Let's start with the benzodiazepine receptor agonist hypnotics.
This table summarizes the newer benzodiazepine receptor agonist hypnotics
that are commonly used with people with insomnia.
Let's start with the benzodiazepine receptor agonist hypnotics.
The most commonly used newer benzodiazepine receptor hypnotics
are indicated in this table.
You can see they include Ambien or Zolpidem,
Ambien CR or Zolpidem MR,
Sonata or Zaleplon, Lunesta or Zopiclone,
and that newest agent, Intermezzo,
which is an under-the-tongue formulation of Zolpidem.
The next column indicates both the adult dosage and the geriatric dosage.
The next three columns indicate the pharmacokinetics or actions of the medications.
The T-Max indicates how long it takes for
maximum availability of the medication to occur in one's system.
You could see that they have a relatively fast onset of
action from about 35 minutes to up to two hours.
Their half lives range from about one hour to five to seven hours.
And as a result, their duration of action can range from short to intermediate,
and in some cases ultra short.
Sonata, for example, has
an ultra short duration of action so that it can be used not just
at the beginning of the night but also the end of the night or the middle of the night.
Finally, the last column indicates the indications for the medications.
Ambien, for example, is used for sleep onset only.
Sonata is used for both onset and maintenance.
And you can see Lunesta can be used also for onset and maintenance.
It's important to note that these medications all act
at the GABBA A benzodiazepine receptor complex,
which is thought to be their putative mechanism of action.
So, how do these benzodiazepine receptor agonists work?
There have been two large scale meta-analyses that have looked at the effects
of benzodiazepine receptor agonists largely the older benzodiazepines and Ambien.
This table shows the effects and the outcomes of these meta-analyses.
You could see the far most column
indicates variety of sleep parameters that we think are important,
sleep latency, wake after sleep onset,
number of awakenings, total sleep time, and sleep quality.
These would be subjective ratings of improvement on these various parameters.
The numbers in the table indicate effect sizes,
which are the difference in standard deviation units between
a treated individual and an individual from a controlled condition with,
by convention, a small effect size being between 0.2 and 0.5,
a medium effect size between 0.5 and 0.8,
and a large effect size greater than 0.8.
From looking at the table, you can see that
these benzodiazepine receptor agonist hypnotics
produce moderate to large effect size on these subjective sleep parameters.
One important factor to consider is that the average treatment length for
the studies in the first meta-analysis was
roughly 35 days and the average length from the second was 14 days.
So, it's important to note that these have largely been evaluated under acute conditions,
that is only for short periods of time.
Lunesta is one exception to that rule.
There have been two large-scale randomized controlled trials of Lunesta.
This slide shows the results from one of them.
In this particular study,
almost 800 individuals with primary insomnia were
randomized to receive either Lunesta 3 milligrams,
or placebo nightly for six consecutive months.
The graph shows the effects of the medication versus placebo on
wake after sleep onset which is middle of the night wakefulness.
You can see from the graph that Lunesta in yellow outperformed placebo
starting at month one and these benefits were
sustained across all six months of the study.
So, the results of both randomized controlled trials indicate that Lunesta,
when taken nightly under randomized controlled conditions,
has benefits on sleep maintenance insomnia for at least six months.
There's at least one open label study that additionally indicates that
the effects are beneficial up to one year in length.
What about if you take the medications not nightly but on a non-nightly basis?
Many patients are instructed to use the medications not every night but only when they
have insomnia difficulties or to sparingly use them under only certain conditions.
This study evaluated the effects of non-nightly use of
Zolpidem or Ambien in individuals with primary insomnia.
In this study, nearly 200 individuals with primary insomnia were
assigned to either intermittent Zolpidem or placebo.
Intermittent was they could use the medication or
placebo a minimum of three days and a maximum of five days.
The graph shows the effects on sleep latency,
that is time fall sleep,
when individuals took the pill on the left,
and when they didn't take the pill on the right.
You could see that relative to placebo,
when individuals took the active Ambien medication,
it benefited ability to fall asleep over the 12 weeks of the study.
However, when they didn't take the medication,
sleep latency returned to baseline and they were no different from placebo.
Results from this particular study indicate that individuals who use Zolpidem on
a non-nightly basis will benefit when taking the pill but there's
no carry over effect to nights when they don't take the medication.
Ralph Lydic, Ph.D.Professor Emeritus, Molecular and Integrative Physiology, Professor Emeritus, Anesthesiology
Helen Baghdoyan, Ph.D.Professor Emeritus, Anesthesiology, Professor Emeritus, Pharmacology, Professor of Psychiatry
