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Insomnia: Recent Advances in Pharmacological Management

(PSYCHIATRIC TIMES) - The pharmacological management of insomnia has a very long history.1 It seems likely that fermented beverages and sedating plant concoctions (such as opium) have been used for millennia for their sleep-promoting effects. With patent medicines came products such as laudanum, which frequently were taken to combat insomnia. This was followed by chloral hydrate in the 1860s and barbiturates in the early 1900s.

Several sedating pharmaceuticals, such as methyprylon, glutethimide, ethchlorvynol, methaqualone, and meprobamate, transiently were popular in the mid-1900s. Although all of these may facilitate sleep, they also are associated with major safety concerns, including toxic effects that may be fatal.

Beginning in the 1960s and 1970s, benzodiazepines and related hypnotics became the most widely used insomnia medications. Recent pharmacological innovations in the treatment of insomnia have includ-ed extended-release and alternate-delivery formulations of existing hypnotics, as well as compounds with entirely new mechanisms of action. Throughout this long history of insomnia treatment, efficacy in promoting sleep has not been the primary challenge. Rather, it has been enhancing sleep safely while avoiding undesired daytime sedation or impairment.

In June 2005, the NIH sponsored the State-of-the-Science Conference on the Manifestations and Management of Chronic Insomnia, which included presentations on the characteristics, causes, and consequences of insomnia, as well as an evidence-based review of the literature on treatment.2 The summary report from the conference panel noted the well-established benefits of cognitive-behavioral therapy and the FDA-approved hypnotics in treating chronic insomnia, but they did not endorse the use of OTC antihistamine sleep aids or sedating antidepressants and antipsychotics because of the lack of efficacy data or the presence of significant safety concerns.2 The report called for longer-term studies of the pharmacological treatment of insomnia that better represented clinical practice and that assessed a broader range of effectiveness outcomes, particularly daytime functioning and the course of comorbid conditions.

One significant recent advance in the prescribing guidelines for insomnia medications relates to the recommended duration of use. The FDA indications for treatment previously specified “short-term” use. Beginning in 2005, the medications approved for the treatment of insomnia have included no implied limitation on duration of use. Long-term safety and efficacy studies have been performed with all of the recently approved medications, including eszopiclone,3,4 zolpidem extended- release,5 and ramelteon.6 All have demonstrated continued efficacy without the development of tolerance, as well as generally positive safety profiles.

Another relatively recent prescribing guideline development has been the specification of an indication for the treatment of sleep maintenance apart from the sleep onset symptoms, which should improve with any of the current insomnia medications.

This article will review the recent advances with the insomnia treatment medications that currently are approved by the FDA and then will discuss compounds that are being investigated as possible insomnia treatments.

Approved Therapies
In the United States, 9 benzodiazepine receptor agonist (BZRA) hypnotic formulations and 1 selective melatonin receptor agonist are approved by the FDA for the treatment of insomnia.7 These medications vary with regard to pharmacodynamic action and pharmacokinetic properties. No single medication is ideal for every insomnia patient—there is no “one size fits all” prescription for managing sleep disturbances. Patients vary in their insomnia symptoms, comorbid disorders, concurrent medications, demographic characteristics, and treatment preferences.

Benzodiazepine receptor agonist hypnotics. The BZRA hypnotics have been the primary pharmacological agents for the treatment of insomnia over the past 4 decades. This category constitutes the compounds incorporating the benzodiazepine structure that were formally indicated for insomnia treatment in the early 1970s and the nonbenzodiazepine agents that became available beginning in the 1990s. All share the same fundamental mechanism of action, although the newer nonbenzodiazepines have selective pharmacodynamic properties that may improve their safety and tolerability.7

BZRAs interact with an allosteric recognition site on the GABAA receptor complex. The result is that more chloride ions can enter the cell and subsequently produce a greater degree of polarization that enhances the natural inhibitory action of GABA.

The newer-generation nonbenzodiazepine BZRA hypnotics lack the defining benzodiazepine structure. Compared with the benzodiazepine hypnotics, the nonbenzodiazepines tend to be more selective for GABAA receptor complexes containing an a1 subunit subtype.7 While several of the benzodiazepine hypnotics have rather long half-lives that may affect daytime functioning, the nonbenzodiazepine hypnotics tend to have considerably shorter half-lives and better target sedation exclusively during the nighttime.

The development of modified-release formulations of BZRA hypnotics has been a key pharmacokinetic innovation within this class. With the use of immediate-release formulations, the fundamental challenge is to provide a blood level of the hypnotic that is adequate to aid sleep maintenance during the night while avoiding undesired sedation or impairment the following morning. When an immediate-release medication with a short half-life does not provide sufficiently sustained action throughout the night, the use of a higher bedtime dose or an alternative with a long half-life is not an ideal solution.

The rationale for a modified- release formulation is that a compound with a relatively short half-life can be prepared in a pill form that allows both rapid and sus-tained release of the medication. The short half-life allows a relatively rapid decline later during the night to minimize the potential for next-day effects.9 The only modified- release hypnotic approved by the FDA is zolpidem extended-release,10 although other agents have been investigated as well.11

Selective melatonin receptor agonist. The approval of ramelteon in 2005 represented a major advance in the pharmacological treatment of insomnia because it was the first compound with an entirely new mechanism of action approved for this indication in 35 years. Ramelteon is a selective agonist for melatonin MT1 and MT2 receptor subtypes, which are most highly concentrated in the hypothalamic suprachiasmatic nucleus (SCN).12 The SCN functions as the master timekeeper of the circadian system. The timing of the sleep-wake cycle is influenced by the SCN, which is entrained by the photoperiod.

The circadian system helps maintain the waking state throughout the day and evening by promoting increasing arousal late in the daytime and into the evening. As bedtime approaches, the circadian arousal declines, leaving the homeostatic sleepiness that has accumulated since sleep last occurred unopposed. Endogenous melatonin has a central role in this process. Normally, the melatonin level is low throughout the daytime, but it gradually rises as bedtime approaches. Melatonin agonist activity decreases the firing rate of SCN neurons, which is thought to decrease circadian arousal. Under normal circumstances, this interaction of the circadian and homeostatic processes allows sleep onset to occur relatively rapidly at bedtime.

Ramelteon’s agonist activity at these SCN receptors enhances sleep onset by decreasing the evening circadian arousal. The approved indication is for the treatment of insomnia characterized by difficulty with sleep onset, which is consistent with the proposed mechanism of action. Ramelteon has been shown to improve sleep during the early portion of the sleep period. It also may reinforce the timing of the circadian system to increase the probability of sleepiness occurring regularly at bedtime. There is no implied limitation in the duration for which it can be prescribed. Ramelteon is classified as nonscheduled by the DEA because of an absence of abuse liability.13

Ramelteon is not a sedating medication, and patients may experience the maximum therapeutic effects over a period of several nights or weeks. Ramelteon is available in a single 8-mg dose. The typical recommendation is to take the medication about 30 minutes before bedtime. Although ramelteon is not associated with cognitive or psychomotor impairment, patients should avoid hazardous activities after taking it. Ramelteon should be avoided in patients with moderate to severe hepatic impairment and in persons concomitantly taking fluvoxamine. It has been associated with a low incidence of somnolence, fatigue, and dizziness.14

The variety of FDA-approved medications allows for customization in developing treatment strategies for patients, depending on their specific sleep-related symptoms, age, substance abuse history, and comorbid condition. Based on the pharmacokinetic properties and mechanism of action, it should be possible to select a medication with effectiveness in improving nighttime symptoms while avoiding undesired next-morning residual effects.

As noted, all of the approved medications have indications for helping with sleep-onset insomnia, but only certain hypnotics are beneficial for sleep maintenance. If substance abuse has been a major problem, a BZRA may not be the initial choice. Similarly, greater caution should be exercised in the medication selection for patients who are more vulnerable to the effects of ataxia or respiratory depression.

Investigational Compounds
Currently, a rich assortment of compounds is being investigated for the treatment of insomnia. Development of some of the molecules now being evaluated has been stimulated by the emerging knowledge of the neurophysiological regulation of sleep and wakefulness. Others have been developed as variations of the current pharmacological strategies for medications approved for the treatment of insomnia or used on an off-label basis. Among these are compounds in early investigational studies, but others have completed phase 3 studies and, if approved by the FDA, could be marketed within 1 to 2 years.

Two new compounds that had been studied extensively for the treatment of insomnia, but which now apparently have been abandoned, are gaboxadol and indiplon. Further studies of gaboxadol, described as a selective extrasynaptic GABAA agonist, were discontinued because of intolerable adverse effects. The development of indiplon, a BZRA hypnotic with a short half-life evaluated in immediate- and modified-release formulations, was discontinued after FDA requests for further studies.

Potential new BZRA hypnotics. The BZRA hypnotics now include those with the benzodiazepine structure, which are relatively nonselective for GABAA subunit subtypes, and the nonbenzodiazepine compounds, which have varying degrees of selectivity for α subtypes. All are immediate-release formulations, with the exception of zolpidem extended-release. As noted above, modifying the release of a hypnotic has been a key pharmacokinetic innovation among sleep medications. Although other BZRA modified- release formulations have been evaluated, none appear to be actively investigated at present.

The other major pharmacokinetic innovation in development is the creation of rapidly absorbed alternate-delivery formulations of BZRA hypnotics. In addition, BZRA compounds with different subtype selectivity are being investigated as possible insomnia treatments.

The argument for BZRA alternate-delivery formulations is they can use oral, nasal, or pulmonary routes to allow more rapid onset of action. An earlier maximum serum concentration of the drug would be accompanied by an earlier decline in the sedating effect, which may help avoid undesired residual sedation. This combination would make such a hypnotic ideal for middle-of-the-night (MOTN) dosing. Currently, none of the insomnia medications is approved for MOTN use and, therefore, cannot be marketed for this indication. Since sleep maintenance difficulty is the most common nighttime insomnia symptom, a medication taken after a nighttime awakening would seem attractive.

The alternate-delivery formulations now being investigated are all based on medications with relatively short half-lives now available in pill form. Most are zolpidem formulations; however, some are based on zaleplon and triazolam. Among the alternate-delivery systems that have been studied are sublingual zolpidem formulations, zolpidem oral dissolving tablet, zolpidem oral spray, inhalation zaleplon, and triazolam nasal spray. The potential benefits of these rapid-acting formulations will need to be balanced against possible specific risks associated with their rapid onset of action.

The available nonbenzodiazepine BZRA hypnotics all have some degree of preferential binding to GABAA receptor complexes containing the α1 subunit subtype, compared with benzodiazepines with similar affinity for multiple α subtypes. It has been suggested that this subtype selectivity improves the tolerability and safety of the nonbenzodiazepine hypnotics. Eszopiclone also exhibits preference for the α3 subtype. Both α1 and α3 subtypes are associated with sedation.

In contrast, compounds with α2 selectivity are anxiolytic but are not sedating. Accordingly, medications with greater α1 or α3 preference might represent advances within the general class of BZRA hypnotics. One unique compound being investigated for the treatment of insomnia is adipiplon, a GABAA α3 partial agonist.

All of the FDA-approved BZRA hypnotics have been characterized as pharmacodynamic antagonists. In addition to the investigational compound adipiplon, clinical trials recently have been performed with other partial agonists. One example is EVT 201, which is reported to be a partial positive allosteric modulator of the GABAA receptor complex.

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