Orexin agonists: two steps forward, one step back

In 1880, Gélineau described a rare syndrome characterized by severe sleepiness with attacks of sleep at inappropriate times during the day and cataplexy, a sudden loss of muscle tone related to emotion; he called this syndrome narcolepsy.1 Patients with narcolepsy also have visual dreamlike hallucinations and sleep paralysis (both characteristic of rapid-eye-movement [REM] sleep), the presence of the HLA-DQB1*06:02 variant, and disturbed nocturnal sleep. This “classic” form of narcolepsy is now called narcolepsy type 1. Narcolepsy type 2 is characterized by sleepiness, aberrant REM periods at the onset of sleep, and no cataplexy. In another syndrome, idiopathic hypersomnia, patients are very sleepy but do not have cataplexy or rapid REM onset. Current management of these disorders involves polypharmacy for most patients, often with incomplete control of symptoms, profound impairment of quality of life, and unwanted adverse effects.