Flumazenil for the treatment of refractory hypersomnolence: Clinical experience with 153 patients

Abstract

Study Objectives: Patients with central disorders of hypersomnolence sometimes do not achieve satisfactory symptom control with currently available wakepromoting medications. Based on the finding that the cerebrospinal fluid from some patients with hypersomnolence demonstrates potentiation of gammaaminobutyric acid (GABA)-A receptors in excess of that of controls, a finding that reverses with flumazenil, we initiated prescribing compounded flumazenil to carefully selected, treatment-refractory hypersomnolent patients. Methods: This retrospective chart review evaluated the first 153 consecutive patients treated with transdermal and/or sublingual flumazenil by physicians at our center from 2013 through January 2015. Results: Patients were 35.5 y old (± 14.4) and 92 (60.1%) were women. Mean Epworth Sleepiness Scale scores prior to flumazenil were 15.1 (± 4.5) despite prior or current treatment with traditional wake-promoting therapies. Symptomatic benefit was noted by 96 patients (62.8%), with a mean reduction in Epworth Sleepiness Scale score of 4.7 points (± 4.7) among responders. Of these, 59 remained on flumazenil chronically, for a mean of 7.8 mo (± 6.9 mo). Female sex and presence of reported sleep inertia differentiated flumazenil responders from nonresponders. Adverse events were common, but often did not result in treatment discontinuation. Serious adverse events included a transient ischemic attack and a lupus vasculopathy, although whether these events occurred because of flumazenil administration is unknown. Conclusions: This chart review demonstrates that sublingual and transdermal flumazenil provided sustained clinical benefit to 39% of patients with treatment-refractory hypersomnolence. Prospective, controlled studies of this GABA-A receptor antagonist for the treatment of hypersomnolence are needed. Commentary: A commentary on this article appears in this issue on page 1321.