1 Introduction

Insomnia is essentially characterized by a complaint of sleep dissatisfaction either in terms of duration or quality associated with difficulties to initiate or maintain sleep. General population studies indicate that these symptoms are extremely prevalent in adults [from 10 % to nearly 60 % according to the different ways insomnia is defined and assessed (Ohayon 2002)]. However, to be considered as a disorder, the sleep disturbance needs to be sustained and long lasting [for instance, at least three times a week for at least 3 months in the DSM-V classification system (American Psychiatric Association 2013)] and has to impact the daytime functioning. Prevalence is about 6–10 % when such criteria are used to define insomnia (American Psychiatric Association 2013), with higher rate in women and older adults particularly in those with chronic medical or psychiatric conditions. About 20 % of patients with insomnia estimate that their disorder seriously impacts their life (Staner et al. 2012). Indeed, poor sleep has been associated with emotional distress and recurrent health problem (Edinger et al. 2000). A prospective study showed that poor sleepers were less effective in their work, less likely to receive promotion, and more likely to be demoted and discharged (Johnson and Spinweber 1983). This is not surprising since, in non-insomniac subjects, a sleep loss of even 1–2 h a night might impair next-day alertness, concentration, attention, memory, mood, and pain threshold (Staner et al. 2012).

Effective treatments for insomnia include both pharmacological and non-pharmacological approaches. The use of non-pharmacological treatment such as sleep hygiene measures, cognitive therapies, relaxation, or sleep restriction is limited by lack of trained providers, understanding of the treatment method, and cost/third party reimbursement (Perlis et al. 2003). Indeed most patients initiate treatments with various nonprescription therapies of unknown risk and benefit such as OTC sedating antihistamines, herbal remedies, dietary supplements, or even rely on alcohol to relieve their sleep difficulties. Effective pharmacological treatment for insomnia should normalize sleep patterns without affecting daytime functioning. First generation hypnotics (such as barbiturates, carbamate, chloral hydrate, methaqualone) and long-acting benzodiazepines were effective in inducing sleep but put patients at risk for next-day residual effects and, for some of them, with additional risks of liver toxicity, dependence, and fatal overdose. The last 20 years have seen the development of safer hypnotic drugs with a better risk/benefit profile, such as cyclopyrrolones (zopiclone, eszopiclone), imidazopyridines (zolpidem), pyrazolopyrimidines (zaleplon, indiplon, lorediplon), melatonin receptor agonists (ramelteon, tasimelteon), orexin antagonists (suvorexant), and low-dose sedative antidepressant drugs (doxepin).

It has to be kept in mind that although sleep initiation and sleep maintenance disturbances most frequently coexist in patients with insomnia disorder, some individuals may complain specifically of either sleep-onset difficulties or of prolonged awakening after sleep onset. Although current diagnostic classification systems such as DSM-V or ICSD offer no operationalized diagnostic criteria for these two insomnia subtypes, the DSM-V still provides for illustrative purpose, quantitative criteria to define sleep initiation, and sleep maintenance difficulties. On this basis, initial (or sleep-onset) insomnia may be considered when sleep latencies are recurrently greater than 20–30 min despite appropriate bedtime hours/sleep habits and middle (or middle-of-the-night) insomnia when patients regularly experience wake times after sleep onset greater than 20–30 min despite adequate sleep conditions.

During these last years, interest in the development of hypnotics that could specifically target these forms of insomnia was growing. A “quick and short” mode of action was favored with transmucosal delivery formulations that disintegrate in the sublingual cavity allowing the drug to be rapidly absorbed and quickly available in the brain by bypassing the first-liver metabolization. With regard to the “short” side of the mode of action, hypnotic drugs such as zolpidem and zaleplon were used due to their short half-life. There are currently two FDA-approved sublingual forms of zolpidem, a standard dose (SL-SD) for the short-term treatment of sleep-onset insomnia (Edluar 5 and 10 mg by Meda Pharmaceuticals) and a low dose (SL-LD) for as-needed treatment of middle-of-the-night (MOTN) insomnia (Intermezzo 1.75 and 3.75 mg by Transcept Pharmaceuticals). This chapter discusses the pharmacology, the efficacy, and the safety of these two sublingual formulations in the treatment of these forms of insomnia.

2 Pharmacology

Zolpidem, a non-benzodiazepine hypnotic acting at GABAa launched in the eighties in France, rapidly became one of the most widely used drugs to treat insomnia, because of its favorable efficacy/balance profile compared to classical benzodiazepines. Due to a short half-life and a selective α1GABAa receptor profile, the drug is a powerful sleep initiation agent with a lower incidence of side effects than benzodiazepines. A complete review of the mechanism of action of zolpidem can be found elsewhere (Staner et al. 2010a).

Sublingual formulations of zolpidem are designed to disintegrate in the sublingual cavity and to be rapidly absorbed after administration. The two zolpidem sublingual formulations (SL-SD and SL-LD) are bioequivalent to the standard immediate oral release (IOR) form of zolpidem (Ambien) (Edluar 2009; Intermezzo 2011). Tmax is somewhat shorter for the sublingual forms, the peak concentration of zolpidem occurring at a mean time of 96 min for IOR zolpidem 10 mg, whereas a median Tmax of 82 min (range: 30–180 min) was found for SL-SD zolpidem 10 mg and a mean Tmax range of 35–75 min for SL-LD zolpidem 3.75 mg. Elimination half-life is comparable between the three formulations [IOR zolpidem 10 mg: 2.53 h (range 1.4–3.8), SL-SD zolpidem 10 mg : 2.65 h (range 1.75–3.77) SL-LD zolpidem 3.75 mg: 2.5 h (range 1.4–3.6)]. As expected IOR zolpidem 10 mg has higher AUC and Cmax values than SL-LD zolpidem 3.75 mg (AUC: 589 ng.hr/mL for IOR zolpidem versus 295 ng.hr/mL in women and 197 ng.hr/mL in men for SL-LD zolpidem; Cmax: 121 ng/mL for IOR zolpidem versus 75 ng/mL in women, and 53 ng/mL in men for SL-LD zolpidem) (Edluar 2009; Intermezzo 2011; Swainston Harrison and Keating 2005).

The oral bioavailability of the drug is estimated at 65–70 % but food delays its absorption. It has been shown that food decreases AUC by 15 %, Cmax by 25 %, increases Tmax by 50 %, and does not influence half-life (Swainston Harrison and Keating 2005). Food induced lower bioavailabilities are also observed with sublingual forms, a finding that could relate to the effect of a meal on salivary pH and its consequence on zolpidem sublingual absorption. Thus, food decreases AUC by 20 % and 19 %, Cmax by 31 % and 42 %, and prolongs Tmax by 28 % and 54 % for Edluar and Intermezzo, respectively (Edluar 2009; Intermezzo 2011). Accordingly, sublingual zolpidem should not be administered with or immediately after a meal.

Zolpidem does not accumulate in the body after repeated administration due to its short half-life. There is a negligible direct excretion of the drug since about 90–95 % of zolpidem is bound to plasma proteins and its clearance is mainly a metabolic one. Cytochrome P450 extensively metabolizes the drug in three main inactive metabolites and only traces of the unchanged compound can be found in urine. The CYP3A4 is the principal isoform responsible for zolpidem metabolism, accounting for about 60 % of net cytochrome-mediated hepatic clearance. Consequently, drugs inducing CYP3A4 such as rifampicine decrease zolpidem AUC, Cmax, and half-life while the converse is observed with CYP3A4 inhibitors such as itraconazole. Detailed review of significant drug interactions can be found elsewhere (Hesse et al. 2003). Oral zolpidem dosage adjustment recommendations for special populations also apply to sublingual forms of the drug. Thus, initial dose should be adjusted to 5 mg for SL-SD zolpidem and 1.75 mg for SL-LD zolpidem in the elderly, in debilitated patients, or in patients with concomitant CNS depressant or with hepatic impairment.

The finding of a gender effect on SL-LD zolpidem metabolism (Greenblatt et al. 2013) (see Table 1 showing that plasma AUC and Cmax parameters are approximately 45 % higher in women than men) has led to the reanalysis of data from studies of standard oral zolpidem products. Results showed that 8 h after taking a single dose of 10 mg of IOR zolpidem, 15 % of women and 3 % of men still had blood zolpidem levels above the threshold of 50 ng per milliliter known to impair driving performance. It has been suggested that low plasma concentrations of free testosterone may contribute to lower CYP3A activity since exposure to testosterone induced CYP3A-mediated biotransformation (Farkas et al. 2013). These findings led the FDA to reconsider the recommended dose of zolpidem for women that has been reduced from 10 to 5 mg for immediate-release products such as IOR zolpidem and SL-SD zolpidem, and from 12.5 to 6.25 mg for controlled-release products (e.g., Ambien CR) (FDA Drug Safety Communication 2013). The recommended doses of SL-LD zolpidem did not change as the label already recommended the lower dosage (1.75 mg) for women.

Table 1 Mean ± SD of gender specific pharmacokinetic parameter of low dose sublingual zolpidem (Intermezzo) (Intermezzo® 2011)
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3 Efficacy

The sleep-promoting effect of zolpidem has been demonstrated in healthy “good sleepers” and in elderly and non-elderly patients with chronic primary or secondary/comorbid insomnia. Zolpidem has been found to improve objective and subjective sleep initiation and maintenance parameters such as sleep-onset latency (SOL), latency to persistent sleep (LPS), wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE). Subjective sleep quality is generally improved but the effects on sleep architecture parameters are less consistent, with some placebo-controlled studies showing increases of stage 2 sleep or decreases of rapid eye movement (REM) sleep, others not. Extensive reviews of these efficacy studies of IOR or CR zolpidem have been published elsewhere (Staner et al. 2010a; Monti et al. 2008) and this section focuses on studies performed with the two sublingual formulations of zolpidem.

3.1 Sublingual Standard Dose of Zolpidem (Edluar)

Two sleep laboratory studies investigated the efficacy of two doses of SL-SD zolpidem (5 and 10 mg), a sublingual tablet designed to provide a more rapid relief of sleep initiation difficulties than IOR zolpidem in patients suffering from insomnia. These two double-dummy crossover trials were devoid of placebo arm since the main objective was to demonstrate the superiority of SL-SD zolpidem over IOR zolpidem in terms of sleep initiation parameters (i.e., SOL and LPS). The first study (Staner et al. 2009) was performed in healthy subjects (17 women and 4 men aged 26.7 ± 5.3 years) using a post-nap model of transient insomnia during which subjects had to perform a daytime nap in order to disrupt subsequent nighttime sleep. Subjects were recorded during 2 consecutive nights and on the day between during a 2-h nap. Treatment (either SL-SD zolpidem 5 mg, SL-SD zolpidem 10 mg, or IOR zolpidem 10 mg) was randomly administered before the second recording night to subjects demonstrating at least 30 min of sleep during the nap recording. Results showed that SL-SD zolpidem 10 mg significantly improved SOL (5.81 min, p < 0.05) and LPS (6.11 min, p < 0.05) compared to IOR zolpidem 10 mg (an improvement around 30 %). There was no difference in SOL and LPS between SL-SD zolpidem 5 mg and IOR zolpidem 10 mg. Sleep maintenance parameters (i.e., WASO, TST, and SE), sleep architecture parameters, and subjective sleep ratings were not significantly different among the three treatments.

The second efficacy study (Staner et al. 2010b) which compared SL-SD zolpidem 10 mg to IOR zolpidem 10 mg was performed in DSM-IV primary insomniacs (37 males aged 35.7 ± 11 years and 42 females aged 45.5 ± 9.5 years) that were recruited in 8 centers after a careful 2-night screening procedure aimed at excluding patients with sleep apnea, periodic leg movement, and including those with a mean LPS greater than 30 min. Other polysomnographic entry criteria were evidence on both nights of no LPS lower than 20 min, a TST lower than 6.5 h, and a WASO of at least 30 min. Results were comparable to those observed in the post-nap study with a 30 % improvement of SOL (8.63 min, p < 0.01) and LPS (10.28 min, p < 0.001) with SL-SD zolpidem 10 mg compared to IOR zolpidem 10 mg. Moreover, SL-SD zolpidem increases SE by 1.56 % (p < 0.05), compared to IOR zolpidem. Other sleep continuity parameters (TST and WASO) and subjective sleep were comparable between the sublingual and oral formulations (Fig. 1).

Fig. 1
figure 1

Effects of immediate oral release of zolpidem 10 mg (IOR Zol 10), sublingual standard dose of zolpidem 5 mg (SLSD Zol 5) and 10 mg (SLSD Zol 10) on mean sleep EEG initiation parameters (in min), latency to persistent sleep (LPS), latency to stage 2 (ST2-L), and latency to stage 1 (ST1-L) in the post-nap (PN) study (Staner et al. 2009) and the primary insomnia (PI) study (Staner et al. 2010b)

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These results were corroborated in another laboratory study (Valente et al. 2013) with healthy volunteers (n = 58) that used a model of transient insomnia (sleep anticipation in 120 min). Compared to IOR zolpidem 10 mg, both SL-SD zolpidem 5 and SL-SD zolpidem 10 mg improved SOL and LPS. However, only the 10 mg SL-SD dose being superior to IOR zolpidem in terms of subjective sleep latency. On the whole the three studies agree with the idea that the sublingual form of zolpidem a more potent sleep inducer than the IOR formulation but is comparable in terms of sleep maintenance.

3.2 Sublingual Low Dose of Zolpidem (Intermezzo)

SL-LD zolpidem was developed to target MOTN insomnia and is currently the single FDA-approved hypnotic to treat this highly prevalent condition. Indeed, about one-third of the general population reported awakenings after sleep onset at least 3 nights per week [i.e., 35 % of 8.937 U.S. residents included in a telephone survey (Ohayon et al. 2010)]. About half of them (i.e., 15 % of the sample) had also difficulty resuming sleep and about a third of them (11 % of the total sample) had both difficulty resuming sleep after awakening and associated daytime impairment (Ohayon et al. 2010). SL-LD zolpidem clearly differs from many widely used hypnotics currently approved by the FDA for sleep onset. It also differs from those approved for nocturnal awakenings and/or prolonged wake time after nocturnal awakenings. Indeed these hypnotics are designed to be taken at bedtime in order to prevent possible sleep disruption while SL-LD zolpidem is approved for as-needed MOTN use after nocturnal awakening.

Two placebo-controlled studies investigating the efficacy of SL-LD zolpidem 3.5 and 1.75 mg are found in the literature. The first one is a 3-way crossover study conducted in 5 US sleep laboratories using a randomized, double-blind, placebo-controlled design that evaluated the efficacy and the safety of two doses of SL-LD zolpidem (1.75 and 3.5 mg) when taken during a scheduled MOTN awakening. Patients were included on basis of a DSM-IV primary insomnia diagnosis and a 4-week history of prolonged MOTN awakenings (i.e., at least 3 nights per week with a mean latency to fall back to sleep of more than 30 min post-awakening). The studied sample comprised of 58 females and 24 males with a mean age of 45.9 years. Treatment was dispended within 5 min after the scheduled MOTN awakening, 4 h after the initial lights out, and outcomes refer to the second 4 h polysomnographic recording. Results show that, compared to placebo, both doses of SL-LD zolpidem significantly decrease LPS and improve TST after the scheduled MOTN awakening (Fig. 2). Subjective sleep-onset latency and subjective TST were also improved with both doses (Roth et al. 2008a).

Fig. 2
figure 2

Mean of main sleep EEG parameters (LPS latency to persistent sleep, TST total sleep time) and subjective sleep (sSOL subjective sleep-onset latency, sTST subjective total sleep time) after MOTN administration of either 1.75 mg SL-LD Zolpidem, 3.5 mg SL-LD Zolpidem, or placebo in the sleep laboratory study (Roth et al. 2008a)

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The second study (Roth et al. 2013) was performed in a sample of 295 non-elderly outpatients (median age 43.1 years, 68.1 % females) with primary insomnia, a history of at least 3 months of MOTN awakenings occurring 3 or more times a week, and an average TST of less than 6.5 h. To qualify for randomization, evidences of at least 3 MOTN awakenings/week of at least 30 min with one of them lasting more than 60 min have to be documented during a 2-week placebo run in period. Patients were then randomized 1:1 to as-needed MOTN dosing with SL-LD zolpidem 3.5 mg or placebo for 28 nights. Across the 4-week period, significantly shorter SOL was reported in patients in the active treatment arm (38.2 min versus 56.4 min, p < 0.001). A significant improvement of TST after MOTN with as-needed SL-LD zolpidem 3.5 mg was only observed during the two first study weeks (p < 0.05), a finding that has to be considered in the light of lower baseline TST values in the placebo group (p < 0.05) and non-treatment specific effects (i.e., those related to protocol requirement consistent with good sleep hygiene practices). Interestingly, patients randomized to SL-LD zolpidem took the drug during the night on 62 % of study nights and did not experience an increase in drug utilization over the 4-week treatment period or rebound insomnia during nights they did not take study drug.

4 Safety

The most common adverse events (>1 % of treated patients) reported in the published trial were somnolence, fatigue, headache, and dysgeusia for SL-SD zolpidem (Staner et al. 2009, 2010b) and headache, nausea, and fatigue for SL-LD zolpidem (Roth et al. 2008a, 2013). More generally types of adverse events for sublingual zolpidem were consistent with the adverse event profile of oral zolpidem. Long-term safety profile for sublingual zolpidem is currently not available; for instance, it is not known whether the two sublingual zolpidem formulations have a different abuse and dependence potential profile than the oral formulation [zolpidem is classified as a Schedule IV controlled substance by federal regulation because of its abuse and dependence potential, especially in patients with previous history of substance abuse and/or concomitant psychiatric illness (Staner et al. 2010a)].

For SL-SD zolpidem 5 and 10 mg, next-day residual effects in terms of vigilance, psychomotor performance as assessed by the critical flicker frequency test and the choice reaction time test (CRT), and attention and concentration as assessed by the digit symbol substitution test (DSST) did not differ from IOR zolpidem 10 mg (Staner et al. 2009, 2010b). Residual effects of SL-SD zolpidem were first estimated on the basis of a daytime pharmacokinetic–pharmacodynamic study performed in healthy subjects (n = 24, range 21–44 years of age). This crossover randomized double-blind study investigated the effects of SL-SD zolpidem (1, 1.75, and 3.5 mg) against placebo administered at 8 am. Results show that psychomotor performance and attention measured by the CRT, the DSST, and the symbol copy test are impaired from 20 min post-dose up to 4 h post-dose with the 3.5 mg dose for certain parameters (Roth et al. 2008b). Because of its middle-of-the-night way of administration, these results led to some concern regarding the next-morning safety of the SL-LD zolpidem 3.5 mg.

In the pivotal laboratory study (Roth et al. 2008a) no statistical differences were observed in the active treatment (i.e., SL-LD zolpidem 1.75 and 3.5 mg) condition compared to placebo condition in terms of DSST and subjective sleepiness both assessed about 4.5 h post-dose. In the repeated-dose outpatients study (Roth et al. 2013), participants were instructed to take their treatment (SL-LD zolpidem 3.5 mg or placebo) if they have at least 4 h of time remaining in bed and to report their daytime sleepiness/alertness every morning whether or not study medication was taken during the night. Results showed that sleepiness/alertness significantly (p < 0.01) improved compared with placebo at every time point after nights during which study medication was taken. On non-dosing nights, no statistically significant differences were noted between drug and placebo for morning sleepiness/alertness.

Finally, a highway driving performance study (Vermeeren et al. 2014) investigated the effect of a single dose of SL-LD zolpidem 3.5 mg administered in the MOTN at 3 and 4 h before driving in 40 healthy volunteers (50 % females). Results indicate that SL-LD zolpidem 3.5 mg taken 3 h before driving may impair driving performance, but that there is a minimal risk of impairing driving performance if the drug is taken ≥ 4 h before driving. No gender differences were observed.

Conclusion

SL-SD zolpidem is a sublingual formulation of zolpidem that improves the onset of sleep compared to the classical oral formulation of zolpidem. The drug has been approved for the short-term treatment of sleep-onset insomnia at a dose of 10 mg in non-elderly man and at the dose of 5 mg in women or in special population (elderly, debilitated patients, patients with concomitant CNS depressant, or with hepatic impairment). Since the sublingual formulation is more potent than the oral formulation with the effect of SL-SD zolpidem 5 mg being similar to those of IOR zolpidem 10 mg, a substitution from the oral 10 mg form to the sublingual 5 mg form would lower drug exposure and possibly improve the safety/efficacy balance. Studies are however needed to test this hypothesis.

SL-LD zolpidem improves the onset of sleep compared to placebo and it is indicated for the treatment of insomnia when MOTN awakening is followed by difficulty returning to sleep. It is an innovative treatment because, in contrast to hypnotics currently labeled for sleep maintenance insomnia, the drug is prescribed on an “as-needed” basis and not prophylactically at bedtime. Recommended dosages are 3.75 mg for non-elderly man and 1.75 mg in women and in special population (elderly, debilitated patients, patients with concomitant CNS depressant, or with hepatic impairment). It has to be stressed that, due to safety issue related to next-morning residual effects, the dose should be taken following MOTN awakenings only if the patient has at least 4 h of sleep remaining.