Pathogenesis of sleep-disordered breathing in the setting of opioid use: a multiple mediation analysis using physiology

Abstract Study Objectives Opioid medications are commonly used and are known to impact both breathing and sleep and are linked with adverse health outcomes including death. Clinical data indicate that chronic opioid use causes central sleep apnea, and might also worsen obstructive sleep apnea. The mechanisms by which opioids influence sleep-disordered breathing (SDB) pathogenesis are not established. Methods Patients who underwent clinically indicated polysomnography confirming SDB (AHI ≥ 5/hour) were included. Each patient using opioids was matched by sex, age, and body mass index (BMI) to three control individuals not using opioids. Physiology known to influence SDB pathogenesis was determined from validated polysomnography-based signal analysis. PSG and physiology parameters of interest were compared between opioid and control individuals, adjusted for covariates. Mediation analysis was used to evaluate the link between opioids, physiology, and polysomnographic metrics. Results One hundred and seventy-eight individuals using opioids were matched to 534 controls (median [IQR] age 59 [50,65] years, BMI 33 [29,41] kg/m2, 57% female, and daily morphine equivalent 30 [20,80] mg). Compared with controls, opioids were associated with increased central apneas (2.8 vs. 1.7 events/hr; p = .001) and worsened hypoxemia (5 vs. 3% sleep with SpO2 < 88%; p = .013), with similar overall apnea–hypopnea index. The use of opioids was associated with higher loop gain, a lower respiratory rate (RR), and higher RR variability. Higher loop gain and increased RR variability mediated the effect of opioids on central apnea, but did not mediate the effect on hypoxemia. Conclusions Opioids have multi-level effects impacting SDB. Targeting these factors may help mitigate the deleterious respiratory consequences of chronic opioid use.