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 wake-promoting medications. Based on the finding that the cerebrospinal fluid from some patients with hypersomnolence demonstrates potentiation of gamma-aminobutyric 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.

Keywords: GABA-A receptor; GABA-related hypersomnia; flumazenil; hypersomnolence; idiopathic hypersomnia; narcolepsy.

Figure 1. Flowchart shows clinical course of patients treated with flumazenil for refractory hypersomnolence.

*Other reasons for discontinuation included one each of: difficulty with dosing while at work, short duration of benefit, desire to become pregnant, and apparent spontaneous remission.