Results from a randomized, controlled, crossover trial show that, compared with placebo, combining viloxazine and trazodone (vilo-trazo) reduced the severity of OSA in adults by more than 50%.1 This illustrates a promising strategy for future OSA treatment.
“OSA pharmacotherapy is an emerging topic in the sleep field,” said senior author Ludovico Messineo, MD, PhD, lead investigator and Assistant Professor at Harvard Medical School and Brigham and Women’s Hospital, Boston. “However, only tirzepatide is approved for OSA currently. Although efficacious, tirzepatide only addresses one cause of sleep apnea—excess weight—and thus cannot be used in the many people who are lean but have OSA. With other OSA drugs on the horizon, we are trying to provide data to expand the offer for alternative therapies for patients with sleep apnea.”
For the study published in Thorax, researchers assigned 24 patients with OSA between 18 and 75 years of age to receive 500 mg viloxazine, 500/75 mg vilo-trazo, or placebo. Study participants took each treatment nightly for two weeks, with a one-week washout between treatments. In-laboratory polysomnography was performed at the end of each crossover period, and the primary outcome was the effect of vilo-trazo vs placebo on apnea-hypopnea index with 4% oxygen desaturation (AHI4). The secondary outcome was the combination’s effect on hypoxic burden with 4% oxygen desaturation (HB4) compared with placebo.
Compared with placebo, vilo-trazo reduced the AHI4 by a mean difference of 10.5 events per hour (95% CI, 6.6-13.6), which corresponded to a 54% reduction in OSA severity (P < .001). Similarly, compared with placebo, vilo-trazo reduced HB4 by a mean difference of 16.7% minutes per hour (95% CI, 9.6-21.8; P < .001). However, compared with placebo, vilo-trazo worsened patient-reported outcomes such as constipation, xerostomia, and insomnia.
The combination of vilo-trazo also increased subjective sleepiness. “Specifically, Epworth Sleepiness Scale scores were about two points higher on the combination vs placebo—an effect comparable to CPAP withdrawal,” Dr. Messineo said. “While unexpected, we believe this likely reflects overdosing of the combination. We are optimistic that lowering the dose could preserve the reduction in OSA severity while avoiding this ‘hangover-like’ effect.”
He noted several limitations of the study, including the small sample size, the absence of a separate treatment arm for trazodone only, and the short duration of drug administration.
“The next step would be doing a dose-finding study,” Dr. Messineo said. “Lower dosages will need to be tested to ensure that the beneficial effects on OSA severity are maintained while minimizing side effects and avoiding negative patient-reported outcomes.”
Nathan C. Nowalk, MD, MSc, a postdoctoral fellow in sleep medicine at the University of Pennsylvania who is not affiliated with the study, said the encouraging results “must be weighed against the burden of side effects. Despite stringent exclusion criteria, five of the randomized participants withdrew for mild adverse events (blurred vision, headache, nausea, increased blood pressure) attributed to the study drug.”
Dr. Nowalk described the efficacy of vilo-trazo in reducing sleep apnea severity as “highly impressive,” but broader adoption will require improved side-effect management and confirmation in larger, long-term studies, he said.
Note: This study was sponsored by Apnimed, the company making the medication, and was performed by multiple authors who either work for, or serve as consultants for, the company.
References
1. Aishah A, Kim M, Gell L, et al. Effect of viloxazine and trazodone in obstructive sleep apnoea: a randomised, placebo-controlled, cross-over study. Thorax. 2025;80(9):641-649. doi:10.1136/thorax-2024-222513
