Exploratory cross-over, trial of augmented RLS with the dopamine receptor 1/5 antagonist ecopipam D1/D5 antagonist ecopipam for augmented RLS

Background: Restless legs syndrome (RLS) is a common condition that initially responds dramatically to dopaminergic therapy. Over time, however, dopaminergics cause augmentation, where symptoms occur earlier and intensify. Animal models suggest this may result from increased dopamine receptor type-1 affinity in the spinal cord. Ecopipam is a potent, specific dopamine-1/5 receptor antagonist. Methods: We performed a small (N = 10) exploratory placebo controlled, cross-over safety trial of ecopipam (25–100 mg/day) for patients with augmented RLS currently taking dopamine agonists. Results: Ecopipam was well tolerated with sedation being the most common adverse event in drug and placebo. Safety scales and serology data were similar to placebo. The study was not powered to demonstrate efficacy and exploratory efficacy data showed no significant improvement compared to placebo, but RLS diaries, the international RLS rating scale, and clinical global impressions all favored drug. No subject worsened on drug or demonstrated rebound worsening after drug discontinuation. Conclusion: Ecopipam was safe and well tolerated in this initial study for RLS. Given the lack of alternate options, larger efficacy studies for augmented RLS, and potentially de novo RLS are justified.