Conversely, long-term opioid use involves peripheral chemoreceptors in addition to its central effects. The mechanism underlying periodic breathing or central apnea patterns during sleep is unclear. Santiago found that the hypercapnic ventilatory response (HCVR) and hypoxic ventilatory response (HVR) both decreased initially after beginning methadone, but after 5 months the HCVR returned to normal and the HVR remained low.33 In a cohort of stable long-term methadone maintenance patients, Teichtahl et al.34 found that the HCVR was reduced but the HVR was increased, which is a recipe for ventilatory instability. These circumstances could result in ventilatory overshoot with arousals, relative hypocapnia, and central apneas.
The irregular, ataxic, underlying breathing pattern often found suggests that the brainstem pattern generators are inherently dysfunctional and may not be responsive to negative-feedback loop signals, as in Cheyne-Stokes respiration or idiopathic CSA, in which periodicity is a prominent feature (Figs. 2 and 3). Mellen et al.35 attributed the irregular breathing pattern to “quantal slowing” due to the differential effects of opioids on the opioid-sensitive pre-Bötzinger complex and the opioid-insensitive preinspiratory neurons. Of particular concern in the perioperative period is that opioids may disable normal protective arousal mechanisms in response to hypoxemia that commonly occurs postoperatively, especially in obese patients who may also have OSA or chronic hypoventilation. The presence of an ataxic underlying breathing pattern in the presence of hypoxemia may also be a warning sign of impending respiratory failure.36,37
In contrast to OSA syndrome, in which the overall prevalence has been established by multiple large epidemiologic studies, there are no corresponding data for CSA because central apneas are manifestations of multiple disease processes. Assessment of the prevalence of opioid-induced respiratory effects during sleep, in particular, is inherently more complicated because opioids are associated with diverse respiratory abnormalities that often overlap owing to their unique pathophysiology: central apneas, obstructive apneas, hypopneas, ataxic breathing patterns, and hypoxemia. We found that obstructive apneas occurred, but, when compared with control populations, the overall prevalence of SDB was increased in the opioid patients owing to the additional presence of CSA. Unfortunately, reliable determination of the prevalence of opioid-induced CSA is confounded by the following limitations: (1) the biases and diversity of the small populations studied. For example, subjects with numerous comorbidities were recruited from detoxification programs or chronic pain clinics, or patients were referred for the evaluation of OSA who happened to be receiving opioids; (2) only 4 of the 8 studies were entirely prospective; (3) various classes and doses of opioids were used, frequently with different timing of administration; (4) numerous other drugs that may affect respiratory control were used simultaneously; (5) baseline polysomnography (PSG) was not available for comparison; (6) the application of standard scoring criteria for central apneas is often made difficult because of an underlying irregular breathing pattern or when the patient is receiving positive airway pressure (PAP) such as adaptive servoventilation; and (7) hypopneas, which occasionally may be quite prolonged and associated with severe hypoxemia because of a blunted arousal response, may be the most common respiratory event, but these are not usually differentiated as central or obstructive. Moreover, other opioid effects, such as hypoxemia and ataxic breathing, were either not described or not quantified in any detail. Our review suggests a mean prevalence of CSA related to opioid therapy of 24%, although the reported range is wide (14.1%–60%). The reason for the wide range was unclear, because it did not seem to be accounted for by any obvious differences in the populations studied.
Well-known risk factors for OSA have been identified from large epidemiologic surveys to formulate clinical prediction models such as the STOP-Bang questionnaire.38–41 None of the current screening instruments or known risk factors have been validated or useful for identifying patients with SDB related to chronic opioid use. Consequently, the tendency to readily suspect OSA in the tired, obese, hypertensive male who snores only serves to misdirect and underdiagnose severe and potentially lethal opioid-induced CSA and hypoxemia in other demographics, such as the nonobese female. At least some patients have OSA with typical risk factors that may prompt investigation, but the chronic use of opioids likely exacerbates SDB and increases the risk of developing more complex sleep apnea that is difficult to treat, particularly with standard continuous positive airway pressure (CPAP) therapy. Only 2 variables seem to be somewhat helpful: (1) dose of opioid and (2) low or normal BMI.
A positive correlation between either oral dose or plasma level was found in 5 of 8 studies.1–4,7 Numerous factors may explain the lack of tight or consistent correlation between opioid dose and effects on respiration during sleep. These include uncertainty about actual amounts of drugs ingested, timing of measurements in the case of blood levels, individual susceptibility due to μ-receptor polymorphism, pharmacokinetics related to body weight, and interactions with concurrent drugs.
It is reasonable to suspect that the use of various drugs in conjunction with opioids should increase the probability of developing CSA. Benzodiazepine/hypnotics depress central nervous system activity and blunt the arousal or ventilatory response to hypoxia and hypercapnia during sleep,42,43 and benzodiazepines may worsen or precipitate SDB in patients with pulmonary and cardiac disease44 and prolong the methadone effect by possibly inhibiting the metabolism of methadone.45 Interestingly, only one study found that benzodiazepines had any additive effect.4 This is not only counterintuitive but is also at variance with standard admonitions. There are insufficient data regarding alcohol and other commonly used substances in these populations that could conceivably increase risk, such as cannabis, tobacco smoke, muscle relaxants, and gabapentin.
Antidepressants appear to act in synergy with methadone to further reduce already blunted HCVR.2 Wang et al.2 reported that 4 of 7 patients (57%) receiving antidepressants had CAI >10/h; however, 4 studies showed that there was no interaction,4,6–8 and there was no information in the other 3 reports.1,3,5 The effect of concurrent medications and chronic opioid-associated CSA was assessed in each of the studies,1–6,8 with the exception of the report by Jungquist et al.,7 and no relationship was observed. The synergy between opioids and sleep deprivation, as might occur in the perioperative environment, also seems plausible and relevant; however, none of the studies has addressed this point. It is almost impossible to exclude concurrent use of various medications as risk factors. Therefore, until more definitive studies can be performed, it would be prudent to avoid potentially exacerbating medications.
The relationship with nonobese status is particularly interesting and has not been thoroughly investigated. The increase in central apneas in patients with lower BMI may be because the dosage was prescribed according to general guideline with a dose range and not as a milligram per kilogram basis. It is possible that patients with smaller BMIs may have a relative overdose versus patients with higher BMIs because of a difference in effect site concentration based on differences in pharmacokinetics.
The effect of opioid-associated CSA on morbidity and mortality has not been well characterized because long-term studies are not available. The current practice of chronic pain management is to use multiple analgesic medications at reduced doses to take advantage of their synergetic effect; however, there are no data to indicate whether this practice alters the risk of ataxic breathing, sleep apnea, or unanticipated death during sleep. Ideally, polysomnography should be performed if symptoms are observed. Whether the treatment of opioid-associated CSA prevents sleep-related mortality is unclear.
There are 4 PAP modalities: (1) continuous positive airway pressure (CPAP); (2) bilevel positive airway pressure (BPAP); (3) automatic self-adjusting positive airway pressure (APAP); and (4) servo-controlled ventilation (ASV or BPAP adapt). (See Table 4 for detailed comparison.) Except for servo-controlled ventilation, practice parameters have been published for all of these modalities for therapy of OSA and CSA not associated with chronic opioid use.57–59
CPAP devices maintain a CPAP with adjustable flow generated by fan-driven or turbine systems to stent the upper airway open and to increase functional residual capacity. A pressure adjusted to abolish flow limitation is prescribed. CPAP can be autotitrated or fixed. In either case, the pressure is adjusted to abolish flow limitation and is thus several cm H2O higher than closing pressure, which is the pressure at which the airway closes completely. Furthermore, the pressure is not determined by PSG. It can be determined during PSG, but can also be determined under other circumstances, such as autotitration at home. Patients with sleep apnea related to opioids often have obstructive events, providing a logical basis for use of CPAP. Five retrospective studies60–64 (Table 4) showed that CPAP therapy does not eliminate or may even increase central apneas.60–63 The use of opioids does not preclude a favorable response to CPAP, but adjunctive oxygen or alternative PAP modalities will be required in most cases.
These devices permit independent adjustment of inspiratory positive airway pressure and expiratory positive airway pressure to target the obstructive and central SDB events. There are different modes of BPAP: Spontaneous (S Mode), Timed (T Mode), and Spontaneous/Timed Mode (ST Mode). In BPAP-ST Mode, a “backup” rate is also set to ensure that patients still receive a minimal number of breaths per minute if they fail to breathe spontaneously. BPAP (S or ST Mode) alone, or with a backup rate and/or oxygen, was effective for treating CSA unresponsive to CPAP62 ,65,66 (Table 4). A recent systematic review also reported the effectiveness of BPAP in eliminating CSA in 62% and ASV in 58% of patients taking chronic opioids.67
Adaptive servoventilation is a relatively new approach in treating CSA, mainly in patients with congestive heart failure or complex apnea related to overtitration with CPAP. Based on an internal algorithm and a moving window sampling of the patient’s minute ventilation, ASV uses a preset or autotitrating end-expiratory pressure to eliminate any obstructive apneas or hypopneas, and it generates variable inspiratory pressure support (usually in the range of 3–10 cm H2O) on a breath-by-breath basis above the expiratory pressure to regulate ventilation to prevent hypocapnic-induced central apneas. Pressure support increases as ventilation wanes and decreases as it waxes. ASV appears to successfully treat CSA associated with chronic opioid use unresponsive to CPAP60,61,63,66 (Table 4).
Unlike OSA, the perioperative risk due to CSA syndromes is unknown. Diagnostic studies for CSA are not standard, and the possibility of opioid-induced SDB, such as CSA, may not even be considered.
Based on our review, none of the usual risk factors for OSA has been useful for screening patients for opioid-induced CSA. However, the following factors should raise concern: (1) the clinical context identified in these studies (i.e., patients receiving methadone or buprenorphine for opioid addiction, patients being treated for chronic pain, and patients who have risk factors or diagnosis of OSA and are also receiving chronic opioids); (2) any patient being treated with an MEDD ≥ 200 mg/d; and (3) patients with low or normal BMI. Although methadone has been most widely implicated, virtually any opioid appears capable of inducing sleep apnea and other respiratory disturbances. In these cases, early awareness can lead to timely recognition and treatment. Patients with underlying CSA may be at increased risk for worsening of CSA when opioids are used for pain relief at night.26–28 Acute ingestion of an extra dose of opioids at night can result in the precipitation of CSA in patients using chronic opioids who were not previously diagnosed with SDB.68
Perioperative management using a multimodal approach with combinations of non-opioid analgesics69–71 requires careful planning to minimize the need for opioids. Preoperative sedative and hypnotic medications should be used with extreme caution, because these medications may worsen CSA/hypoxemia in some patients. Non-opioid analgesics,72–84 regional anesthesia techniques and epidural or peripheral nerve catheters, perioperative infusions of lidocaine, and local anesthetic infiltration can decrease the postoperative requirement of opioids.85–88
Improved postoperative monitoring is a key to reducing the risk of central apnea. Patient-specific, anesthetic, and surgical factors determine the requirements for postoperative monitoring. Central apnea patients undergoing major surgery who require postoperative opioid should be monitored with continuous oximetry and respiratory rate at night, because there may be an increased risk of worsening of CSA when opioids are used for pain relief in the evening.26–28 Recurrent respiratory events in the postanesthesia care unit, including apnea for ≥10 seconds, bradypnea of <9 breaths/min, pain-sedation mismatch, or desaturation to <90%, can be used to identify patients at high risk of postoperative respiratory complications.89 Macintyre et al.90 proposed that sedation level is a more reliable sign of opioid-induced respiratory depression than respiratory rate, because multiple reports suggest that opioid-induced ventilatory impairment is not always accompanied by a decrease in respiratory rate. Thus, sedation scoring systems should be used postoperatively to recognize opioid-induced ventilatory impairment, so that appropriate interventions are triggered.90 CPAP may not be effective, and BPAP with a backup rate may be useful in treating the central apneic episodes and hypercapnia. If patients with opioid-associated CSA are on PAP before the surgery, PAP should be resumed as soon as possible postoperatively.
The prevalence of SDB in all populations receiving chronic opioids is high (42%–85%), and the prevalence of CSA is much higher than in the general population (24%). The respiratory patterns associated with opioids are distinctive, and severe nonapneic hypoxemia can be observed. The usual risk factors seen in patients with OSA are not reliably predictive in patients with opioid-related SDB, and therapy with CPAP is often ineffective. The possibility of CSA and other disturbances should be considered in any person being treated with chronic opioids, especially if the MEDD ≥ 200 mg/d. The risk appears to be greater in nonobese persons but is not clearly increased by concurrent benzodiazepines. There are many limitations to the published studies, and the clinical outcomes of patients with documented CSA due to opioids are not known. Evidence-based research on the perioperative management of patients with opioid-associated CSA is also lacking. Surgical patients with opioid-associated CSA may be more vulnerable to sedation, anesthesia, and analgesics. Supplemental oxygen should be used to treat hypoxemia; however, higher levels of monitoring are needed in patients with opioid-induced SDB because of reduced arousal and ventilatory responses to hypoxemia/hypercapnia. When CPAP is ineffective, adaptive servoventilation or BPAP support with a backup rate is often adequate. Precautions, including screening, diagnosis and treatment of unrecognized CSA, use of multimodal, opioid-sparing analgesic regimens, and increased postoperative monitoring should be taken in these patients. There is a need for further prospective studies on the perioperative risks and management of these patients.
Opioids were converted to oral morphine equivalent daily dose (mg) by multiplying the daily dose of opioids by the designated multiplier for each type of opioid given in the following Appendix table.
The authors thank Marina Englesakis, BA (Hons) MLIS, Information Specialist, Surgical Divisions, Neuroscience & Medical Education, Health Sciences Library, University Health Network, Toronto, ON, Canada, for her assistance with the literature search.
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