Fast-Acting Sublingual Zolpidem for Middle-of-the-Night Wakefulness

Abstract

Sleep disorders (somnipathies) are conditions characterized by disruptions of sleep quality or of sleep pattern. They can involve difficulty falling asleep (prolonged sleep onset latency), difficulty staying asleep (disturbance of sleep maintenance), sleep of poor quality (unrefreshing), or combinations of these and can lead to poor health and quality of life problems. A subtype of sleep-maintenance insomnia is middle-of-the-night wakefulness, a relatively common occurrence. Zolpidem, a nonbenzodiazepine benzodiazepine receptor agonist, allosterically modulates an ion channel and increases the influx of Cl(-), thereby dampening the effect of excitatory (sleep disrupting) input. Recently, product label changes to some zolpidem containing products have been implemented by the FDA in order to reduce the risk associated with their morning after residual side effects. A new formulation of zolpidem tartrate (Intermezzo) sublingual tablet, an approved product indicated exclusively for the treatment of middle-of-the-night wakefulness and difficulty returning to sleep, did not have its label changed. We present a short summary of its basic science and clinical attributes in light of the recent regulatory changes for zolpidem products.

Figure 1

The prevalence of nightly nocturnal awakenings by age group (based on data from Ohayon) [64].

Figure 2

The pentameric structure of the GABA_A receptor is composed of 4-transmembrane monomeric subunits (a disulfide bond in the N-terminal extracellular domain, characteristic of the family of cys-loop receptors which includes the GABA_A receptor, is depicted). Zolpidem allosterically enhances Cl⁻ influx, which hyperpolarizes the neuronal transmembrane potential (at I), thereby making it less likely to fire in response to excitatory input (at E).