Morphine alters respiratory control but not other key obstructive sleep apnoea phenotypes: a randomised trial

Abstract

Accidental opioid-related deaths are increasing. These often occur during sleep. Opioids such as morphine may worsen obstructive sleep apnoea (OSA). Thus, people with OSA may be at greater risk of harm from morphine. Possible mechanisms include respiratory depression and reductions in drive to the pharyngeal muscles to increase upper airway collapsibility. However, the effects of morphine on the four key phenotypic causes of OSA (upper airway collapsibility (pharyngeal critical closure pressure; Pcrit), pharyngeal muscle responsiveness, respiratory arousal threshold and ventilatory control (loop gain) during sleep) are unknown.21 males with OSA (apnoea–hypopnoea index range 7–67 events·h−1) were studied on two nights (1-week washout) according to a double-blind, randomised, cross-over design (ACTRN12613000858796). Participants received 40 mg of MS-Contin on one visit and placebo on the other. Brief reductions in continuous positive airway pressure (CPAP) from the therapeutic level were delivered to induce airflow limitation during non-rapid eye movement (REM) sleep to quantify the four phenotypic traits. Carbon dioxide was delivered via nasal mask on therapeutic CPAP to quantify hypercapnic ventilatory responses during non-REM sleep.Compared to placebo, 40 mg of morphine did not change Pcrit (−0.1±2.4 versus −0.4±2.2 cmH2O, p=0.58), genioglossus muscle responsiveness (−2.2 (−0.87 to −5.4) versus −1.2 (−0.3 to −3.5) μV·cmH2O−1, p=0.22) or arousal threshold (−16.7±6.8 versus −15.4±6.0 cmH2O, p=0.41), but did reduce loop gain (−10.1±2.6 versus −4.4±2.1, p=0.04) and hypercapnic ventilatory responses (7.3±1.2 versus 6.1±1.5 L·min−1, p=0.006).Concordant with recent clinical findings, 40 mg of MS-Contin does not systematically impair airway collapsibility, pharyngeal muscle responsiveness or the arousal threshold in moderately severe OSA patients. However, consistent with blunted chemosensitivity, ventilatory control is altered.

The noradrenergic agent reboxetine plus the antimuscarinic hyoscine butylbromide reduces sleep apnoea severity: a double‐blind, placebo‐controlled, randomised crossover trial

“…Sleep staging, cortical arousals and respiratory events were scored by a board registered sleep technician according to AASM guidelines (Berry et al 2012). Epiglottic pressure was measured ∼1.5 cm below the base of the tongue using a pressure-tipped catheter inserted through the nose (Martins et al 2020;Messineo et al 2020).…”

“…Multiunit genioglossus and tensor palatini electromyography (EMG) was measured using bipolar, Teflon-coated, fine-wire intramuscular electrodes as described previously (Eckert et al 2013;Eckert, 2018;Martins et al 2020;Messineo et al 2020). Prior to sleep, participants performed tongue protrusions and swallows to quantify maximal EMG activity.…”

Clinical implications of opioid-induced ventilatory impairment

“…Martins et al., in a follow-on study to the previously described study, found upper airway collapsibility measured using pharyngeal pressure monitoring was unaffected by morphine. 23 Loop gain was found to be reduced after morphine administration, supporting the concept that this is a possible mechanism for improved oxygenation in some OSA patients by stabilising breathing.…”

“…20 In one experimental animal study, opioids were demonstrated to reduce the tone of upper airway muscles; however, clinical correlates of impaired ventilation through obstruction by this mechanism have not been demonstrated in humans. [21][22][23] Nonetheless, the ability of opioids to impair ventilation by obstruction due to sedation provides reason for the more encompassing term of OIVI 24 (Figure 3).…”

“…In others, and this is likely to be dose related, a deleterious neurodepressant effect may predominate by at least one and possibly all three mechanisms: impaired rhythm generation to induce central apnoea; chemoreceptor impairment of ventilatory drive; or cortically preventing arousals. 23…”