Novel Developments in the Pharmacological Management of Insomnia

The broad category of benzodiazepine receptor agonists (BZRA) indicated for treating insomnia includes benzodiazepine hypnotics, characterized by the presence of a seven-member diazepine ring linked with a benzene ring, and the so-called nonbenzodiazepines with unique structures but having pharmacodynamic actions similar to the benzodiazepines. These BZRA hypnotics all share the property of being positive allosteric modulators of γ-aminobutyric acid (GABA) responses at the GABA_A receptor complex (2). GABA is the most widespread central nervous system (CNS) inhibitory neurotransmitter and it additionally has a key hypothalamic (ventrolateral preoptic nucleus) role in the regulation of sleep and waking (3). The complex is a five-subunit, transmembrane structure with a central chloride channel. The GABA_A receptor is most commonly comprised of two α, two β, and one γ glycoprotein subunit. When GABA attaches to a recognition site between the α and β subunits, extracellular chloride ions are allowed to enter the neuron thereby producing an inhibitory effect that reduces the likelihood of an action potential. More chloride ions are permitted to enter the cell when GABA attaches and a BZRA compound simultaneously interacts with a benzodiazepine recognition site at the interface of α and γ subunits, thereby enhancing the inhibitory effect and potentially contributing to clinical sedation, anxiolytic, muscle relaxant, and anticonvulsant effects. There is heterogeneity among the α subunits with at least six identified subtypes (4). Benzodiazepine hypnotics tend to interact with multiple subunit subtypes, while nonbenzodiazepines have greater selectivity for the α₁ or α₃ subunits, depending on the specific medication. It has been argued that this more targeted pharmacodynamic action affords clinical benefits for the nonbenzodiazepines, such as improved tolerability and decreased potential for withdrawal effects on discontinuation. However, the sedation associated with α₁ agonist activity remains linked with the risk for amnesia and ataxia.

Because of the relatively low abuse potential, the DEA categorizes both the benzodiazepines and nonbenzodiazepine hypnotics as Schedule IV controlled substances. Controlled clinical trials have not demonstrated tolerance to the sleep-promoting action of these medications, although rebound insomnia may occur for several nights following sudden discontinuation. Generally, these hypnotics are tolerated well with the more common adverse effects including headache, dizziness, nausea, somnolence, and fatigue.

Table 1 readily demonstrates that there is considerable variation in the pharmacokinetic properties among the BZRA hypnotics. All of these medications that are indicated for treating insomnia are relatively rapidly absorbed and therefore can enhance sleep onset. Predictably, the longer elimination half-life drugs have a greater potential for improving sleep maintenance, but also will increase the risk for next-day residual sleepiness and impairment. Several of the benzodiazepine hypnotics have half-lives of several days, and so they should be used cautiously, especially with nightly dosing. With the exception of triazolam, the benzodiazepine hypnotics have intermediate to long half-lives. One general advantage of the nonbenzodiazepine hypnotics is the shorter half-lives, ranging from about 1 to 6 hours in adults.

The FDA approved all of the benzodiazepine hypnotics between 1970 and 1990. They are available only in immediate-release capsule or tablet formulations. Initially, the nonbenzodiazepine hypnotics were approved by the FDA in the 1990s only in immediate-release formulations, but more recently several alternate delivery products have been approved. Eszopiclone and zaleplon still are available only as immediate-release tablets. Novel zolpidem formulations approved by the FDA in recent years include a controlled-release preparation and three products designed for oral absorption.

Zolpidem, as an extended-release formula, was developed to enhance the efficacy for patients with sleep maintenance insomnia. It is a bilayer tablet providing immediate and slightly delayed medication releases. The intrinsic, moderately short half-life of the compound allowed a sufficient decrease in the blood level by the end of the night to minimize next-morning adverse effects. New efficacy and safety trials were required for the FDA approval of this formulation with new medication doses. These studies included long-term assessments that allowed the FDA to approve zolpidem extended-release for the treatment of insomnia without the short-term wording in the label of the immediate-release version (5, 6). Similarly, long-term clinical trials with eszopiclone provided the basis for the approved indication without an implied restriction on the duration of use (7). Eszopiclone and zolpidem extended-release remain the only BZRA hypnotics without the short-term use indication, with the exception of the sublingual dissolvable zolpidem intended for as-needed middle-of-the-night use.

The rationale for the three novel oral-absorption zolpidem medications are a.) more rapid absorption with associated faster onset and offset of sedation and potential side effects, b.) the reduction of first-pass hepatic effects associated with gastrointestinal absorption, and c.) the convenience of the products not requiring water or the swallowing of a pill. These new zolpidem preparations include two intended for bedtime use as an alternative to the immediate-release tablet and the third with a lower-dose dissolvable tablet intended specifically for middle-of-the-night awakenings.

The bedtime alternate delivery zolpidems have the same prescribing guidelines and doses as the original immediate-release zolpidem tablets. The doses are 5 and 10 mg to be taken at bedtime for the short-term treatment of insomnia. One formulation is a dissolvable tablet and the other is an oral spray. The oral spray is designed for one actuation to provide a 5 mg dose, so two sprays are required for the 10 mg dose. The supplied bottle should provide for 60 metered actuations. Limited clinical data are available for these two products since no clinical efficacy trials were necessary for their FDA approvals. Both were granted approval through the FDA 505(6, 2) streamlined pathway intended to encourage drug development innovation without the need of repeating the preclinical and clinical studies already performed for medications that were previously approved. Manufacturing and pharmacokinetic bioequivalence studies are the primary requirements for this approval pathway. Except for the specific use instructions for a particular formulation, the remainder of the prescribing information in the label remains the same. This is why the indications for these recently approved alternate delivery zolpidem formulations still have the short-term treatment wording, despite the earlier approved zolpidem extended-release product having no implied limitation on the duration of use.

The most recent zolpidem product has been the sublingual dissolvable formulation that is the first to have an indication for use on an as-needed basis for middle-of-the-night awakenings––the most common insomnia complaint. Of course, a bedtime hypnotic dose may be sufficient to prevent a middle-of-the-night awakening, but a patient would need to take the dose nightly since the nighttime awakening might not be predictable. Therefore, one argument for the as-needed middle-of-the-night dosing would be an overall decrease in the medication exposure. This sublingual zolpidem is a lower-dose dissolvable formulation that should allow rapid onset of sleep promotion and a relatively short duration of action to prevent residual adverse effects. The indication specifies that it may be used “when a middle-of-the-night awakening is followed by difficulty returning to sleep” but is not indicated “when the patient has fewer than 4 hours of bedtime remaining before the planned time of waking.” In sublingual tablet form, the available doses are 1.75 and 3.5 mg. Because women tend to metabolize zolpidem more slowly than men, the recommended dose is 1.75 mg for women and 3.5 mg for men. Geriatric patients, people with hepatic impairment, and individuals also taking CNS depressants all should take the 1.75 mg dose.

One recent update regarding the BZRA hypnotic medication class was the 2013 FDA Drug Safety Communication recommending lower zolpidem doses for women due to their slower metabolism and possible excessive blood levels the morning following bedtime dose (8). Therefore, initial doses for women should be 5 mg for immediate-release and 6.25 mg for extended-release preparations. The lower middle-of-the-night sublingual dose for women was already established. The FDA communication also suggested considering these lower doses for men because they often provide sufficient efficacy.

Endogenous melatonin has a central role in the regulation of the sleep-wake cycle, particularly with regard to the circadian system that strongly influences the timing of sleep and wakefulness. In humans and other diurnal species, the circadian cycle, with entrainment by the photoperiod, optimizes the ability to sleep during the nighttime. The evening rise in melatonin production decreases the circadian-driven evening arousal and thereby facilitates sleep onset at bedtime. Accordingly, exogenous melatonin may be able to enhance this process by promoting sleep onset and have stabilizing or phase-shifting effects on the circadian system.

Ramelteon is the only melatonin receptor agonist currently approved by the FDA for the treatment of insomnia, although at least one other is being reviewed for a circadian rhythm sleep disorder indication. The specific ramelteon indication is for the treatment of insomnia characterized by sleep onset difficulty. It functions as a selective agonist for the MT₁ and MT₂ melatonin receptor subtypes, which are present in high concentrations in the suprachiasmatic nucleus and maintain the rhythmicity of the circadian cycle. Ramelteon is rapidly absorbed and has a half-life of about 2.6 hours and an active metabolite with a half-life of less than 5 hours (4).

Ramelteon does not directly promote sedation and therefore does not share many of safety issues associated with BRZA hypnotics. There is limited potential for drug interactions, although it should not be combined with fluvoxamine due to a possible ramelteon blood level increase from fluvoxamine’s CYP-1A2 isoenzyme inhibition. It also should be avoided with severe hepatic impairment. Ramelteon has been shown to be safe in patients with sleep apnea and chronic obstructive pulmonary disease (COPD) (9, 10). Owing to an absence of abuse potential, the DEA regards ramelteon as an unscheduled medication.

Appropriate patient selection is an important consideration with ramelteon, because it may not be benefit early morning awakenings or middle-of-the-night sleep disturbances. The absence of a prominent sedating effect may lead patients to conclude initially that the medication is not beneficial for their sleep onset difficulty; however, continued use may allow optimum effects to be achieved after several nights or a few weeks.

Histamine is a prominent wake-promoting neurotransmitter that in the CNS emanates from cell bodies in the hypothalamic tuberomammillary nucleus. Histamine H₁ receptor antagonists have sedating properties and therefore have the potential to enhance sleep and treat insomnia. A single histamine receptor antagonist now is approved by the FDA with a specific indication for the treatment of insomnia characterized by difficulty with sleep maintenance. Although doxepin was initially approved as an antidepressant in 1969, the use of very low dose doxepin for insomnia was granted approval in 2010. Unlike other antidepressants, doxepin has very high selectivity for the histamine H₁ receptor (11). At very low doses, including the 3 mg and 6 mg approved doses, the pharmacodynamic action is almost exclusively the antihistamine sedating effect. Therefore, there is minimal risk of adverse effects associated with other tricyclic antidepressants or with doxepin at higher doses, which are as high as 300 mg for the treatment of depression.

The placebo-controlled clinical trials for the bedtime use of low-dose doxepin found it to be more effective than the placebo in helping the insomnia subjects remain asleep during the latter part of the night (12, 13). Although the elimination half-life is rather long, a combination of the very low dose and the morning alerting effects of other wake-promoting neurotransmitters seems to prevent residual sedation for most patients. The prescribing guidelines suggest the 6 mg dose for adults and the 3 dose mg for elderly insomnia patients. Owing to the lack of any abuse liability, it is considered a nonscheduled medication by the DEA. Unlike other antidepressants, including higher doses of doxepin, these low doses for insomnia do not require the black-box suicidal thinking or behavior warning.