C21-10 Acetazolamide Ameliorates Breathing Instability in Opioid-associated Sleep Disordered Breathing

Abstract Introduction Chronic prescription opioid use can exert ventilatory depression and yet increase the loop gain or chemoresponsiveness. Alternative therapies to mitigate opioid-associated sleep disordered breathing (SDB) are needed. We sought to examine whether oral acetazolamide (ACZ) can enhance breathing stability in opioid-associated SDB by reducing loop gain and/or by enhancing cerebrovascular responsiveness to CO2 (CVR). We hypothesized that in patients with opioid-SDB, ingestion of ACZ will alleviate breathing instability during NREM sleep by reducing the apneic threshold (AT) and loop gain, and/or by increasing CVR. Methods Nine participants with opioid-associated SDB (age:57.8±15.5 yr, BMI:30.2±6.2 kg/m2, 7 males, 2 females, apnea-hypopnea index (AHI) 31.1±21.9/hour (hr), central apnea hypopnea index (CAHI) 6.1±9.1/hr were randomized to oral ACZ 500 mg vs. placebo drug twice a day for 6 days. On day-4, while on the drug, middle cerebral artery velocity (MCAV) was measured while awake using transcranial doppler ultrasound, using published methods. Multiple trials with hyperoxic hypercapnia breathing interspersed with room air breathing determined the cerebrovascular conductance (CVC):ΔMCAV/Δmean arterial pressure, and the slope of CVR:ΔCVC/ΔPETCO2, where Δ=trial value minus baseline value. This was followed by measurement of AT using noninvasive mechanical ventilation during NREM sleep and PSG on the following night while still on the drug. Plant gain (PG) and controller gain (CG), components of loop gain, were determined, using published methods. Averaged data from multiple CVR and AT trials are reported. Serum opioid levels were measured on the experimental night, with morphine equivalent dose:145±292 mg on ACZ study night, 127±279 mg on placebo study night. Serum bicarbonate levels confirmed use of ACZ: ACZ vs placebo:19.4±3.1mEq/L vs. 26.6±2.6mEq/L (p 0.005). Results Nine participants have completed both arms of the study. CVR could be determined in 7 out of 9 participants while AT was completed in all 9. Data are presented as ACZ vs. placebo: Conclusion In participants with opioid-associated SDB, oral ACZ significantly decreased the AT during NREM sleep by reducing the plant gain, indicating increased breathing stability compared with placebo drug, associated with reduction in the severity of SDB. However, there was no change in CVR with ACZ. Future clinical trials will establish the role of ACZ as an alternative or adjunctive therapy for opioid-associated SDB. This abstract is funded by: VHA CSRD 1I01CX001938-02A0