Obstructive sleep apnea (OSA) is a disorder wherein the throat muscles repeatedly relax during sleep, causing airway collapse, prolonged pauses in breathing, sleep fragmentation, poor blood oxygenation, and autonomic activation [1]. OSA is prevalent among middle-aged people and can result in significant cardiovascular and neurocognitive impairments [1, 2]. So far, pharmaceutical treatments for sleep apnea have not been successfully developed, but recent research has identified sulthiame as a promising compound to explore. 

The medical community once considered OSA to be a purely anatomical problem, but new research has revealed that non-anatomical problems contribute to the development of the disorder in up to 70% of patients [2]. This discovery is significant given that the efficacy of continuous positive airway pressure (CPAP), the mainstay therapy for OSA, is limited by poor patient compliance and incomplete tolerability [1, 3]. CPAP devices must be worn for at least four hours a night, but due to reasons such as discomfort, many patients fail to meet this threshold, resulting in residual sleep apnea [3]. 

Studies centered on the phenotypes associated with OSA have led to major advances in treatment [1]. Researchers have identified four phenotypes associated with OSA [1]. One of these is high respiratory loop gain, which is when breathing tends to overcompensate after a disruption. Overcompensation can lead to further apnea after the initial disruption. This reportedly contributes to 30 to 40% of OSA cases [2]. Compounds that quell the carbonic anhydrase enzyme improve ventilation and, thus, can eliminate respiratory drive fluctuations [2].  

One such compound is sulthiame, a drug traditionally used to combat benign childhood epilepsy [1]. Sulthiame is notable not only because it inhibits carbonic anhydrase but also because of its typically transient and mild side effects [1]. The central adverse reactions associated with sulthiame use are hyperventilation, dyspnea, gastrointestinal dysfunction, and paresthesia, all of which rarely become serious [1].  

As of now, only a few studies have explored the relationship between sulthiame and obstructive sleep apnea, but their findings have been promising. Strassberger et al. conducted a double-blind, parallel-group experiment on 56 patients with OSA [4]. Over four weeks, the patients either received 200 mg of sulthiame, 400 mg of sulthiame, or a placebo [4]. By contrast to the subjects in the placebo group, those who took sulthiame displayed markedly reduced duration of apnea and decreased hypoxic load [4]. 

Hedner et al.’s more recent experiment further reinforced the beneficial effects of sulthiame on obstructive sleep apnea [1]. This trial was set up similarly to Strassberger and colleagues’ study: 68 patients received either 200 or 400 mg of sulthiame or a placebo every day for four weeks [1]. Not only was sulthiame exceedingly safe – only six patients left the study due to adverse drug reactions, none of which were serious – but it also led to an average decrease of twenty sleep apnea events per hour [1]. This latter result is unprecedented among carbonic anhydrase inhibitors. 

Although these results are positive, more studies are necessary to test the effects of sulthiame. Furthermore, in considering the findings of the Hedner et al. study, some practitioners have raised important doubts about sulthiame. For one, the study did not report any sulthiame-related improvements in quality of life or sleepiness [5]. Additionally, sulthiame’s effects are primarily on respiratory instability, which means that breathing issues can persist despite its use [5]. This also means that patients who take it may not note any significant differences in their conditions [5]. Indeed, only a few of the subjects reported the resolution of their moderate to severe sleep apnea [2].  

While sulthiame can safely contribute to significant reductions in sleep apnea events, it may not be a complete treatment for OSA. However, it is possible that sulthiame paired with other interventions, like daytime tongue stimulation or oral negative pressure, could become an effective treatment for obstructive sleep apnea [5]. 

References 

[1] J. Hedner et al., “A Randomized Controlled Clinical Trial Exploring Safety and Tolerability of Sulthiame in Sleep Apnea,” American Journal of Respiratory and Critical Care Medicine, vol. 205, no. 12, p. 1461-1469, June 2022. [Online]. Available: https://doi.org/10.1164/rccm.202109-2043OC. 

[2] C. N. Schmickl, B. A. Edwards, and A. Malhotra, “Drug Therapy for Obstructive Sleep Apnea: Are We There Yet?,” American Journal of Respiratory and Critical Care Medicine, vol. 205, no. 12, p. 1379-1381, June 2022. [Online]. Available: https://doi.org/10.1164/rccm.202109-2043OC. 

[3] J. Hedner and D. Zou, “Drug Therapy in Obstructive Sleep Apnea,” Sleep Medicine Clinics, vol. 13, no. 2, p. 203-217, June 2018. [Online]. Available: https://doi.org/10.1016/j.jsmc.2018.03.004. 

[4] C. Strassberger et al., “Reduced hypoxic burden following carbonic anhydrase inhibition in obstructive sleep apnea – a randomized placebo-controlled study,” European Respiratory Journal, vol. 58, no. 65, 2021. [Online]. Available: https://doi.org/10.1183/13993003.congress-2021.PA747. 

[5] S. Kreimer, “Sulthiame Found Safe and Tolerable for Obstructive Sleep Apnea,” Neurology Today, Updated April 7, 2022. [Online]. Available: https://journals.lww.com/neurotodayonline/Fulltext/2022/04070/Sulthiame_Found_Safe_and_Tolerable_for_Obstructive.5.aspx?context=LatestArticles.