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The broad objective of this investigation is to assess the safety and efficacy of oral therapy with dexmedetomidine for the induction and maintenance of restful sleep.
Specific Aim 1: Investigate the safety profile of dexmedetomidine in a phase I dose finding study.
Hypothesis 1.1. Oral/sublingual dexmedetomidine will maintain cardiovascular stability Hypothesis 1.2. Oral/sublingual dexmedetomidine will result in electroencephalographic evidence of spindle and slow/delta oscillation.
Specific Aim 2: Investigate the efficacy of dexmedetomidine for inducing sleep in a Phase II randomized double-blind placebo-controlled study.
Hypothesis 2.1. Oral/sublingual will reduce sleep latency Hypothesis 2.2. Oral/sublingual dexmedetomidine will improve sleep efficiency
Evidence For Repurposing Dexmedetomidine as a Sleep Therapeutic
Dexmedetomidine is an alpha-2 adrenergic agonist that is typically administered as an anesthetic adjunct. Patients who are sedated with dexmedetomidine are arousable and responsive in a manner that is very similar to that seen in people who are sleeping. Dexmedetomidine is thought to alter arousal primarily through its actions on pre-synaptic alpha-2A adrenergic receptors on neurons projecting from the LC. Dexmedetomidine binding hyperpolarizes LC neurons, decreasing norepinephrine release. Hyperpolarization of LC neurons results in loss of inhibitory inputs to the pre-optic area of the hypothalamus and excitatory inputs to the cortex, basal forebrain and the central thalamus. The pre-optic area sends GABAergic and galanergic inhibitory projections to the major arousals centers in the midbrain, pons and hypothalamus. Hence, loss of inputs from the LC is thought to result in sleep-like state, due to activation of inhibitory pathways from the pre-optic area to the arousal centers along with loss of excitatory inputs to the cortex, basal forebrain and the central thalamus. Not surprisingly, as in non-REM II sleep, spindles and slow oscillations are associated with the altered state of arousal that is induced by dexmedetomidine. It is important to note the behavioral and neurophysiologic similarities between dexmedetomidine-induced altered arousal and sleep occurs because activation of inhibitory inputs from the pre-optic area is an essential component of how non-REM sleep is initiated.
The investigators recently conducted a clinical trial (NCT01485380) that utilized a combination of high-density EEG and Fludeoxyglucose Positron Emission Tomography/Magnetic Resonance (PET/MR) imaging to study the brain states induced by dexmedetomidine. Results from this clinical trial of dexmedetomidine suggests that this drug may be used to induce and maintain a brain state that closely approximates non-REM II sleep state characterized by sleep spindles, and slow-delta oscillations. Similar to non-REM sleep, the investigators also found that dexmedetomidine decreased cerebral blood flow and cerebral metabolism, but maintained cortico-cortical functional connectivity patterns. These results lend to a very specific rhythms based hypothesis of the mechanisms necessary to engage sleep. Can successful sleep state switching be accomplished in humans by inducing a non-REM II state and then allowing indigenous sleep mechanism to engage normal sleep cycling. Until now, it has been unclear whether any pharmacological agent can induce a state that closely approximates natural sleep or sleep state switching. The possibility that dexmedetomidine could be used as a sleep therapy has not been readily apparent because it is currently marketed as an intravenous drug. Furthermore, a systems neuroscience approach to studying the dexmedetomidine-induced brain state had previously not been accomplished. A key strength of this proposal is that it is based upon compelling results obtained from our recently conducted Phase I/II proof-of-concept clinical study (NCT01485393) where the investigators established the safety, efficacy, dosing paradigm, and dose for successfully using dexmedetomidine to induce sleep, which is characterized by non-REM I-III and REM sleep states. Therefore, the investigators hypothesize that oral dexmedetomidine will shorten sleep latency by inducing a non-REM II state that will allow indigenous sleep mechanisms to engage successful sleep state switching into non-REM III and REM sleep states, conferring the restorative benefits of sleep.
Currently dexmedetomidine is not available in an oral or sub-lingual preparation. However, the intravenous form of dexmedetomidine has a buccal bioavailability of approximately 86% and an oral bioavailability of approximately 16%. In our clinical practice of anesthesiology, the oral solution of dexmedetomidine, which is the intravenous formulation administered at up to 5 times the typical intravenous bolus dose of 1mcg/kg has been used off-label and shown to be effective as a sedative. Thus, the investigators expect that the oral reformulations of dexmedetomidine will be bioavailable and efficacious. Importantly, the oral administration of dexmedetomidine solution at up to 5 times of the recommended bolus dose does not appear to result in either of the two commonly reported side effects of hypotension and bradycardia that are associated with intravenous administration of dexmedetomidine. Therefore, the investigators expect oral dexmedetomidine to be efficacious and safe for administration in humans.
In summary, existing sleep medications are non-specific sedatives with significant cognitive side effects. However, our systems neuroscience based studies and proof-of-concept studies strongly suggest that dexmedetomidine is biochemically and neurophysiologically well suited to engage the natural mechanisms that drive sleep. Thus, this study will demonstrate a putative new class of sleep therapeutics to treat insomnia. If this research is successful, the investigators will see a resolution to the problem of morbidity caused by insomnia and side effects of current sleep therapeutics.
Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Dexmedetomidine, Saline Placebo
Massachusetts General Hospital
Not yet recruiting
Massachusetts General Hospital
Published on BioPortfolio: 2016-06-29T20:53:21-0400
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