Intranasal Dexmedetomidine and Zolpidem for Treatment of Primary Insomnia

A Randomized, Placebo-controlled Crossover Trial of Intranasal Dexmedetomidine and Zolpidem for Treatment of Primary Insomnia

Insomnia is a significant public health burden, increasing work absenteeism and health care costs in a large proportion of the population. It causes altered cognition, emotional disturbances, and reduced quality of life. The purpose of this study is to determine whether the sleep promoting effect of dexmedetomidine is superior to the conventional sleep promoting drug, zolpidem.

The main outcome of this study is to measure the time taken to fall asleep. Investigators will also look at incidences of wakening after sleep onset, sleep quality and wake time during sleep.

Study Overview

• Status: Recruiting
• Conditions: Insomnia
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Zolpidem; Other: Placebo

Detailed Description

Insomnia is a significant public health burden, increasing work absenteeism and health care costs in a large proportion of the population. It causes altered cognition, emotional disturbances, and reduced quality of life. Most epidemiologic studies have found that about one-third of adults report at least one symptom of insomnia e.g. difficulty initiating sleep or maintaining sleep. There are also similar problems related to circadian rhythm disturbance as seen in shift workers and "jet lag". Research indicates that DNA damage is apparent in doctors subjected to sleep deprivation. Traditional currently available hypnotics which are used to initiate and maintain sleep ("sleeping tablets") are either benzodiazepines (BZD) or the so-called Z-drugs (zolpidem, zopiclone and zaleplon) which are a class of psychoactive drugs that are very benzodiazepine-like in nature and act by allosterically activating gamma-aminobutyric acid receptor A (GABAA). They have virtually superseded benzodiazepines but have almost entirely the same pharmacodynamic effects and, therefore, exhibit similar action, side-effects, and risks. Despite their name, these drugs do not induce natural sleep as manifest by EEG. They are central nervous system depressants that disproportionately promote non-rapid eye movement (NREM) sleep while suppressing REM sleep. Selective REM sleep deprivation in humans has adverse effects on memory consolidation and pain perception. Other problems with these drugs include numerous reports of misuse, abuse and dependence, paradoxical reactions, increased risk of road traffic accidents and exacerbation of asthma. A retrospective cohort study of more than 100,000 age- and sex-matched patients showed that those who used these drugs were 3 times more likely to die prematurely during the 7 -year follow-up period than those who did not, with significant dose-response associations shown for benzodiazepines and the "Z drugs". New evidence-based clinical practice guidelines for the treatment of insomnia disorder were recently developed using the GRADE methodology (Grading of Recommendations, Assessment, Development, and Evaluation) and represent the first comprehensive, systematic analysis of single agents for treatment. Unfortunately, the level of evidence for all recommendations was "weak" meaning that the strength of the evidence in the published data were low. Notably, all the recommended treatments for sleep onset insomnia, besides ramelteon, a melatonin receptor agonist , are Z-drugs or BZD hypnotics. For sleep maintenance insomnia, three of five of the treatment options are Z-drugs or BZDs. The US Food and Drug Administration has recently put a Boxed Warning on Z drugs since serious injuries and death from complex sleep behaviours have occurred in patients with and without a history of such behaviours. These behaviours can occur after just one dose. Clearly, better pharmacological treatment is warranted. Dexmedetomidine is a highly selective alpha-2 adrenergic receptor antagonist that acts on the locus ceruleus1 in the brain to produce dose dependent sedation, anxiolysis and analgesia with no respiratory depression and only modest haemodynamic effects. It has been extensively studied and used for both adult and paediatric sedation, premedication, intensive care and in perioperative settings to prevent emergence delirium after anaesthesia. The sedative effect of this drug is unique in that it produces prominent slow wave activity in the electroencephalogram (EEG) resembling stage 2 NREM sleep with facilitated arousal (as with natural sleep). Of the sleeping states, the NREM sleep period seems fundamental because it happens first (wakefulness to NREM) and lasts the longest. It has even been suggested as a suitable drug to induce torpor in manned space flight. The intravenous formulation is also efficacious when administered by the intranasal route in both children and adults. Since this is not associated with any unpleasant sensation, there is increasing use for paediatric premedication and procedural sedation. The bioavailability of intranasal dexmedetomidine administered by atomiser or by drops is approximately 40% in healthy adult volunteers with an inter-individual variability of around 30%. The pharmacokinetic and pharmacodynamic profiles of the two modes of administration are similar and both are equally effective in inducing adequate sedation.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Micheal Garnet Irwin, M.B. Ch.B; Phone Number: 22553303/ 97018342; Email: mgirwin@hku.hk

Study Locations

• China
  • Guangdong
    • Hong Kong, Guangdong, China, 999077
      • Recruiting
      • HKU Li Ka Shing Faculty of Medicine
      • Contact: Chong; Phone Number: (852)22553749

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 25 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants aged between 18 to 25 years, with DSM-5 insomnia disorder. Insomnia will be diagnosed and confirmed by a clinical interview and will have an Insomnia Severity Index score of ≥ 15.

Exclusion Criteria:

1. Comorbid diagnosis of psychiatric disorders ( major depression, anxiety disorders, bipolar disorders and psychotic disorders)
2. Obstructive sleep apnoea as determined by an Apnea Hypoapnea Index of >15 or snoring.
3. Restless legs, or periodic limb movements during sleep as measured by the Periodic Limb Movements Index with arousal of > 15 per hour
4. Obesity (body mass index > 30)
5. Known or suspected cardiovascular, pulmonary, metabolic disease or diabetes as confirmed by the clinician interview during recruitment
6. Pregnancy
7. Anyone who has taken trans-meridian travel across more than one time-zone or worked night shifts in the preceding three months
8. Consuming prescribed or non-prescription sleep medication in the past month

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; a placebo oral tablet and intranasal saline at 0.02 ml/kg
Experimental: Dexmedetomidine	Drug: Dexmedetomidine; 2 mcg/kg of undiluted dexmedetomidine [= 0.02 ml/kg] and oral placebo tablet
Active Comparator: Zolpidem	Drug: Zolpidem; zolpidem 10 mg and intranasal saline 0.02 ml/kg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep onset latency	Sleep onset latency is a measure of how long it takes for the participant to fall asleep once the participant gets into bed. This will be measured in minutes and reported as minutes for each of the treatments	720 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of wakening after sleep onset; Sleep quality; Wake time during sleep	Incidence of wakening after sleep onset: This is a measure of how many times the participant will wake up after falling asleep. It will be measured as count data. Sleep quality: This is a subjective measure and will be given as a score from a survey completed by the participant. The data will be reported as count data Wake time during sleep: This will be detected with the polysomnography and will be reported in total minutes	720 minutes

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Investigators: Principal Investigator: Micheal Garnet Irwin, M.B. Ch.B, The University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2022
• Primary Completion (Anticipated): September 1, 2023
• Study Completion (Anticipated): September 1, 2024

Study Registration Dates

• First Submitted: October 12, 2022
• First Submitted That Met QC Criteria: November 7, 2022
• First Posted (Actual): November 14, 2022

Study Record Updates

• Last Update Posted (Actual): November 14, 2022
• Last Update Submitted That Met QC Criteria: November 7, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Insomnia; Dexmedetomidine; Zolpidem
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Initiation and Maintenance Disorders; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; GABA Agents; Sleep Aids, Pharmaceutical; GABA-A Receptor Agonists; GABA Agonists; Dexmedetomidine; Zolpidem
• Other Study ID Numbers: UW 21-386

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No