Chronic pain is associated with sleep apnea severity but attenuated by intermittent hypoxemia in people using opioids

Patients using long-term opioids for pain often have uncontrolled symptoms which might drive ongoing opioid use and contribute to the opioid public health crisis. Opioids also cause sleep disordered breathing (SDB), which might impact pain via arousals and hypoxemia, with potential for a vicious cycle. Adults with noncancer pain using opioids daily for >3 months were recruited. Subjects underwent pain and sleep questionnaires, pain tolerance via 10°C cold pressor testing, and polysomnography. Hypoxic burden was determined from polysomnographic signal analysis. Participants (n = 143) had a median (interquartile range) age of 60 (51, 67) years, body mass index 29 (25, 35) kg/m 2 . 80 (56%) subjects were female. The median daily morphine equivalent dose was 20 (10, 45). 78% had an apnea-hypopnea index (AHI) >5/hour and 41% with AHI >15/hour. PROMIS pain interference scores differed across SDB severity, with increased symptoms in mild and moderate but not severe SDB. With increasing AHI, there was worsened pain (β = 2.2 [95% confidence interval [CI]: 0.08, 4.4]; β std = 1.3; P = 0.043), but this relationship was attenuated at higher levels of hypoxic burden (per interaction; β = -0.42 [95% CI: -0.78, -0.06]; β std = -0.85; P = 0.023). During cold pressor testing, there was a reduced time to hand withdrawal with increasing AHI (hazard ratio [HR] 2.60 [95% CI: 1.48, 4.57]; P = 0.001), but this was also attenuated at higher hypoxic burden (HR: 0.86 [95% CI: 0.78, 0.94]; P = 0.002). Overall, SDB is linked with worsened pain in those using opioids for chronic pain, but hypoxemia attenuates the effect. Individuals with the same AHI may have different symptoms depending on hypoxic burden. Interventional studies will help elucidate mechanisms and the role for SDB treatment in pain management.