0507 The Effects of Acute Morphine on Obstructive Sleep Apnea Endotypes: A Secondary Analysis of a Double-blind, Placebo-controlled, Randomized Trial

Abstract Introduction Opioids are associated with respiratory suppression and may worsen obstructive sleep apnea (OSA). We characterized the polysomnographic and endotypic changes among people with OSA exposed to morphine. We hypothesized that morphine would modulate ventilatory control and that greater baseline ventilatory instability would be associated with favorable polysomnographic responses. Methods We performed secondary data analysis of 60 males with OSA (aged 44.4±11.7 years, BMI 29.3±3.9 kg/m2) from a double-blind, placebo-controlled, randomized, crossover trial of 40mg oral morphine versus placebo. Endotypic traits (loop gain, arousal threshold, ventilatory response to arousal (VRA), pharyngeal muscle compensation, and collapsibility) were estimated from polysomnography using established computational methods. Paired t-tests were used to compare morphine versus placebo on OSA endoyptes. Correlations between baseline endotypes or endotype changes and treatment response were examined using Pearson correlation and linear regression with interaction terms, stratified by OSA severity (severe: apnea-hypopnea index [AHI≥30 events/h, n=11; non-severe: AHI< 30 events/h, n=49). Primary outcomes were changes in AHI, oxygen desaturation index (ODI), and oxygen saturation nadir (SpO₂ nadir). Results Morphine significantly reduced the VRA (35±21 vs. 27±19% above eupnea; mean difference -9% [95% CI -15 to -2];p=0.012), while other endotypes were not systematically different. Greater VRA reduction correlated with improvement in SpO₂ nadir (r=-0.367, p=0.004). Baseline OSA endotypes did not correlate with AHI changes. However, stratified and interaction analyses revealed that baseline loop gain was associated with ODI changes in a severity-dependent manner (interaction p< 0.001). In severe OSA, higher baseline loop gain was associated with greater ODI reduction (r=-0.62, p=0.041), but not in those with mild-moderate OSA (r=-0.11, p=0.443). Conclusion A single 40mg dose of morphine attenuates the ventilatory response to arousal in men with OSA. The correlation between VRA reduction and oxygenation improvement suggests that excessive post-arousal hyperventilation perpetuates ventilatory instability through CO₂ washout and respiratory depression. Morphine may stabilize ventilatory control and reduce desaturation events by dampening arousal-induced overshoot. High baseline loop gain is associated with a reduction in ODI with morphine in those with severe OSA, indicating ventilatory control instability is a therapeutic target in this subgroup. These severity-dependent relationships indicate morphine's effects depend on underlying OSA pathophysiology. Support (if any)