Wakefulnesspromoting

Wakefulness-promoting agents are a class of medications designed to reduce excessive daytime sleepiness and improve alertness in conditions such as narcolepsy, obstructive sleep apnea with EDS, shift work sleep disorder, and some forms of fatigue related to multiple sclerosis. They are distinct from traditional stimulants in their mechanisms and generally have a lower potential for abuse, though misuse can still occur.

The most commonly used wakefulness-promoting drugs include modafinil and armodafinil. Their exact mechanism is not fully understood, but they appear to enhance wakefulness by affecting brain arousal systems, including dopamine and norepinephrine pathways, and may interact with the orexin (hypocretin) system. Pitolisant is an H3 receptor antagonist/inverse agonist that increases hypothalamic histamine release to promote wakefulness. Solriamfetol inhibits dopamine and norepinephrine reuptake, promoting wakefulness through monoaminergic pathways separate from orexin signaling.

Indications typically include narcolepsy and obstructive sleep apnea with daytime sleepiness; shift work sleep disorder is another common use. Solriamfetol is approved for excessive daytime sleepiness due to narcolepsy and OSA in many regions, with additional regional indications explored for MS-related fatigue. Treatment should be individualized, with consideration of comorbidities and potential interactions with other medications.

Safety and adverse effects commonly include headache, nausea, insomnia, and anxiety. Cardiovascular effects such as elevated heart rate or blood pressure can occur. Serious rash is rare but possible. Drug interactions, particularly with agents affecting the CYP enzyme system, are important to monitor. In the United States, modafinil and armodafinil are Schedule IV controlled substances; pitolisant and solriamfetol are prescription medications not classified as controlled substances. Regulatory approvals vary by country.