Thompson MJ, Clinger BN, Simonds RM, Hochheimer CJ, Lahaye LA, Golladay GJ. Probability of undiagnosed obstructive sleep apnea does not correlate with adverse pulmonary events nor length of stay in hip and knee arthroplasty using intrathecal opioid. J Arthroplasty. 2017;32:2676–2679.
33. Zotou A, Siampalioti A, Tagari P, Paridis L, Kalfarentzos F, Filos KS. Does epidural morphine loading in addition to thoracic epidural analgesia benefit the postoperative management of morbidly obese patients undergoing open bariatric surgery? A pilot study. Obes Surg. 2014;24:2099–2108.
34. Abdelmageed WM, Elquesny KM, Shabana RI, Abushama HM, Nassar AM. Analgesic properties of a dexmedetomidine infusion after uvulopalatopharyngoplasty in patients with obstructive sleep apnea. Saudi J Anaesth. 2011;5:150–156.
35. Blake DW, Yew CY, Donnan GB, Williams DL. Postoperative analgesia and respiratory events in patients with symptoms of obstructive sleep apnoea. Anaesth Intensive Care. 2009;37:720–725.
36. Lee LA, Wang PC, Chen NH, et al. Alleviation of wound pain after surgeries for obstructive sleep apnea. Laryngoscope. 2007;117:1689–1694.
37. Huang HC, Lee LA, Fang TJ, Li HY, Lo CC, Wu JH. Transnasal butorphanol for pain relief after uvulopalatopharyngoplasty: a hospital-based, randomized study. Chang Gung Med J. 2009;32:390–399.
38. Madani M. Effectiveness of Stadol NS (butorphanol tartrate) with ibuprofen in the treatment of pain after laser-assisted uvulopalatopharyngoplasty. J Oral Maxillofac Surg. 2000;58:27–31.
39. Yang L, Sun DF, Wu Y, Han J, Liu RC, Wang LJ. Intranasal administration of butorphanol benefits old patients undergoing H-uvulopalatopharyngoplasty: a randomized trial. BMC Anesthesiol. 2015;15:20.
40. Brown KA, Laferrière A, Lakheeram I, Moss IR. Recurrent hypoxemia in children is associated with increased analgesic sensitivity to opiates. Anesthesiology. 2006;105:665–669.
41. Brown KA, Laferrière A, Moss IR. Recurrent hypoxemia in young children with obstructive sleep apnea is associated with reduced opioid requirement for analgesia. Anesthesiology. 2004;100:806–810.
42. Brown KA, Morin I, Hickey C, Manoukian JJ, Nixon GM, Brouillette RT. Urgent adenotonsillectomy: an analysis of risk factors associated with postoperative respiratory morbidity. Anesthesiology. 2003;99:586–595.
43. Chung F, Liao P, Yegneswaran B, Shapiro CM, Kang W. Postoperative changes in sleep-disordered breathing and sleep architecture in patients with obstructive sleep apnea. Anesthesiology. 2014;120:287–298.
44. Doufas AG, Tian L, Padrez KA, et al. Experimental pain and opioid analgesia in volunteers at high risk for obstructive sleep apnea. PLoS One. 2013;8:e54807.
45. Doufas AG, Tian L, Davies MF, Warby SC. Nocturnal intermittent hypoxia is independently associated with pain in subjects suffering from sleep-disordered breathing. Anesthesiology. 2013;119:1149–1162.
46. Khalid I, Roehrs TA, Hudgel DW, Roth T. Continuous positive airway pressure in severe obstructive sleep apnea reduces pain sensitivity. Sleep. 2011;34:1687–1691.
47. Sadhasivam S, Chidambaran V, Ngamprasertwong P, et al. Race and unequal burden of perioperative pain and opioid related adverse effects in children. Pediatrics. 2012;129:832–838.
48. Sanders JC, King MA, Mitchell RB, Kelly JP. Perioperative complications of adenotonsillectomy in children with obstructive sleep apnea syndrome. Anesth Analg. 2006;103:1115–1121.
49. Smith MT, Wickwire EM, Grace EG, et al. Sleep disorders and their association with laboratory pain sensitivity in temporomandibular joint disorder. Sleep. 2009;32:779–790.
50. Turan A, You J, Egan C, et al. Chronic intermittent hypoxia is independently associated with reduced postoperative opioid consumption in bariatric patients suffering from sleep-disordered breathing. PLoS One. 2015;10:e0127809.
51. Tsai WH, Remmers JE, Brant R, Flemons WW, Davies J, Macarthur C. A decision rule for diagnostic testing in obstructive sleep apnea. Am J Respir Crit Care Med. 2003;167:1427–1432.
52. Sun Z, Sessler DI, Dalton JE, et al. Postoperative hypoxemia is common and persistent: a prospective blinded observational study. Anesth Analg. 2015;121:709–715.
53. Weingarten TN, Flores AS, McKenzie JA, et al. Obstructive sleep apnoea and perioperative complications in bariatric patients. Br J Anaesth. 2011;106:131–139.
54. Svider PF, Pashkova AA, Folbe AJ, et al. Obstructive sleep apnea: strategies for minimizing liability and enhancing patient safety. Otolaryngol Head Neck Surg. 2013;149:947–953.
55. Cozowicz C, Olson A, Poeran J, et al. Opioid prescription levels and postoperative outcomes in orthopedic surgery. Pain. 2017;158:2422–2430.
56. Rosenberg J, Wildschiødtz G, Pedersen MH, von Jessen F, Kehlet H. Late postoperative nocturnal episodic hypoxaemia and associated sleep pattern. Br J Anaesth. 1994;72:145–150.
57. Isono S, Sha M, Suzukawa M, et al. Preoperative nocturnal desaturations as a risk factor for late postoperative nocturnal desaturations. Br J Anaesth. 1998;80:602–605.
58. Lehman S, Antic NA, Thompson C, Catcheside PG, Mercer J, McEvoy RD. Central sleep apnea on commencement of continuous positive airway pressure in patients with a primary diagnosis of obstructive sleep apnea-hypopnea. J Clin Sleep Med. 2007;3:462–466.
59. Mason M, Cates CJ, Smith I. Effects of opioid, hypnotic and sedating medications on sleep-disordered breathing in adults with obstructive sleep apnoea. Cochrane Database Syst Rev. 2015:Cd011090.
60. Kehlet H. Manipulation of the metabolic response in clinical practice. World J Surg. 2000;24:690–695.
61. Epstein LJ, Kristo D, Strollo PJ Jr, et al.; Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009;5:263–276.
62. Rabbitts JA, Groenewald CB, Dietz NM, Morales C, Räsänen J. Perioperative opioid requirements are decreased in hypoxic children living at altitude. Paediatr Anaesth. 2010;20:1078–1083.
63. Laferrière A, Liu JK, Moss IR. Neurokinin-1 versus mu-opioid receptor binding in rat nucleus tractus solitarius after single and recurrent intermittent hypoxia. Brain Res Bull. 2003;59:307–313.
64. Moss IR, Laferrière A. Central neuropeptide systems and respiratory control during development. Respir Physiol Neurobiol. 2002;131:15–27.
65. Kajimura S, Aida K, Duan C. Insulin-like growth factor-binding protein-1 (IGFBP-1) mediates hypoxia-induced embryonic growth and developmental retardation. Proc Natl Acad Sci U S A. 2005;102:1240–1245.
66. Brown KA. Intermittent hypoxia and the practice of anesthesia. Anesthesiology. 2009;110:922–927.
67. Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45:27–37.
68. Haack M, Scott-Sutherland J, Santangelo G, Simpson NS, Sethna N, Mullington JM. Pain sensitivity and modulation in primary insomnia. Eur J Pain. 2012;16:522–533.
69. Raymond I, Nielsen TA, Lavigne G, Manzini C, Choinière M. Quality of sleep and its daily relationship to pain intensity in hospitalized adult burn patients. Pain. 2001;92:381–388.
70. Smith MT, Klick B, Kozachik S, et al. Sleep onset insomnia symptoms during hospitalization for major burn injury predict chronic pain. Pain. 2008;138:497–506.
71. Waters KA, McBrien F, Stewart P, Hinder M, Wharton S. Effects of OSA, inhalational anesthesia, and fentanyl on the airway and ventilation of children. J Appl Physiol (1985). 2002;92:1987–1994.
72. Sadhasivam S, Chidambaran V. Pharmacogenomics of opioids and perioperative pain management. Pharmacogenomics. 2012;13:1719–1740.
73. Berend KR, Ajluni AF, Núñez-García LA, Lombardi AV, Adams JB. Prevalence and management of obstructive sleep apnea in patients undergoing total joint arthroplasty. J Arthroplasty. 2010;25:54–57.
74. Kapala M, Meterissian S, Schricker T. Neuraxial anesthesia and intraoperative bilevel positive airway pressure in a patient with severe chronic obstructive pulmonary disease and obstructive sleep apnea undergoing elective sigmoid resection. Reg Anesth Pain Med. 2009;34:69–71.
75. Parikh SN, Stuchin SA, Maca C, Fallar E, Steiger D. Sleep apnea syndrome in patients undergoing total joint arthroplasty. J Arthroplasty. 2002;17:635–642.
76. Ostermeier AM, Roizen MF, Hautkappe M, Klock PA, Klafta JM. Three sudden postoperative respiratory arrests associated with epidural opioids in patients with sleep apnea. Anesth Analg. 1997;85:452–460.
77. Pellecchia DJ, Bretz KA, Barnette RE. Postoperative pain control by means of epidural narcotics in a patient with obstructive sleep apnea. Anesth Analg. 1987;66:280–282.
78. Horlocker TT, Burton AW, Connis RT, et al. Practice guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration. Anesthesiology. 2009;110:218–230.
79. de Lacy J, Miller-Burnett M, Bonsell P, Stith K, Sanchez S. Implementation of an innovative postoperative monitoring approach for patients with obstructive sleep apnea. Healthc Manage Forum. 2014;27:S6–S16.
80. Gali B, Whalen FX, Schroeder DR, Gay PC, Plevak DJ. Identification of patients at risk for postoperative respiratory complications using a preoperative obstructive sleep apnea screening tool and postanesthesia care assessment. Anesthesiology. 2009;110:869–877.
81. Lynn LA, Curry JP. Patterns of unexpected in-hospital deaths: a root cause analysis. Patient Saf Surg. 2011;5:3.
82. Ayas NT, Laratta CR, Coleman JM, et al.; ATS Assembly on Sleep and Respiratory Neurobiology. Knowledge gaps in the perioperative management of adults with obstructive sleep apnea and obesity hypoventilation syndrome: an official American Thoracic Society workshop report. Ann Am Thorac Soc. 2018;15:117–126.
83. Benumof JL. Obstructive sleep apnea in the adult obese patient: implications for airway management. Anesthesiol Clin North America. 2002;20:789–811.
84. Gammon BT, Ricker KF. An evidence-based checklist for the postoperative management of obstructive sleep apnea. J Perianesth Nurs. 2012;27:316–322.
85. Weinger MB, Lee LA. No patient shall be harmed by opioid-induced respiratory depression. APsF Newsletter 2011;26:21–28.
86. de Raaff CAL, Gorter-Stam MAW, de Vries N, et al. Perioperative management of obstructive sleep apnea in bariatric surgery: a consensus guideline. Surg Obes Relat Dis. 2017;13:1095–1109.
87. Baluch A, Mahbubani S, Al-Fadhli F, Kaye AD, Kaye A, Frost EA. Anesthetic care of the patient with obstructive sleep apnea. Middle East J Anaesthesiol. 2009;20:143–152.
88. Cozowicz C, Poeran J, Olson A, Mazumdar M, Mörwald EE, Memtsoudis SG. Trends in perioperative practice and resource utilization in patients with obstructive sleep apnea undergoing joint arthroplasty. Anesth Analg. 2017;125:66–77.
89. Turner K, VanDenkerkhof E, Lam M, Mackillop W. Perioperative care of patients with obstructive sleep apnea: a survey of Canadian anesthesiologists. Can J Anaesth. 2006;53:299–304.
90. Auckley D, Cox R, Bolden N, Thornton JD. Attitudes regarding perioperative care of patients with OSA: a survey study of four specialties in the United States. Sleep Breath. 2015;19:315–325.
91. McCarter T, Shaik Z, Scarfo K, Thompson LJ. Capnography monitoring enhances safety of postoperative patient-controlled analgesia. Am Health Drug Benefits. 2008;1:28–35.
92. Kasuya Y, Akça O, Sessler DI, Ozaki M, Komatsu R. Accuracy of postoperative end-tidal Pco2
measurements with mainstream and sidestream capnography in non-obese patients and in obese patients with and without obstructive sleep apnea. Anesthesiology. 2009;111:609–615.
93. Schumann R, Kwater AP, Bonney I, et al. Respiratory volume monitoring in an obese surgical population and the prediction of postoperative respiratory depression by the STOP-bang OSA risk score. J Clin Anesth. 2016;34:295–301.
94. Roop K. What are the post-op risks in patients who have obstructive sleep apnea? To what extent are patients with obstructive sleep apnea syndrome (OSAS) at increased risk for postoperative complications? Are there any specific interventions that reduce the risks? J Respir Dis. 2008;29:389.
95. Venn RM, Hell J, Grounds RM. Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care. Crit Care. 2000;4:302–308.
96. Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg. 2004;98:153–158.
97. Lin TF, Yeh YC, Lin FS, et al. Effect of combining dexmedetomidine and morphine for intravenous patient-controlled analgesia. Br J Anaesth. 2009;102:117–122.
98. Hendolin H, Kansanen M, Koski E, Nuutinen J. Propofol-nitrous oxide versus thiopentone-isoflurane-nitrous oxide anaesthesia for uvulopalatopharyngoplasty in patients with sleep apnea. Acta Anaesthesiol Scand. 1994;38:694–698.
99. Gilbert MS, Hanover RM, Moylan DS, Caruso FS. Intramuscular butorphanol and meperidine in postoperative pain. Clin Pharmacol Ther. 1976;20:359–364.
100. Du BX, Song ZM, Wang K, et al. Butorphanol prevents morphine-induced pruritus without increasing pain and other side effects: a systematic review of randomized controlled trials. Can J Anaesth. 2013;60:907–917.
101. Talbert RL, Peters JI, Sorrells SC, Simmons RS. Respiratory effects of high-dose butorphanol. Acute Care. 1988;12(suppl 1):47–56.
102. Añez Simón C, Rull Bartomeu M, Rodríguez Pérez A, Fuentes Baena A. Intranasal opioids for acute pain. Rev Esp Anestesiol Reanim. 2006;53:643–652.
103. Cannon CR. Transnasal butorphanol: pain relief in the head and neck patient. Otolaryngol Head Neck Surg. 1997;116:197–200.
104. Bolden N, Smith CE, Auckley D. Avoiding adverse outcomes in patients with obstructive sleep apnea (OSA): development and implementation of a perioperative OSA protocol. J Clin Anesth. 2009;21:286–293.
105. Kaldjian LC, Jones EW, Rosenthal GE. Facilitating and impeding factors for physicians’ error disclosure: a structured literature review. Jt Comm J Qual Patient Saf. 2006;32:188–198.
106. Kaldjian LC, Jones EW, Rosenthal GE, Tripp-Reimer T, Hillis SL. An empirically derived taxonomy of factors affecting physicians’ willingness to disclose medical errors. J Gen Intern Med. 2006;21:942–948.
107. Leape LL. Reporting of adverse events. N Engl J Med. 2002;347:1633–1638.
108. Taylor JM, Gropper MA. Critical care challenges in orthopedic surgery patients. Crit Care Med. 2006;34:S191–S199.
109. Benumof JL. Obstructive sleep apnea in the adult obese patient: implications for airway management. J Clin Anesth. 2001;13:144–156.
110. Catley DM, Thornton C, Jordan C, Lehane JR, Royston D, Jones JG. Pronounced, episodic oxygen desaturation in the postoperative period: its association with ventilatory pattern and analgesic regimen. Anesthesiology. 1985;63:20–28.
111. Robinson RW, Zwillich CW, Bixler EO, Cadieux RJ, Kales A, White DP. Effects of oral narcotics on sleep-disordered breathing in healthy adults. Chest. 1987;91:197–203.
112. Eckert DJ. Phenotypic approaches to obstructive sleep apnoea: new pathways for targeted therapy. Sleep Med Rev. 2018;37:45–59.
113. Subramani Y, Singh M, Wong J, Kushida CA, Malhotra A, Chung F. Understanding phenotypes of obstructive sleep apnea: applications in anesthesia, surgery, and perioperative medicine. Anesth Analg. 2017;124:179–191.
114. Doufas AG. Opioids and sleep-disordered breathing. ASA Newsl. 2017;81:24–26.
115. Taylor S, Kirton OC, Staff I, Kozol RA. Postoperative day one: a high risk period for respiratory events. Am J Surg. 2005;190:752–756.
116. Overdyk F, Dahan A, Roozekrans M, van der Schrier R, Aarts L, Niesters M. Opioid-induced respiratory depression in the acute care setting: a compendium of case reports. Pain Manag. 2014;4:317–325.
117. Caplehorn JR, Drummer OH. Mortality associated with New South Wales methadone programs in 1994: lives lost and saved. Med J Aust. 1999;170:104–109.
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