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 They have virtually superseded benzodiazepines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.
