Somnipathies can impact different aspects of good quality sleep. They include difficulty falling asleep (i.e., onset latency), and/or staying asleep (disturbance of sleep maintenance, and the subtype of middle-of-the-night wakefulness), poor quality sleep (viz., not refreshing), or some combination of these. All can lead to poor health and quality of life problems.

There are two widely accepted treatments for insomnia: cognitive behavioral therapy for insomnia (CBT-I) and pharmacotherapy [1] [12] . CBT-I is a structured behavioral approach typically including education and training in relaxation techniques, good sleep hygiene, stimulus control, sleep restriction, and cognitive techniques, which designed to identify and mitigate negative cognitive and behavioral influences on sleep [13] .

The pharmacotherapeutic approach usually works much more rapidly than CBT-I does (minutes vs weeks), and is just as effective short-term, but it might have less carry-over effect than CBT-I [1] [13] . And of course CBT-I carries no risk of adverse effects. However, CBT-I availability is limited, time-consuming, and expensive. Less than 5% of chronic insomniacs utilize CBT-I, [14] and pharmacotherapy remains the primary treatment [1] .

The inhibitory amino acid GABA (γ-aminobutyric acid) acts through the GABA_A receptor to play an important role in sleep/wake cycles [26] [27] [28] . Binding of either GABA itself or an exogenous agonist analog to the GABA_A receptor, which is a ligand-gated ionotropic type receptor, increases Cl⁻ ion influx down its concentration difference from the extracellular side to the intracellular side of neurons. Since the neuronal transmembrane resting potential difference is already negative, the influx of Cl⁻ hyperpolarizes the neuron, i.e., increases the transmembrane potential difference, producing a post-synaptic inhibitory potential (IPSP). The resultant hyperpolarization means that the neuron is less likely to fire in response to an excitatory input, which favors sleep.

Because of their efficacy and safety in short-term use, BZDs have been popular choices for short term treatment of insomnia. BZDs produce their effect by binding to specific sites (BzRs) on the GABA_A receptor complex, producing allosteric modulation, inhibition of neuronal excitation, and an increase in speed of sleep onset and increase in total sleep time [29] [30] [31] . The BZDs represent an advance over preceding sedatives, including barbiturates, in that they are more selective and produce fewer adverse effects. However, they also have the potential for tolerance and dependence, and produce their own set of adverse effects such as disruption of psychomotor function, impairment of memory, paradoxical excitement, depression, and potential teratogenicity. [32] And they are a special problem for elderly patients, because of the potential for cognitive impairment, delirium, falls, and bone fractures [33] . In response to the problems associated with the BZDs, non-BZD BzRAs were developed to minimize adverse effects and abuse potential associated with the BZDs.

Chemically, zolpidem is an imidazopyridine, not a benzodiazepine, but pharmacologically it acts the same way, that is, as a benzodiazepine receptor agonist. It displays selective binding affinity and functional efficacy at GABA_A receptors that contain α1 subunits [19] . Since subunits in addition to α-1 have been associated with sedative action and sleep continuity, the molecular mechanism underlying the clinical efficacy of zolpidem’s hypnotic action is likely to involve subunits other than α-1.

Zolpidem’s pharmacokinetics and efficacy favor its short-term use for insomnia: it is rapidly distributed to the central nervous system [34] , it does not have active metabolites, it is rapidly eliminated, and it does not accumulate after repeated administration [35] . And in most patients it reduces sleep latency [36] [37] , without altering sleep stages [38] , it does not cause residual morning-after effects [38] [39] [40] [41] [42] , and it does not cause rebound insomnia after short-term administration [36] [43] [44] .

As a result of its favorable pharmacologic properties, zolpidem is the active ingredient in several products commercially marketed to treat insomnia. The lingual spray offers a means of administration that has the advantages of easy access (favors better compliance), and distribution onto a large and highly-vascularized surface area (Figure 1).

Speed of sleep onset is important for treatment of insomnia. Sleep latency (the time it takes to fall asleep) relates to sleep efficiency (the proportion of bedtime asleep), because if a person is able to fall asleep quickly, they are more likely to have an efficient sleep, and cycle normally through rapid eye movement sleep (REM) and non-rapid eye movement sleep. The oral route is relatively slow compared to other routes and subjects a drug to a first-pass metabolism effect. Thus, bioavailability is generally low and slow compared to other routes. Additionally, this can be a problematic delivery modality for patients with dysphagia, or elderly patients that have difficulty swallowing tablets.

Consistency of dose is another important characteristic that is favorable for treatment of insomnia. Although bioequivalence is defined and required by regulatory control, caution is warranted, even if in a minority of situations [45] [46] .

This was a single-center, four-way crossover, open-label, dose-ranging, multiple-treatment study. There were four treatment groups: zolpidem oral tablets (AMBIEN, 5 or 10 mg) and zolpidem LS (5 or 10 mg). Zolpidem LS was administered to each study participant, without water, by spraying the drug formulation into the mouth (one actuation of the pump = 5 mg; two actuations of the pump = 10 mg). The participants were instructed not to swallow for a period of 30 seconds and to avoid intentional swallowing for up to five minutes following dosing, if possible. AMBIEN was administered with water. Treatments were separated by a period of about one week.

A total of 48 healthy male and female participants (18 - 45 yo, BMI ≤ 30 kg/m²) were enrolled; 45 completed the study. The three participants did not complete the study due to (one each): vomiting after receiving AMBIEN (10 mg), unrelated personal incident, vomiting after receiving zolpidem LS (10 mg). Most of the participants were Caucasian (N = 22) or Black (N = 18), the remainder were Hispanic (N = 2) or Asian (N = 1). The mean age of the participants in the analyses was 29.3 years (range = 19 - 45 yr), the mean weight was 74 kg (range = 55 - 95 kg), and the mean BMI was 26 kg/m² (22 - 30 kg/m²).

Measurements of plasma concentrations of zolpidem were made using a validated high-performance liquid chromatography (HPLC) method with mass spectrometric (MS/MS) detection methodology. Plasma samples were spiked with an internal standard, zolpidem-d₆, processed by protein precipitation, and analyzed using reversed-phase HPLC with MS/MS detection.

Pharmacokinetic parameters were calculated for each participant from the plasma concentration levels of zolpidem. The area under the concentration-time curve (AUC), maximum drug concentration (C_max), time to maximum drug concentration (T_max), time to first detectable drug concentration (T_det), time to plasma drug concentration associated with sedation (≥20 ng/mL) (T_ther), elimination half-life (t_1/2), and other parameters were evaluated.

Two primary measures were used. For one measure, within 15 minutes prior to dosing and at 12 and 22 minutes after dosing, each of the participants self-assessed their level of drowsiness using a scale ranging from “a little” to “a lot” on a 100-mm visual analog scale (VAS) for each of 12 descriptors of sedation. For the other measure, at the same visits, the participants performed the Digit Symbol Substitution Test (DSST), which is an assessment of attention, perceptual speed, motor speed, visual scanning and memory, within 15 minutes prior to dosing and at 13 and 23 minutes after dosing. During the DSST assessment, each participant was given a piece of paper with 9 symbols corresponding to 9 digits. Below these were 3 rows of digits with empty boxes. The participants were asked to fill in as many corresponding symbols as possible within 90 seconds.

An analysis of bioequivalence comparing each treatment group to each of the others when the data were normalized to a dose of 10 mg revealed:

· The 5 mg AMBIEN tablet was not bioequivalent with the 10 mg AMBIEN tablet

· Zolpidem LS 5 and 10 mg doses were bioequivalent to the 10 mg AMBIEN tablet

· There was a gender-effect irrespective of dose normalization in which C_max, AUC_0→T, and AUC_0→∞ are significantly higher in females than in males, with a significantly longer half-life and slower clearance also observed in female participants

· There was no gender-treatment effect found in any of the pharmacokinetic analyses

· There was no treatment-effect found in any of the pharmacokinetic analyses

Two potential indications of therapeutic efficacy were measured in the study: a visual analog scale (VAS), and change from baseline in the Digit Symbol Substitution Test (DSST). The VAS test turned out to be an unreliable measure. It yielded only sporadic differences, and there was no apparent pattern or consistency with reference to when the differences were observed. Consequently, only the DSST is summarized below.

The most common AEs experienced by study participants were diplopia, dizziness, euphoric mood, headache, and nausea. Only dizziness occurred in more participants after zolpidem LS (10 mg) than after AMBIEN (10 mg). In order of decreasing incidence of AEs, dizziness, diplopia, and headache were the most common among female participants, while euphoric mood, diplopia, and dizziness were the most common among male participants. No deaths or serious adverse effects (SAEs) occurred during the study.

There were no AEs indicative of local adverse reactions in the oral cavity after treatment with zolpidem LS (either 5 mg or 10 mg).