Pilot study of Pitolisant, a histamine-3 inverse agonist, as adjunct therapy for refractory restless legs syndrome

• Published in: Sleep medicine Vol. 133; p. 106634
• Main Author: Ondo, William G.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2025
• Subjects: Aged; Clinical trial; Female; Humans; Male; Middle Aged; Pilot Projects; Piperidines - administration & dosage; Piperidines - adverse effects; Piperidines - therapeutic use; Pitolisant; Restless legs syndrome; Restless Legs Syndrome - drug therapy; Treatment Outcome; Pitolisant; Restless legs syndrome; Clinical trial
• ISSN: 1389-9457; 1878-5506; 1878-5506
• DOI: 10.1016/j.sleep.2025.106634

Restless leg syndrome (RLS) treatments include iron, dopaminergics, gabapentinoids, and opioids, but symptoms often become refractory over time. Sedating antihistamines, which cross the blood-brain border, frequently exacerbate RLS. Pitolisant is a stimulant Histamine-3 inverse agonists that increases CNS histamine transmission. It is currently used to treat narcolepsy. This open label trial titrated pitolisant to a maximum dose of 35.6 mg in the AM, in inadequately treated patients currently taking at least 1 RLS medication. Primary efficacy was the International RLS Rating Scale (IRLSRS) at 8 weeks, while on stable other RLS medications. Secondary endpoints included assessments of fatigue, sleepiness, and cognition. Patients then took pitolisant for 8 additional weeks with allowed changes to their other RLS treatments. We enrolled 21 subjects (age 67.6 ± 10.2 years, 12 male, 16 with a family history of RLS) who took concurrent dopaminergics (15), gabapentinoids (9), and opioids (8), with 11 subjects on dual therapy. Two subjects dropped: AE of “worse ADHD/irritability” (1) and lost to follow-up (1). Two other subjects took a final dose of <35.6 mg. At week 8, the IRLSRS scale improved from 24.5 ± 4.6 to 17.2 ± 5.5, p < 0.001, N = 21), and 8/19 report marked or very marked improvement. The RLS-6 (p = 0.005) and Epworth Sleep scale also improved (p < 0.01). Scales for fatigue, cognition, and depression were unchanged. Adverse events were reported by 9 subjects including insomnia in 6. Pitolisant was generally well tolerated and improved RLS scales. The data suggests more improvement in daytime consequences of RLS compared to lessening of the core RLS symptoms. Controlled trials are justified. •Sedating Histamine-1 antagonists can worsen RLS, suggesting increasing CNS histamine via pre-synaptic Histamine-3 inverse agonists like pitolisant might improve RLS.•Open label pitolisant, up to 37.5 mg/day, improved the IRLS scale from 24.5 ± 4.6 to 17.2 ± 5.5, p < 0.001, (N = 21) at week 8.•Pitolisant was well tolerated with insomnia (N = 6) the most common adverse event.•Specific IRLS questions suggests more improvement in daytime functioning compared to reduction in the core RLS features.