Opioids and Respiratory Related Consequences

Introduction:

Opioids have been used for thousands of years ¹. Although exact origins are opaque, opium was likely to have been initially isolated from poppy plants in ancient Sumer (now Iraq). Opium was used in religious rituals and for pleasure, but also employed in a medical fashion for pain and for euthanasia. Trade brought opium to Europe, India, and China, and with the drug came widespread recognition of issues of tolerance, addiction, and abuse. In 1806, Serturmer extracted the active ingredient in opium and named it morphine after the god of dreams, Morpheus. By the mid-1800’s, morphine was being employed in surgical procedures, post-operative care, and for chronic pain.

Additional opioids became available through the 1900’s, including natural “opiates” (e.g., heroin), synthetic “opioids” (e.g., meperidine, methadone, fentanyl), partial agonists (e.g., buprenorphine), and opioid antagonists (e.g., naloxone). Similarly, investigations led to discovery of different opioid receptors (i.e., mu, delta, kappa) and endogenous opioids (i.e., enkephalins, endorphins). Opioids are currently some of the most widely used medications in the hospital setting, particularly in the United States ².

Most recently, opioids have been infamous for the ongoing opioid epidemic. Increases in opioid use were noted in the 1990s, driven by several political, social, and demographic factors ³. Despite being labeled as a public health emergency in 2017, opioid-related deaths have continued to increase, with most recent data finding over 81,000 deaths in 2023 ⁴. While many of these deaths have been linked with “overdose” in the setting of opioid misuse or untreated opioid use disorder (OUD), opioids taken even as prescribed carry substantial risks related to their respiratory effects ⁵. Given that opioids continue to play an important role in pain management, palliative care, and as treatment for OUD, an in-depth understanding of respiratory issues related to opioids is critical for clinicians, particularly those caring for hospitalized patients.

In this chapter, our aims are to 1) elucidate current understanding of the physiological effects of opioids on breathing, 2) examine several common clinical scenarios in which respiratory complications of opioids might be seen in the hospital setting, and 3) discuss strategies to manage respiratory issues related to opioids and mitigate risks.

Respiratory effects of opioids

Respiratory effects are a cardinal feature of opioids. Physiological control of breathing studies have established that administration of opioids impact breathing responses to CO2 as well as O2 (i.e., chemoreflex sensitivity) ^6,7. In general, opioids appear to blunt the response to CO2, whereby increasing CO2 levels stimulate ventilation to a lesser extent than without opioids. Acutely, these changes are to a large extent driven by a reduction in respiratory rate response, rather than tidal volume ⁶. Of note, there appear to be differences in these control of breathing responses between acute opioid exposure and longer-term use; responses to CO2 are less blunted and responses to O2 may actually increase following several months of use ⁷. Other respiratory effects of opioids include irregular breathing and effects on alertness that might impact wakefulness drive to breathe – i.e. opioids may induce sleep during which minute ventilation falls and CO2 rises.

In terms of neurobiology, respiratory effects have been localized to several key brainstem loci involved in generation and modulation of breathing, including the pre-Botzinger complex ⁸, the Kolliker-Fuse nucleus ⁹, and other sites. Neurons in the pre-Botzinger and Kolliker-Fuse express the mu-opioid receptor, with multiple lines of evidence indicating that opioid effects at these sites are responsible for changes in respiratory patterns and responses; for detailed review see ¹⁰.

Clinical entities

There are several recognized clinical entities resulting from the respiratory effects of opioids, although there can be overlap between conditions (Table 1):

Table 1.

Clinical entities attributed to opioid use: OIRD, OSA, and CSA

	OIRD	OSA + opioids	CSA due to opioids
Setting	Acute (or acute on chronic) opioid use	Long-term or acute opioid use in patients with OSA	Long-term opioid use Specific effects of acute on chronic opioid use not known
Risk factors	Higher opioid doses Underlying OSA Cardiopulmonary disease Individual: Sex, genetics	OSA risk factors: increasing age, male sex, higher BMI No clear opioid dose cutoff	No clear opioid dose cutoff, but often >50-90 mg morphine equivalents per day
Diagnosis	Respiratory rate <10 Somnolence/Sleepiness Sustained or intermittent hypoxemia Hypercapnia	AASM OSA diagnostic criteria: Apnea-hypopnea index >5 events/hr with symptoms, or >15 events/hr	AASM “CSA due to substance” diagnostic criteria: >5 central apneas+hypopneas/h r and >50% of events are central Opioid use Symptoms Not attributable to other disorder
Treatment	Stop opioids Naloxone Intubation	Opioid reduction CPAP ASV if treatment emergent central apneas	Opioid reduction ASV or Bilevel ST (often fails CPAP) Unclear: Supplemental oxygen, respiratory stimulants (e.g., acetazolamide)
Comments	With severe bradypnea (i.e., RR<6), prolonged expiratory pauses can look like central apneas	With chronic opioid use, mixed apneas, central apneas, and excess hypoxemia on PSG may be seen Acute opioid use can worsen hypoxemia in some patients with OSA	Breathing pattern can be irregular/ataxic (i.e., Biot’s breathing), or may be more periodic Bilevel without backup rate may worsen apneas

Opioid-induced respiratory depression

With acute (or acute on chronic) administration of opioids, breathing may be suppressed to a level where gas exchange is overtly impaired, a life-threatening condition termed opioid-induced respiratory depression (OIRD). There is no gold-standard definition of OIRD; criteria have variably included thresholds of respiratory rate, hypoxemia, hypercapnia, and level of consciousness. In general, a reduction of respiratory rate to less than 10 breaths per minute is highly suspicious for OIRD.

Not all OIRD episodes are clinically recognized. Episodes might not be detected when patients are in unmonitored settings, with some resolving spontaneously but nonetheless indicating substantial risk as a “near miss”. Intermittent or sustained drops in oxygen saturation (via pulse oximetry / SpO2) often triggers recognition of OIRD, although it should be noted that pulse oximetry is not very sensitive for hypoventilation and thus may only detect OIRD at a late stage. Desaturations and severe bradypnea with prolonged inter-breath intervals might be mis-attributed to sleep apnea (Figure 1). In terms of monitoring level of sedation/sleepiness, the degree of respiratory depression may be greater than the reduction in responsiveness to noxious stimuli ¹¹. Capnometry can be employed to better reflect ventilation, either via continuous end-tidal or transcutaneous monitoring, although the utility of this level of monitoring towards improving outcomes is not established. A blood gas can be used to definitively confirm hypoventilation, although often the context is sufficient to presumptively diagnose OIRD and decide on treatment prior to blood gas results being returned. PCO2 from venous blood gas generally overestimates arterial PCO2; the use of a conversion equation to estimate arterial PCO2 from venous blood gas results has superior agreement to a fixed conversion factor (e.g., commonly used procedure of subtracting 4 mmHg) ¹².

Figure 1.

Three-minute respiratory polygraphy recording of an inpatient being administered opioid medications who was noted to have intermittent desaturations. Note the average respiratory rate of approximately 5 breaths per minute, with some grouped breathing. Although central apneas are scored during the long expiratory pauses, the severe bradypnea indicates that this is opioid induced respiratory depression rather than central sleep apnea.

The major determinant of OIRD is opioid dose, although there is substantial variation across individuals such that a threshold cannot be established. Similarly, OIRD can be seen with enteral, parenteral, and neuraxial opioid use, as well as patient-controlled analgesia ¹³. A risk score to determine patients who are at risk for OIRD has been published (predictors: age ≥60 years by decade, sex, opioid naivety, sleep disorders, and chronic heart failure) ¹⁴.

When clinically recognized, OIRD can often be “reversed” using an opioid receptor antagonist such as naloxone, with several considerations:

1. The dose of naloxone must be carefully considered. Naloxone is a mu-opioid receptor antagonist and thus can reverse the central nervous system respiratory and analgesic effects of opioids. In patients with long-term opioid use, naloxone can precipitate opioid withdrawal. On the other hand, high potency opioids such as fentanyl might require higher naloxone doses.

2. If the administered opioid half-life is substantially longer than that of naloxone, OIRD may re-occur. If this scenario is suspected, close monitoring should occur with repeat dosing of naloxone or a continuous infusion.

3. Intubation and mechanical ventilation should be implemented if level of consciousness fails to rapidly improve or the patient is unstable, with support provided until OIRD resolves. Delaying supportive care increases risks of end-organ damage including hypoxic encephalopathy and aspiration pneumonia/pneumonitis, or recognition of an etiology other than OIRD responsible for the clinical picture. The use of (NIV) ventilation in OIRD is not generally advised due to concerns about safety and effectiveness ¹².

4. Clinicians should be aware of other potential causes of inadequate ventilation including fentanyl rigid chest (or, wooden chest) syndrome. In rigid chest syndrome, acute administration of opioids (particularly higher doses of lipophilic drugs) leads to central tonic activation of chest, abdominal, and glottic musculature and difficulty ventilating including with high pressures on mechanical ventilation ¹⁵. While rigid chest can be reversed with naloxone, intubation and neuromuscular blockade is more often employed as emergent management.

Sleep disordered breathing

Outside of overt respiratory depression, opioids can contribute to sleep disordered breathing (SDB), including both central sleep apnea (CSA) and obstructive sleep apnea (OSA).

In individuals using opioids long-term, data suggest up to 50% of patients have evidence of central sleep apnea (CSA) with a dose-dependent but highly variable relationship to opioid dose ^16-21. Opioid-related CSA may be characterized by a periodic (i.e., grouped) breathing, or more chaotic (i.e., ataxic) pattern, sometimes called Biot’s breathing. Sustained and even diurnal hypoxemia may be present, along with hypercapnia ²². The pathogenesis of CSA in the setting of long-term opioid use appears to be related to multilevel opioid effects on control of breathing and possibly arousal ²³. Opioid elimination has been shown to resolve CSA. Continuous positive airway pressure (CPAP) has a variable effect (Figure 2A), while non-invasive ventilation with adaptive servoventilation (ASV) mode appears effective at resolving central apneas (Figure 2B) ^24,25. ASV may be superior to bilevel spontaneous-timed ventilation although ASV may not augment ventilation in those with hypercapnia ²⁶.

Figure 2.

Polysomnographic titration studies of an obese patient with diagnosis of obstructive sleep apnea, use of oral morphine and intrathecal hydromorphone, and a history of ICU admission for hypercapnic respiratory failure. A) CPAP titration (with supplemental oxygen) was performed with inadequate control of respiratory events due to emergent central apneas. Also note that the breathing pattern has variable breath-to-breath timing and amplitude consistent with an ataxic pattern. B) Adaptive servoventilation titration (on room air) was performed with better control of central apneas. As breathing stabilizes, the algorithm adjusts IPAP to a more stable lower pressure. Note that mild sustained hypoxemia persists even with control of respiratory events. ASV may stabilize breathing but may not improve hypoventilation.

In terms of OSA, the impact of opioids appears to be more nuanced. Studies in rodents have suggested effects of opioids on hypoglossal motor neurons that might predispose to upper airway hypotonia and collapse. However, the acute administration of morphine 40 mg to humans did not increase the number of respiratory events overall, although some people with lower responsiveness to CO2 did have worsened AHI and hypoxemia, highlighting individual risk factors ²⁷. In terms of long-term opioid use, cross sectional studies in humans have not found worsened obstructive apneas but have noted increased central apneas and worsened hypoxemia ^23,25,28. In those with OSA, chronic use of opioids is a risk factor for failure of first-line continuous positive airway pressure (CPAP) treatment due to emergent and persistent respiratory events (i.e., complex sleep apnea, or treatment emergent sleep apnea) ^29-32. Overall, opioids appear to contribute to the severity and complexity of OSA ^{22,25,27,33-35,36}.

Factors influencing respiratory effects of opioids

Although there is in general a dose-dependent relationship of opioids on both OIRD and SDB, there is substantial individual variability in respiratory effects of opioids. Potential factors include:

1. Opioid type. While data are limited, opioids with high lipophilicity, longer half-life, and more active metabolites are expected to have a higher risk of respiratory complications. Methadone has been specifically identified in one study as having an increased risk of CSA ³⁷. Use of partial agonists (e.g., buprenorphine) or intrathecal administration via implanted pumps are increasingly common; these strategies may have a lower risk of respiratory depression ³⁸ but nonetheless can still cause SDB ³⁹.

2. Concomitant use of other centrally active medications. Medications that impact control of breathing and/or wakefulness drive to breathe are likely to interact with opioids. Central sleep apnea has been linked with non-opioid medications, mainly GABA agonists such as gabapentin and baclofen ²¹; worsened CSA with these medications and opioids is likely. In terms of potential for OIRD, co-administration of benzodiazepines has been linked with additive risks to opioids ⁴⁰. Rodent models have also found worsened respiratory depression with NMDA receptor antagonists (e.g., ketamine) ⁴¹.

3. Biological sex. In general, women demonstrate lower chemoreflex sensitivity than men and have a decreased risk of CSA from other etiologies, including high altitude CSA (19) and Cheyne-Stokes respirations (20). However, in the setting of opioids, women appear to demonstrate more depression in chemoreflexes than men, which might increase acute risk for respiratory depression ⁴². In addition, women are prescribed more opioids and higher doses than men, although it is unclear whether this might relate to greater pain or lower intrinsic sensitivity to analgesic effects of opioids ⁴³.

4. OPRM1 genotype. OPRM1 polymorphisms have been investigated for potential links to opioid responses and safety ⁴⁴, most prominently the A118G variant (prevalence ranging from 4-60% depending on ethnicity) ⁴⁵. Studies have suggested that the genotype associates with the degree of opioid-induced respiratory depression ⁴⁶. In a recent study using acute morphine administration, patients with OSA and the carriers of the A118G OPRM1 polymorphism had a significantly different morphine effect on awake ventilatory chemosensitivity and hypoxemia during sleep ²⁷.

Respiratory complications of opioids in hospitalized patients

Perioperative considerations

Opioids are commonly used during surgical and interventional procedures, including those involving general anesthesia and lighter sedation. OIRD is a major concern in the post-operative period: According to a recent meta-analysis, the incidence of postoperative OIRD was 5.0 cases per 1000 anesthetic administrations, with 85% occurring within 24 hours post-operatively ⁴⁷. Risk factors for post-operative OIRD include cardiac disease (OR: 1.7), pulmonary disease (OR: 2.2), and OSA (OR: 1.4). Increased post-operative monitoring has been advocated to reduce the risk of adverse outcomes, although definitive recommendations are not available ⁴⁸.

Patients with underlying OSA have an approximately two-fold higher risk for perioperative complications compared with patients without OSA ⁴⁹. Whether these risks are similar for those with underlying CSA are unclear. While several factors might contribute to this risk, acutely administered opioids and OIRD are likely to play a role. Moreover, pain might be higher in those with OSA, along with changes in sensitivity to analgesic and respiratory effects of opioids ⁵⁰. Treatment of OSA before surgery might reduce the risks of opioids, although likely this depends on the severity of OSA, surgical risks, and planned post-operative care. Guidelines are available for clinicians ⁵¹. In general, pre-operative treatment should be considered in patients with severe OSA, diurnal hypoxemia or hypercapnia, or pulmonary hypertension.

Hospital and discharge considerations

Similar to the post-operative setting, patients who are administered new opioids in the hospital are also at increased risk for OIRD and/or worsening of pre-existing SDB ³⁶. In hospitalized patients, underlying OSA has been identified as a risk factor for decompensated respiratory failure, perhaps via opioid exposure and OIRD as in the post-operative setting ⁵². Similarly, in a study of patients using opioids on the medical ward, a history of sleep disorders including sleep apnea was identified as having increased risk for OIRD ¹⁴.

The optimal management for hospitalized patients with previously unrecognized SDB associated with opioid use is not clear. To the extent possible, acute pain management strategies should minimize opioids both in the hospital and at discharge. For chronic opioid use, dose reduction must be a gradual process over weeks to months; aggressive reduction may increase risks of withdrawal and other complications. Inpatient sleep studies are available at some institutions, usually using respiratory polygraphy which may have limited sensitivity for central apneas. Whether inpatient initiation of PAP/NIV is warranted in this group has not been examined. Given data indicating substantial risks of discharge without PAP/NIV in patients with other hypoventilation syndromes ⁵³, it is likely prudent to initiate treatment in patients with serious gas exchange abnormalities including hypercapnia, rather than waiting for post-hospital follow up. Treatment in this setting would include 1) excluding OIRD as the cause of gas exchange issues, and 2) hospital initiation of nocturnal non-invasive ventilation. Given that ASV is unlikely to be available in the hospital setting and may not be appropriate if hypoventilation is present, use of bilevel spontaneous-timed mode is a practical option to facilitate safe discharge. Close post-discharge follow up with polysomnographic titration to optimize SDB treatment is essential.

Conclusions

Opioids can have substantial effects on breathing and sleep that are relevant for hospitalized patients. With acute use of opioids, OIRD is a major concern in both the post-operative and hospital ward settings, and risk is higher in the setting of SDB. Chronic use of opioids can cause CSA, and complicate OSA, sometimes with daytime gas exchange abnormalities. Treatment of SDB in the setting of opioids may help improve outcomes.

Key points:

1. Acute administration of opioids can cause opioid-induced respiratory depression (OIRD), a life-threatening condition that is common and potentially under-recognized in hospitalized patients.

2. Acute opioid use may contribute to increased risk of post-operative complications amongst those with unrecognized or untreated sleep apnea, potentially via OIRD. Selective preoperative evaluation, close post-operative monitoring, and opioid sparing strategies may help.

3. Sustained use of opioids can cause central sleep apnea and complicate obstructive sleep apnea, sometimes with daytime gas exchange abnormalities. Factors influencing risk include opioid dose and patient-level susceptibility.

4. Hospitalized patients with SDB should minimize acute use of opioids as able. In those using chronic opioids, inpatient evaluation and treatment of SDB may be warranted particularly in those with hypercapnia.

Synopsis:

Opioids are widely used in acute and chronic pain management, but have significant respiratory effects that pose risks, especially in hospital settings. Opioid-induced respiratory depression (OIRD) occurs when opioids suppress the body's response to CO2, leading to life-threatening gas exchange impairment. OIRD is an emergency requiring treatment with opioid antagonists such as naloxone, and sometimes intubation and mechanical ventilation. Patients with pre-existing sleep disordered breathing (SDB) are at increased risk of complications related to acute opioid administration such as OIRD. Chronic use of opioids causes central sleep apnea with an irregular breathing pattern, and contributes to complexity in managing obstructive sleep apnea. Mitigating respiratory risks of opioids involves limiting doses, careful monitoring, and sometimes the use of respiratory support like non-invasive ventilation.