Mechanisms of opioid‐induced respiratory depression in sleep apnoea: new insights for anaesthesiology

An established cornerstone of pain management, opioids are commonly prescribed in the clinical setting for postoperative and/or chronic pain. Despite their potent analgesic properties, however, they have many well-established side effects such as nausea, vomiting, sedation, constipation and respiratory depression. Of particular interest is the phenomenon of opioid-induced respiratory depression, a precarious combination of central respiratory depression, decreased level of consciousness, and upper airway obstruction attributable to decreased upper airway tone. Such events pose a significant risk to individuals with comorbid conditions, notably to those with sleep apnoea. Past investigation into the consequences of intermittent hypoxia and sleep fragmentation have revealed that sleep apnoea contributes to hyperalgesia, as well as a greater response to administered exogenous opioids. By extension, such individuals are more susceptible to opioid-induced respiratory depression. Several contributory mechanisms have been proposed, one of which is the upregulation of mu-opioid receptors as a result of intermittent hypoxia increasing sensitivity to opioids (Gupta et al. 2018). Although a link between the two has been established, there remains a gap in our knowledge as to exactly why sleep apnoea increases opioid-induced respiratory depression and mortality. The current investigation by Brackley et al., published in The Journal of Physiology (Brackley et al. 2020), seeks to demonstrate the role of endogenous opioids in opioid-induced respiratory depression. By approximating intermittent bouts of hypercapnic hypoxia, they simulate the conditions of sleep apnoea to evaluate the tonic suppression of neural inspiration by endogenous opioids, as well as heightened susceptibility for opioid-induced respiratory depression. Through a review of the methods and results of this study, we aim to make new connections to the clinical discipline of anaesthesiology. We outline three approaches for practitioners to consider in order to reduce the potential risks of opioid-induced respiratory depression in the clinical setting and suggest potential next steps for future investigation. Brackley et al. investigated the effects of chronic intermittent bouts of hypercapnic hypoxia (CIHH), a mainstay of sleep apnoea, on opioid-induced respiratory depression (2020). The authors hypothesized that male Sprague–Dawley rats subjected to intermittent hypercapnic hypoxia would have increased susceptibility to opioid-induced respiratory depression compared with a normoxic control group. To test this, rats were exposed to repeated cycles of hypercapnic and hypoxic conditions (10 cycles per hour, simulating moderate sleep apnoea) throughout their sleep phase for 7 days. Rats were then given various doses of fentanyl – a synthetic opioid often used both in the induction of patients during general anaesthetic performed in many surgical procedures and for its analgesic properties. Subsequently, phrenic nerve activity was assessed to determine inspiratory muscle motor output. The authors confirmed their model showing that the CIHH group had increased haematocrit levels. In anaesthetised/ventilated rats, Brackley et al. (2020) report greater respiratory depression in the CIHH versus the normoxic group after exposure to systemic fentanyl, particularly at higher doses (20 and 50 μg/kg). Specifically, the increased doses were able to suppress phrenic nerve activity to a greater extent in the CIHH group and for a longer duration. The researchers then investigated the effect of naloxone alone on endogenous opioids in CIHH and normoxic groups. They demonstrated that naloxone alone had the ability to increase phrenic nerve activity amplitude in the CIHH group only. By using this method, the researchers determined that rats subjected to intermittent hypercapnia/hypoxia had increased endogenous opioids, thus leading to increased risk of opioid-induced respiratory depression. Lastly, Brackley et al. (2020) sought to examine respiratory depression in conscious, non-ventilated rats. The research team observed that a moderate dose of fentanyl (20 mg/kg) decreased respiratory rate in CIHH rats only, which corresponded with a greater number of prolonged apnoeas. In sum, this unique area of research attempts to provide novel insight into factors influencing opioid adverse effects, specifically exploring sleep apnoea as a comorbidity. This study was the first to demonstrate increased endogenous opioids as a result of intermittent hypoxia with hypercapnia. This CIHH model was developed to mimic some of the pathophysiological conditions experienced by sleep apnoea patients, and as such, offers new insights for the field of anaesthesiology and perioperative patient care. Although this article focused on pain, we believe the results are applicable to the field of anaesthesia as many patients with sleep apnoea undergo surgical procedures and are anaesthetised with opioids during general anaesthesia. A general anaesthetic ‘cocktail’ typically includes, among other medications, a potent opioid (fentanyl, hydromorphone, etc.) that is helpful in providing patients with analgesia from the stimulation of intubation and reducing pharyngeal tone to easily manipulate the patient's airway. However, if a patient suffers from sleep apnoea that is undiagnosed and/or not appropriately treated, they are at risk of the synergistic effect of the opioid induction agent on top of their baseline elevated endogenous opioids. These additive opioid doses may lead to a plethora of risks including opioid-induced respiratory depression, difficulty rousing the patient postoperatively, and prolonged length of hospital stay (Mörwald et al. 2018). In addition to identifying physiological mediators related to respiratory depression, we believe the findings of this study also highlight the potential risks of following an anaesthetic protocol without special consideration for patients with sleep apnoea. To mitigate some of these theoretical risks, we propose a three-pronged approach. First, clinicians could increase focus in their preoperative assessments related to sleep apnoea. This can be achieved by improving screening (i.e. using validated tools such as a STOP-BANG questionnaire) for undiagnosed sleep apnoea in suspected patients with risk factors before undergoing major surgery (Nagappa et al. 2017). Risk factors such as obesity, increased neck circumference,and family history of sleep apnoea can alert a clinician to begin the diagnostic testing during the preoperative assessment phase. Next, newly diagnosed patients or patients with pre-existing sleep apnoea should be optimized preoperatively and counselled on minimizing risks (smoking cessation, weight loss, etc.) and maintaining compliance with continuous positive airway pressure (CPAP) before surgery. Similarly, Gislason et al. (1989) found that 80% of endogenous opioids were reduced in obstructive sleep apnoea patients after surgical correction of their pathology. This further supports the notion of ensuring patients are adequately optimized for surgery (including appropriate compliance on CPAP for sleep apnoea). Finally, after optimizing the patient's pre-existing condition, the anaesthetist may implement a multimodal analgesic approach during the perioperative period to minimize opioid consumption and ultimately, opioid-induced respiratory depression. The current investigation by Brackley et al. (2020) utilized a rigorous methodology to demonstrate their hypothesis. Using measures such as cervical vagotomy to isolate the central respiratory actions of fentanyl, or mitigating CIHH-increased sensitivity to anaesthesia with a conscious, spontaneously breathing control were logical steps in avoiding confounders and should be considered a strength. Additionally, their use of intermittent hypercapnic hypoxia showed a profound effect after just 7 days, demonstrating that they were able to create an effective model that isolated a key feature of sleep apnoea. Concomitantly, this model is somewhat limited as CIHH can only be used to simulate specific aspects of sleep apnoea. Common in the population of patients with sleep apnoea are comorbid conditions such as obesity, although attempts to simulate these additional conditions would likely introduce confounders to the results of this study. By extension, this weakens the external validity of this investigation as it applies to that clinical population of individuals with sleep apnoea. Brackley et al. (2020) are the first to identify an increase in endogenous opioids in the context of chronic intermittent hypercapnic hypoxia, as seen in the pathophysiology of sleep apnoea. Not only do they conclude that endogenous opioids are implicated as a contributing factor to sleep apnoea, but that this also increases opioid-induced respiratory depression. These conclusions are particularly relevant for the field of anaesthesiology, further demonstrating the risks associated with the use of opioids such as fentanyl in patients with sleep apnoea. We have outlined approaches for clinicians to focus on preoperative screening for the condition, to counsel and optimize patients before surgery, and to consider utilizing multimodal analgesic approaches to reduce opioid consumption. Future projects could consider examining the effects of CIHH protocol cessation, perhaps to simulate conditions of sleep apnoea treatment. Moreover, further investigations could seek to identify the mechanisms responsible for the increase in endogenous opioid release, or perhaps if there are changes in receptor expression. Each new discovery advances our understanding of sleep apnoea, which can be applied through a better standard of care. None of the authors have any conflicts of interest that pertain to this manuscript. All authors have contributed equally to the work presented. No funding was received that pertains to this manuscript.

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