Objective: Determine the efficacy and tolerability of pitolisant for adjunct therapy in patients with refractory restless legs syndrome (RLS)

Background: RLS treatments include iron, dopaminergics, gabapentinoids, and opioids but symptoms often become refractory over time.  Sedating anti-histamines, 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.

Method: This is an open label trial of pitolisant titrated up to maximum dose of 35.6 mg in the AM in inadequately treated patients currently taking at least 1 RLS medication.  Primary efficacy was the IRLS and CGI at 8 weeks while on stable other RLS medications, LOCF.  Secondary endpoints included assessments of fatigue, sleepiness, and cognition.  Patient could then take pitolisant for 8 additional weeks with allowed changes in their other RLS treatments.

Results: We enrolled 21 subjects (age 67.6±10.2 years, 12 male, 16 with a family h/o RLS) who took concurrent dopaminergics (13), gabapentinoids (9), and opioids (5), with 8 subjects on dual therapy.  Two subjects dropped: AE of “worse ADHD” (1) and lost to f/u (1).  Two subjects took a final dose of <35.6mg.  The IRLS scale improved from 24.5± (5.6) to 14.5± (5.0), p<0.001, N=19), and 8/19 report marked or very marked improvement. Epworth Sleep scale also improved (p<0.01). AEs were reported by 8 including (insomnia 5, irritability 3).  In the flexible dose period, no patient consistently reduced their other RLS medications.

Conclusion: Pitolisant was generally well tolerated and improved RLS symptoms.  Controlled trials are justified.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pitolisant-as-adjunct-therapy-for-refractory-restless-legs-syndrome/