Flumazenil for the Treatment of Primary Hypersomnia
| Status: | Completed |
|---|---|
| Conditions: | Insomnia Sleep Studies |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 12/14/2017 |
| Start Date: | September 2010 |
| End Date: | January 2012 |
A Ten Subject, Double-Blind, Placebo-Controlled Trial of Single Day Dosing of Sublingual Flumazenil in Individuals With Primary Hypersomnia or Excessively Long Total Sleep Time and Excess Endogenous Potentiation of GABA-A Receptors
The term 'hypersomnia' describes a group of symptoms that includes severe daytime sleepiness
and sleeping long periods of time (more than 10 hours per night). Sometimes, hypersomnia is
caused by a problem with the quality of sleep occurring at night, for instance when nighttime
sleep is disrupted by frequent breathing pauses. In other cases, however, hypersomnia occurs
even when nighttime sleep is of good quality. These cases of hypersomnia are presumed to be a
symptom of brain dysfunction, and so are referred to as hypersomnias of central (i.e., brain)
origin, or primary hypersomnias.
The causes of most of these primary hypersomnias are not known. However, our group has
recently identified a problem with the major brain chemical responsible for sedation, known
as GABA. In a subset of our hypersomnia patients, there is a naturally-occurring substance
that causes the GABA receptor to be hyperactive. In essence, it is as though these patients
are chronically medicated with Valium (or Xanax or alcohol, all substances that act through
the GABA system), even though they do not take these medications.
Current treatment of central hypersomnias is limited. For the fraction of cases with
narcolepsy, there are FDA-approved, available treatments. However, for the remainder of
patients, there are no treatments approved by the FDA. They are usually treated with
medications approved for narcolepsy, but sleep experts agree that these medications are often
not effective for this group of patients.
Based on our understanding of the GABA abnormality in these patients, we evaluated whether
flumazenil (an medication approved by the FDA for the treatment of overdose of GABA
medications or the reversal of GABA-based anesthesia) would reverse the GABA abnormality in
our patients. In a test tube model of this disease, flumazenil does in fact return the
function of the GABA system to normal. The investigators have treated a few patients with
flumazenil and most have felt that their hypersomnia symptoms improved with this treatment.
To determine whether flumazenil is truly beneficial for primary hypersomnia, this study will
compare flumazenil to an inactive pill (the placebo). All subjects will receive both
flumazenil and the placebo at different times, and their reaction times and symptoms will be
compared on these two treatments to determine if one is superior. Currently, flumazenil can
only be given through an injection into a vein (i.e., intravenously). This study will
evaluate this intravenous dosing as well as a new form of flumazenil, which is taken as a
lozenge to be dissolved under the tongue. If this study shows that flumazenil is more
effective than placebo in the treatment of hypersomnia, it will identify a potential new
therapy for this difficult-to-treat disorder.
and sleeping long periods of time (more than 10 hours per night). Sometimes, hypersomnia is
caused by a problem with the quality of sleep occurring at night, for instance when nighttime
sleep is disrupted by frequent breathing pauses. In other cases, however, hypersomnia occurs
even when nighttime sleep is of good quality. These cases of hypersomnia are presumed to be a
symptom of brain dysfunction, and so are referred to as hypersomnias of central (i.e., brain)
origin, or primary hypersomnias.
The causes of most of these primary hypersomnias are not known. However, our group has
recently identified a problem with the major brain chemical responsible for sedation, known
as GABA. In a subset of our hypersomnia patients, there is a naturally-occurring substance
that causes the GABA receptor to be hyperactive. In essence, it is as though these patients
are chronically medicated with Valium (or Xanax or alcohol, all substances that act through
the GABA system), even though they do not take these medications.
Current treatment of central hypersomnias is limited. For the fraction of cases with
narcolepsy, there are FDA-approved, available treatments. However, for the remainder of
patients, there are no treatments approved by the FDA. They are usually treated with
medications approved for narcolepsy, but sleep experts agree that these medications are often
not effective for this group of patients.
Based on our understanding of the GABA abnormality in these patients, we evaluated whether
flumazenil (an medication approved by the FDA for the treatment of overdose of GABA
medications or the reversal of GABA-based anesthesia) would reverse the GABA abnormality in
our patients. In a test tube model of this disease, flumazenil does in fact return the
function of the GABA system to normal. The investigators have treated a few patients with
flumazenil and most have felt that their hypersomnia symptoms improved with this treatment.
To determine whether flumazenil is truly beneficial for primary hypersomnia, this study will
compare flumazenil to an inactive pill (the placebo). All subjects will receive both
flumazenil and the placebo at different times, and their reaction times and symptoms will be
compared on these two treatments to determine if one is superior. Currently, flumazenil can
only be given through an injection into a vein (i.e., intravenously). This study will
evaluate this intravenous dosing as well as a new form of flumazenil, which is taken as a
lozenge to be dissolved under the tongue. If this study shows that flumazenil is more
effective than placebo in the treatment of hypersomnia, it will identify a potential new
therapy for this difficult-to-treat disorder.
Inclusion Criteria:
- Hypersomnia (meeting clinical criteria for idiopathic hypersomnia with or without long
sleep time, narcolepsy lacking cataplexy, or symptomatic hypersomnia not meeting
International Classification of Sleep Disorders 2 (ICSD-2) criteria inclusive of
habitually long sleep periods of > 10 hours/day)
- evidence for GABA-related abnormality, as demonstrated by our in-house, in vitro assay
- age > 18
- high performance liquid chromatography/liquid chromatography tandem mass spectrometry
verification of the absence of exogenous benzodiazepines (BZDs).
Exclusion Criteria:
- Contraindications to use of flumazenil (pregnancy, hepatic impairment, seizure
history, pre-menstrual dysphoric disorder, traumatic brain injury, cardiac disease
(left ventricular diastolic dysfunction), or cardiac dysrrhythmia.
- Current use of a BZD or BZD-receptor agonists
- moderate or severe sleep apnea (RDI > 15/hr), severe periodic limb movement disorder
(PLMI > 30/hr)
- diagnosis of narcolepsy with cataplexy, as determined by ICSD-2 criteria and confirmed
by absence of cerebrospinal fluid (CSF) hypocretin
- metabolic disorders such as severe anemia, adrenal insufficiency, severe iron
deficiency, vitamin B12 deficiency, or hypothyroidism that may explain symptoms of
hypersomnia
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