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Sleep-disordered breathing in patients chronically using opioids

Sleep-disordered breathing in patients chronically using opioids
Author:
Shirin Shafazand, MD, MS, FRCP(C), FCCP, FAASM
Section Editor:
M Safwan Badr, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: Aug 17, 2022.

INTRODUCTION — Prescription opioid use for chronic non-cancer pain has increased dramatically over the past two decades. Although the prevalence and impact of respiratory depression due to opioids were at one time de-emphasized [1], there is now a growing appreciation for the adverse effects of chronic opioid use, including increased mortality [2]. Emerging data also suggest that there is an increased incidence of sleep-disordered breathing (SDB) with chronic opioid use, with possible negative consequences.

Given the relatively high prevalence of both obstructive sleep apnea (OSA) and chronic pain in the general population, clinicians are likely to encounter patients with pre-existing or undiagnosed OSA who are using opioids for chronic pain. Awareness of the sleep and respiratory effects of chronic opioid use is essential in the safe management of these patients [3].

The effects of chronic opioid use on sleep architecture and respiration during sleep, and the diagnosis and treatment of opioid-associated SDB are reviewed here. Acute opioid use and its impact on patients with OSA in the perioperative setting are discussed separately. The respiratory and other effects of acute opioid intoxication are also reviewed separately. (See "Surgical risk and the preoperative evaluation and management of adults with obstructive sleep apnea" and "Intraoperative management of adults with obstructive sleep apnea" and "Postoperative management of adults with obstructive sleep apnea" and "Acute opioid intoxication in adults".)

EFFECTS OF OPIOIDS ON SLEEP AND RESPIRATION

Sleep architecture — Limited data suggest that opioids are disruptive to sleep architecture, despite their sedative effects. Acute opioid use causes more frequent shifts in sleep states, increased arousals from sleep, an increase in non-rapid eye movement (NREM) stage 2 sleep, and reductions in total sleep time, amount of slow wave (stage N3) sleep, and rapid eye movement (REM) sleep [4]. (See "Stages and architecture of normal sleep".)

With chronic opioid use, there is a tendency for the percent time spent in REM and slow wave sleep to normalize, but there is an increase in daytime sleepiness and reported fatigue [5]. Withdrawal from chronic opioid use may lead to insomnia, increased arousals from sleep, and rebound in REM and slow wave sleep.

Respiratory control — The control of breathing during wakefulness is a complex interaction between central respiratory centers, central and peripheral chemoreceptors, and lung mechanical/stretch receptors, with input from voluntary behaviors and environmental stimuli. (See "Control of ventilation".)

During both wakefulness and REM sleep, control of breathing is primarily determined by the central respiratory centers and secondarily by metabolic controls of breathing, involving inputs from peripheral and central chemoreceptors that detect changes in carbon dioxide, oxygen levels, or pH. During NREM sleep, metabolic controls play an important role in respiration.

Variations in respiration occur during the course of normal sleep, many of which may be vulnerable to the effects of opioids.

During NREM sleep, breathing usually remains regular, with a small decrease in total minute ventilation related to a decrease in respiratory rate and a small decrease in tidal volume [6]. Respiratory drive in response to hypercapnia and activity in the accessory muscles of respiration are decreased, and activity in upper airway muscles is often reduced. This may increase upper airway resistance in normal individuals [7], but is thought to play a more important role in those predisposed to sleep-disordered breathing (SDB). (See "Pathophysiology of upper airway obstruction in obstructive sleep apnea in adults", section on 'Determinants of upper airway patency'.)

During REM sleep, breathing is irregular, with breath-to-breath variations in tidal volume. There may be significant hypercapnia seen in some individuals during REM, and an increase in upper airway resistance with diminished upper airway dilator muscle tone may occur. Additionally, minute ventilation depends largely on the diaphragm alone, as the accessory muscles of respiration become partially atonic during REM sleep, whereas the diaphragm is spared.

Acute and chronic administration of opioids may affect many of these processes during both wakefulness and sleep. Opioids decrease awake central respiratory drive, with a resultant decrease in tidal volume, respiratory rate, and minute ventilation. The central and peripheral responses to hypoxic and hypercapnic stimuli are diminished during wakefulness. Acutely, opioid administration has also been associated with increased upper airway resistance and rigidity of accessory muscles of respiration [6,8].

During sleep, the combination of physiologic changes in respiration and chronic opioid use can lead to significant alterations and irregularity in breathing. The exact mechanism of central apneas associated with chronic opioid use is unknown but may be due in part to the respiratory instability that is caused by reduced hypercarbic ventilatory drive and increased hypoxemic ventilatory drive [9,10].

There are fewer data on the long-term impact of chronic opioid use on respiratory and ventilatory parameters during wakefulness, and more research is needed to determine whether any of the changes are persistent or clinically significant. Hypoxemia and hypercarbia during wakefulness have been observed in some chronic opioid users.

PREVALENCE — Sleep-disordered breathing (SDB) is an umbrella term used to describe varying combinations of hypoventilation, obstructive apneas, central apneas, mixed apneas, and irregular breathing during sleep. (See "Polysomnography in the evaluation of sleep-disordered breathing in adults".)

Central sleep apnea (CSA) is the most common form of SDB in opioid users, although mixed patterns may occur and the quality of the data is limited. Most studies are small and consist of referral populations. In two studies that reported on the relative distribution of central versus obstructive apneas among chronic opioid users, CSA was four to six times more common than obstructive sleep apnea (60 versus 10 percent and 30 versus 8 percent) [11,12].

A systematic review on CSA and chronic opioid use identified eight studies comprising 560 patients [13]. In this review, the overall prevalence of SDB (defined as an apnea-hypopnea index [AHI] ≥5) ranged from 42 to 85 percent, with the highest estimate obtained in a cohort of patients specifically referred for evaluation of sleep apnea. The mean prevalence of CSA was 24 percent. In studies that reported the central sleep apnea index (CAI), the mean CAI ranged from 5 to 13 per hour [14].

In a study of 50 patients on long-term methadone maintenance therapy and matched controls, the mean AHI was significantly higher in patients on methadone (44 versus 30 per hour), and this was primarily due to an increase in central apneas (13 versus 2 per hour) [15]. The severity of central apneas correlated in part with methadone levels in blood, awake arterial carbon dioxide tension (PaCO2) levels, concomitant antidepressant use, reduced ventilatory response to hypercapnia, increased ventilator response to hypoxemia, and widened awake alveolar-arterial oxygen pressure gradients.

RISK FACTORS — Risk factors for sleep-disordered breathing (SDB) in patients chronically using opioids are not well established but appear to be largely distinct from classical risk factors for obstructive sleep apnea (OSA; eg, advancing age, obesity, male sex).

The most consistently identified risk factors are low to low-normal body mass index and daily dose of opioid [13,16,17]. In particular, daily doses greater than 200 mg morphine dose equivalents appear to confer higher risk [16]. SDB has been observed in stable patients enrolled in methadone maintenance programs as well as those receiving high potency opioids for management of cancer-related pain [8,15]. The type of opioid used appears to be less important than the morphine dose equivalent in conferring SDB risk.

Other risk factors identified in some but not all studies include concomitant antidepressant use and concomitant benzodiazepine use [14,15]. The concomitant use of gabapentinoids (gabapentin, pregabalin) and opioids has been associated with increased odds of opioid-related deaths [18]. While the underlying etiology is not clearly defined, this may in part be due to an increased risk of respiratory depression when the drugs are used together. The US Food and Drug Administration (FDA) has issued a warning about the co-prescription of opioids and gabapentinoids [19]. No data are available on the joint impact of opioids and gabapentin on breathing during sleep, but it is highly likely that the respiratory depression noted during sleep is even more pronounced in the setting of existing sleep apnea and may even contribute to the development of SDB in those without prior sleep apnea.

Some overlap with recognized risks factors for OSA does exist. In a study of over 330 patients seen at university-affiliated pain clinics, the two factors independently associated with increased risk of moderate-to-severe SDB were higher scores on the STOP-Bang questionnaire (a screening tool for OSA) and lower daytime oxyhemoglobin saturation (SpO2) [17].

CLINICAL FEATURES — The phenotype of sleep-disordered breathing (SDB) associated with chronic opioid use differs from central sleep apnea (CSA) due to other conditions. Abnormalities generally fall under three domains [13]:

Altered or irregular respiratory patterns, in particular ataxic breathing, also known as Biot's respiration. This pattern is characterized by breaths that are irregular in tidal volume and frequency, interspersed with central pauses (waveform 1).

Apneas and hypopneas, which are often predominantly central (waveform 2); prolonged obstructive hypopneas may also be seen (waveform 3).

Abnormalities in gas exchange (eg, hypoxemia, hypercarbia).

In one study of 98 patients with chronic pain, opioids were potentially responsible for hypoxemia (defined as oxygen saturation <90 percent) in 10 percent of patients during wakefulness [20]. Additionally, during sleep, 8 percent of patients exhibited hypoxemia not clearly related to apneas and hypopneas.

Irregular breathing patterns are particularly common during non-rapid eye movement (NREM) sleep. In one study, ataxic breathing was present in 70 percent of 50 patients on chronic opioid therapy during NREM sleep, including 92 percent of patients taking a daily morphine equivalent dose greater than 200 mg [14].

Daytime symptoms of SDB are variable and often nonspecific. Patients may have no complaints or they may report daytime sleepiness and fatigue, which may also be attributed to underlying disease, opioid use, or other medications. Nighttime sleep disturbances may be reported by the patient or a bed partner, or not at all.

DIAGNOSIS — Sleep-disordered breathing (SDB) among patients who use opioids is primarily a polysomnographic diagnosis, and disease severity is established based on a combination of polysomnogram (PSG) results and clinical symptoms.

Patient selection for polysomnography — Diagnosis of SDB in patients chronically using opioids requires a high index of suspicion and PSG, as there are few reliable symptoms during wakefulness, and central apneas or irregular breathing patterns during sleep may not be apparent to the patient or to a bed partner.

Off the available screening questionnaires for obstructive sleep apnea (OSA), higher scores on the STOP-BANG instrument have been shown, in a predictive model, to be associated with higher odds of SDB in patients who chronically use opioids [17]. However, use of the instrument has not been validated as a selection tool for PSG. Given this, patient selection for PSG is challenging. Adding to the uncertainty is the relative lack of outcome data in patients with opioid-associated SDB. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Screening questionnaires'.)

Until more data are available to guide clinical decision making, we suggest using a combination of clinical symptoms of disturbed sleep (eg, excessive daytime sleepiness, reports of poor sleep quality, frequent arousals from sleep), known risk factors for CSA in patients who chronically use opioids (eg, high daily opioid dose), and high-risk comorbid conditions (eg, heart failure, respiratory disease) to select patients for PSG. In practice, there should be a low threshold to obtain PSG in any patient on chronic opioid therapy who complains of excessive daytime sleepiness or any symptom of disturbed sleep, particularly when the daily morphine dose equivalent is greater than 200 mg, as the pretest probability of SDB in this population is quite high. (See 'Prevalence' above and 'Risk factors' above.)

In-laboratory attended PSG is the test of choice in this setting. Use of end-tidal or transcutaneous carbon dioxide monitoring during PSG is required to diagnose sleep-related hypoventilation. Home sleep apnea testing (HSAT) is not advised in cases of suspected opioid-related SDB, since the likelihood of central apneas is high and HSAT cannot reliably distinguish between obstructive and central apneas. (See "Central sleep apnea: Risk factors, clinical presentation, and diagnosis", section on 'Diagnostic evaluation' and "Polysomnography in the evaluation of sleep-disordered breathing in adults", section on 'Ventilation'.)

Diagnostic criteria — The International Classification of Sleep Disorders, third edition (ICSD-3) criteria for diagnosis of CSA due to opioids (or other medications or substances) require all of the following [21]:

The patient is taking an opioid or other respiratory depressant.

The patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia (difficulty initiating or maintaining sleep, frequent awakenings, or nonrestorative sleep).

PSG reveals ≥5 central apneas and/or central hypopneas per hour of sleep; the number of central apneas and/or central hypopneas is >50 percent of the total number of apneas and hypopneas; and there is no evidence of Cheyne-Stokes breathing. (See "Polysomnography in the evaluation of sleep-disordered breathing in adults".)

The disorder is not better explained by another current sleep disorder.

Diagnostic criteria for OSA in patients chronically using opioids are identical to those of the general population. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Diagnosis'.)

TREATMENT — Treatment of opioid-associated sleep-disordered breathing (SDB) involves lowering or eliminating the opioid dose, avoidance of concomitant medications that may worsen hypoxemia during sleep, and positive airway pressure (PAP) therapy in selected patients.

Lowering the opioid dose — Most data support a dose-response relationship between opioid daily dose and severity of sleep-disordered breathing (SDB) [13]. Therefore, lowering or eliminating the opioid dose should be considered first-line therapy, when possible. Consideration should be given to alternative non-opioid analgesics and other therapeutic pain control modalities. (See "Approach to the management of chronic non-cancer pain in adults".)

Concomitant drugs — Patients receiving opioids for chronic pain or those in methadone maintenance programs may also use other prescription medications, including benzodiazepines, antidepressants, and gabapentinoid drugs (eg, gabapentin, pregabalin), which can contribute to worsening hypoxemia and hypercarbia during sleep. In the setting of SDB, the doses of these medications should be reduced if possible when prescribed concomitantly with opioids [22].

Positive airway pressure therapy — There is scant direct evidence upon which to base treatment recommendations regarding PAP therapy for SDB in patients chronically using opioids. It is not entirely clear whether central apneas, in the absence of hypoxemia, have significant and long-term clinical effects in this patient population, and it is not known whether specific treatment of the central apneas will result in positive short- or long-term outcomes.

Treatment decisions must therefore be individualized based on disease severity, symptom severity, and patient willingness to accept PAP therapy. We typically suggest a trial of PAP therapy in patients with hypoxemia during sleep, those with moderate to severe SDB (apnea-hypopnea index [AHI] >15), and those with mild SDB (AHI 5 to 15) who also report poor sleep quality or nighttime sleep disturbances.

Although continuous positive airway pressure (CPAP) therapy is an effective first-line therapy for OSA, its effectiveness in the setting of opioid-induced SDB is less encouraging. Several small studies have shown that CPAP therapy eliminates the obstructive events but has minimal effect on ataxic breathing and hypoxemia, and may even worsen the central apnea associated with chronic opioid therapy [23-28]. Other PAP modalities such as rate-controlled bilevel PAP (BPAP) and adaptive servo-ventilation (ASV) may be more effective, but data are limited to small case series, and no trials have compared different modalities in patients with opioid-associated SDB [25,29,30].

A 2021 systemic review highlighted the paucity of evidence on the treatment of SDB associated with chronic opioid use but concluded that rate-controlled BPAP or ASV may be more effective than CPAP in normalizing the apnea-hypopnea index (AHI) [31]. None of the studies reported on long-term outcomes such as morbidity and mortality [31].

Of note, the SERVE-HF trial found that ASV increased cardiovascular and all-cause mortality in patients with CSA and heart failure with reduced ejection fraction (≤45 percent) [32]. Therefore, ASV should be avoided in the subset of patients with opioid-induced central apnea who have concomitant heart failure and reduced ejection fraction. (See "Central sleep apnea: Treatment", section on 'Patients with ejection fraction ≤45 percent'.)

PAP titration and mode selection in patients with opioid-induced SDB should be done in conjunction with an experienced sleep specialist. The particular PAP mode prescribed is best determined during overnight attended (in-laboratory) polysomnography (PSG). Titration is typically started with CPAP and then switched to ASV or BPAP with a back-up rate to eliminate observed respiratory events (apneas and hypopneas) and ensure adequate oxygenation. On occasion, a second night of PAP titration may be necessary. (See "Mode selection for positive airway pressure titration in adult patients with central sleep apnea syndromes", section on 'Patients with CSA and opioid use'.)

Supplemental oxygen — During in-laboratory PSG and titration, some patients have significant sleep-related hypoxemia (eg, baseline oxygen saturation <90 percent) that persists despite PAP therapy, with desaturations that are not clearly associated with apneas and hypopneas. In these patients, supplemental oxygen is typically administered along with PAP therapy in order to maintain oxygen saturation >90 percent during sleep. Oxygen alone (without PAP therapy) is not adequate therapy for opioid-associated SDB.

The cause of persistent sleep-related hypoxemia in these patients is presumed to be hypoventilation due to the opioids themselves in most cases. Further evaluation may be indicated if there is clinical suspicion for underlying lung or cardiac disease or if hypoxemia is also present during wakefulness.

The risk of oxygen-induced hypercapnia in patients with opioid-induced SDB is unknown. Noninvasive carbon dioxide monitoring is not routinely performed during PSG in adults but may be used if there is clinical concern for hypoventilation. (See "Polysomnography in the evaluation of sleep-disordered breathing in adults", section on 'Ventilation'.)

FOLLOW-UP AND MONITORING — Patients who are started on positive airway pressure (PAP) therapy should be monitored by the prescribing clinician, typically a sleep physician, within the first few weeks of initiation of therapy and at minimum once more during the first year, then at least yearly thereafter. Adherence to therapy should be objectively documented at each visit.

Repeat polysomnography (PSG) should be considered if opioid medication dose is increased, if the patient reports new clinical symptoms or sleep disturbance, and/or when PAP machine inquiry suggests residual apnea-hypopnea index (AHI) >5 and suboptimal therapy. (See "Management of obstructive sleep apnea in adults", section on 'Follow-up'.)

PROGNOSIS — The long-term effects of sleep-disordered breathing (SDB) in patients who chronically use opioids are not currently known. However, a robust body of literature in the general population indicates that patients with SDB, in particular obstructive sleep apnea (OSA), are at increased risk for a range of adverse outcomes, including impaired daytime function, accidents, cardiovascular morbidity, metabolic dysregulation, and all-cause mortality.

While more studies are needed, irregular or ataxic breathing has been shown to be a sensitive predictor of impending respiratory depression in adults and children, potentially explaining, at least in part, the increased mortality observed with chronic opioid use [33].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sleep-related breathing disorders in adults".)

SUMMARY AND RECOMMENDATIONS

Effects of opioids on sleep and breathing – Chronic opioid therapy is associated with significant alterations and irregularity in breathing during both sleep and wake in many patients. Sleep-disordered breathing (SDB) includes varying combinations of hypoventilation, obstructive and central apneas (waveform 2), mixed apneas, and irregular breathing patterns during sleep. (See 'Effects of opioids on sleep and respiration' above.)

The most common form of SDB associated with chronic opioid use is central sleep apnea (CSA), which is identified in approximately 25 percent of patients. (See 'Prevalence' above and 'Clinical features' above.)

Risk factors for SDB in patients with chronic opioid use – The two most consistently identified risk factors for SDB in patients who chronically use opioids are low to low-normal body mass index and daily dose of opioid, with a daily morphine dose equivalent >200 mg associated with highest risk. Low SpO2 has been associated with obstructive sleep apnea (OSA), and high daily morphine dose equivalent has been associated with CSA. (See 'Risk factors' above.)

Diagnosis – Diagnosis of SDB requires a high index of suspicion and observed polysomnography (PSG), as there are few reliable symptoms during wakefulness, and central apneas during sleep may not be apparent to the patient or to a bed partner.

PSG should be considered in any patient on chronic opioid therapy who complains of excessive daytime sleepiness or any symptom of disturbed sleep, particularly when the daily morphine dose equivalent is greater than 200 mg, as the pretest probability of SDB in this population is quite high. (See 'Diagnosis' above.)

Treatment

Medication adjustments – Lowering or eliminating the opioid dose is the preferred first-line therapy, when possible. Concomitant drugs that may be contributing to SDB, such as benzodiazepines, should also be decreased or discontinued. (See 'Lowering the opioid dose' above and 'Concomitant drugs' above.)

Positive airway pressure (PAP) therapy – PAP has been used in the treatment of opioid-induced SDB with varying success, but there are no agreed upon criteria for use of PAP in this setting. We suggest a trial of PAP in patients who have hypoxemia during sleep, moderate to severe SDB (apnea-hypopnea index [AHI] >15), or mild SDB (AHI 5 to 15) with reports of poor sleep quality or nighttime sleep disturbances (Grade 2C).

The decision to use continuous positive airway pressure (CPAP) versus rate controlled bilevel PAP (BPAP) or adaptive servo-ventilation (ASV) should be individualized at the time of PAP titration. In-laboratory titration is recommended and close clinical follow-up is necessary. (See 'Positive airway pressure therapy' above.)

Role of supplemental oxygen – In addition to PAP therapy, patients with significant hypoxemia during sleep (ie, persistent baseline oxygen saturation <90 percent despite PAP therapy, desaturations not clearly associated with apneas and hypopneas) are generally treated with oxygen to maintain oxygen saturation >90 percent. (See 'Supplemental oxygen' above.)

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