A randomized, placebo-controlled, double-blind crossover trial assessing the combination of noradrenergic/serotonergic reuptake inhibitor and an antimuscarinic agent for the treatment of obstructive sleep apnea.

Abstract

Rationale: Recent evidence has demonstrated that the combination of atomoxetine (selective norepinephrine reuptake inhibitor) and oxybutynin (antimuscarinic inhibitor) greatly reduced OSA severity. Conversely, trials using serotonergic agonists have had poor success in reducing OSA severity despite previous studies demonstrating potential mechanistic pathways for improving upper airway patency. Notably, atomoxetine and oxybutynin also did not improve OSA severity when taken alone. It is therefore possible that serotonergic agents also need to be delivered in combination therapy to be efficacious. Moreover, adding a serotonergic component to the noradrenergic and antimuscarinic drug combination may further reduce OSA severity. We therefore aimed to assess the impact that (1) milnacipran and (2) duloxetine (two noradrenergic/serotonergic reuptake inhibitors), in combination with oxybutynin has on OSA severity. Method(s): A randomized, double-blind, 4 way cross-over, placebo-controlled trial in 10 OSA patients was performed with the following drug conditions administered as oral capsules prior to bedtime: 1) milnacipran/oxybutynin combination 50/5mg, 2) duloxetine/oxybutynin combination 60/5mg, 3) oxybutynin 5mg, 4) placebo. Patients received each drug condition separately across four overnight in-lab polysomnography (PSG) studies ~1-week apart. The primary outcome was OSA severity measured by the Apnea/Hypopnea Index (AHI) from overnight PSG. In order to understand how each drug combination altered OSA pathophysiology four key OSA traits (collapsibility, muscle compensation, arousal threshold, loop gain) were measured non-invasively from the PSG validated techniques. Values reported as mean+/-SD Results: All drug combinations did not significantly reduce the overall AHI compared to placebo (p=0.24). Total sleep time was consistent across each condition (p=0.92), although duloxetine/oxybutynin significantly reduced time spent in REM sleep (3.5 [4.15] vs 9.11 [7.71] %total sleep time, p=0.045). Interestingly, the combination of duloxetine/oxybutynin did reduce the supine AHI (deltaAHI -8.87 [11.15] events/h, p=0.04). Notably, airway collapsibility was improved with both duloxetine/oxybutynin (78.41 [11.54] %eupneic ventilation, p=0.002) and milnacipran/oxybutynin (71.01 [20.01] %eupneic ventilation, p=0.014) compared to placebo (64.82 [22.27] %eupneic ventilation). The arousal threshold was also lowered by Milnacipran/oxybutynin compared to placebo (146.9 [22.56] vs 158.3 [22.24] %eupneic ventilation, p=0.03) and a similar near-significant trend was seen in the duloxetine/oxybutynin condition (141.6 [27.3] %eupneic ventilation, p=0.06). Conclusion(s): The combination of two noradrenergic/serotonergic reuptake inhibitors with an antimuscarinic agent was not effective in reducing overall OSA severity. However, the combination of duloxetine/oxybutynin was able to decrease collapsibility and improve the supine AHI, indicating that this combination may be useful in a subset of carefully selected patients. Trial Registration: ACTRN12618001499279.