Flumazenil for the Treatment of Refractory Hypersomnolence: Clinical Experience with 153 Patients

Trotti, Lynn Marie; Saini, Prabhjyot; Koola, Catherine; LaBarbera, Vincent; Bliwise, Donald L.; Rye, David B.

doi:10.5664/jcsm.6196

Cited by 54 publications

(27 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A trial (NCT01183312) utilized retrospective chart review of 153 patients treated with flumazenil transdermal cream and/or sublingual flumazenil titrated up to 12 mg 4×/d 55. The study showed symptomatic reduction in sleepiness in 62.8% of patients, with mean reduction of ESS by 4.7±4.7.…”

Section: New Developments and Future Therapiesmentioning

confidence: 99%

New developments in the management of narcolepsy

Abad

Guilleminault

2017

NSS

View full text Add to dashboard Cite

Narcolepsy is a life-long, underrecognized sleep disorder that affects 0.02%–0.18% of the US and Western European populations. Genetic predisposition is suspected because of narcolepsy’s strong association with HLA DQB1*06-02, and genome-wide association studies have identified polymorphisms in T-cell receptor loci. Narcolepsy pathophysiology is linked to loss of signaling by hypocretin-producing neurons; an autoimmune etiology possibly triggered by some environmental agent may precipitate hypocretin neuronal loss. Current treatment modalities alleviate the main symptoms of excessive daytime somnolence (EDS) and cataplexy and, to a lesser extent, reduce nocturnal sleep disruption, hypnagogic hallucinations, and sleep paralysis. Sodium oxybate (SXB), a sodium salt of γ hydroxybutyric acid, is a first-line agent for cataplexy and EDS and may help sleep disruption, hypnagogic hallucinations, and sleep paralysis. Various antidepressant medications including norepinephrine serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants are second-line agents for treating cataplexy. In addition to SXB, modafinil and armodafinil are first-line agents to treat EDS. Second-line agents for EDS are stimulants such as methylphenidate and extended-release amphetamines. Emerging therapies include non-hypocretin-based therapy, hypocretin-based treatments, and immunotherapy to prevent hypocretin neuronal death. Non-hypocretin-based novel treatments for narcolepsy include pitolisant (BF2.649, tiprolisant); JZP-110 (ADX-N05) for EDS in adults; JZP 13-005 for children; JZP-386, a deuterated sodium oxybate oral suspension; FT 218 an extended-release formulation of SXB; and JNJ-17216498, a new formulation of modafinil. Clinical trials are investigating efficacy and safety of SXB, modafinil, and armodafinil in children. γ-amino butyric acid (GABA) modulation with GABAA receptor agonists clarithromycin and flumazenil may help daytime somnolence. Other drugs investigated include GABAB agonists (baclofen), melanin-concentrating hormone antagonist, and thyrotropin-releasing hormone agonists. Hypocretin-based therapies include hypocretin peptide replacement administered either through an intracerebroventricular route or intranasal route. Hypocretin neuronal transplant and transforming stem cells into hypothalamic neurons are also discussed in this article. Immunotherapy to prevent hypocretin neuronal death is reviewed.

show abstract

Section: New Developments and Future Therapiesmentioning

confidence: 99%

New developments in the management of narcolepsy

Abad

Guilleminault

2017

NSS

View full text Add to dashboard Cite

show abstract

“…Although this enhancement of GABAergic transmission has not been shown to be causal to sleepiness or long sleep durations in patients with IH, biological plausibility is demonstrated by the known GABAergic mechanisms of sleep onset and maintenance, as well as the prominent role of GABA-A receptor agonists/modulators in the production of pharmacologic sleep and anesthesia (9–12). Further, symptoms of IH are reversible in some patients with use of GABA-receptor antagonists or negative allosteric modulators (see Treatment Resistance , below) (8, 13, 14). …”

Section: Introductionmentioning

confidence: 99%

Idiopathic Hypersomnia

Trotti

2017

Sleep Medicine Clinics

Self Cite

View full text Add to dashboard Cite

Idiopathic hypersomnia (IH) is a chronic neurological disorder that results in daytime sleepiness, frequently accompanied by long nocturnal or daytime sleep, unrefreshing sleep, difficulty in awakening, cognitive dysfunction, and autonomic symptoms. The cause of idiopathic hypersomnia is presently unknown, although a genetic predisposition is suggested by the strong family history of similar symptoms. Dysfunction of autonomic, inflammatory, or immune systems has been proposed, and patients with IH have been found to have an endogenous modulator of GABA-A receptors within their cerebrospinal fluid. Diagnosis of IH involves a careful clinical history, with particular attention to the possibility of other disorders with similar symptomatology, and objective testing with actigraphy, polysomnography, and multiple sleep latency testing. There are no FDA-approved treatments for IH symptoms, which are typically treated with off-label use of medications approved for narcolepsy. Modafinil is first line and supported by two randomized, controlled trials in IH patients. A substantial fraction of IH patients are refractory or intolerant to standard treatments, and different treatment strategies, employing novel therapeutics, are necessary in these cases. Even with current treatment options, quality of life and safety may remain impaired in patients with this challenging chronic disease.

show abstract

“…Flumazenil is a competitive antagonist of benzodiazepines without intrinsic activity upon GABA signaling 10–12 , so the most parsimonious explanation for its relieving sleepiness is via reversal of endogenous PAMs of GABA A Rs. 13 Sustained, clinically-significant benefit was observed in ~40% of 153 treatment-refractory hypersomnolent subjects with open-label use of compounded flumazenil. 13 …”

Section: : Clinical Implicationsmentioning

confidence: 99%

“…13 Sustained, clinically-significant benefit was observed in ~40% of 153 treatment-refractory hypersomnolent subjects with open-label use of compounded flumazenil. 13 …”

Section: : Clinical Implicationsmentioning

confidence: 99%

Rigor, reproducibility, and in vitro cerebrospinal fluid assays: The devil in the details

Moody

Talwar

Jenkins³

et al. 2017

Annals of Neurology

Self Cite

View full text Add to dashboard Cite

Divergent results and misinterpretation of non-significant findings remain problematic in science – especially in retrospective, hypothesis generating, translational research.1 When such divergence occurs, it is imperative that the cause of the divergence be established. In their recent paper in Annals of Neurology, Dauvilliers et al2 challenged our earlier finding that cerebrospinal fluid (CSF) from some patients with unexplained excessive daytime sleepiness enhances the activation of GABAA receptors (GABAA-R)3. They present data from 15 subjects in which they were unable to find evidence of enhanced activation of GABAA receptors. Here we: 1) establish how flaws in Dauvilliers’ experimental design account for this difference; 2) present new data demonstrating the robustness and reproducibility of our methods and 3) summarize the clinical promise of GABAA-R antagonism in treating IH and related disorders.

show abstract

Flumazenil for the Treatment of Refractory Hypersomnolence: Clinical Experience with 153 Patients

Abstract: A commentary on this article appears in this issue on page 1321.

Cited by 54 publications

References 21 publications

New developments in the management of narcolepsy

New developments in the management of narcolepsy

Idiopathic Hypersomnia

Rigor, reproducibility, and in vitro cerebrospinal fluid assays: The devil in the details

Contact Info

Product

Resources

About