Primary Psychiatry. 2007;14(8):27-30

Dr. Erman is clinical professor in the Department of Psychiatry at the University of California, San Diego School of Medicine, is a staff scientist for the Scripps Research Institute Department of Neuropharmacology, and is the president of Pacific Sleep Medicine Services.

Disclosures: Dr. Erman is a consultant to Cephalon, Mallinckrodt, Neurocrine, sanofi-aventis, and Takeda; is on the speaker’s bureaus of Forest, sanofi-aventis, and Takeda; is on the advisory boards of Cephalon, Neurocrine, sanofi-aventis, and Takeda; has received grant/research support from Arena, Cephalon, Eli Lilly, GlaxoSmithKline, Mallinckrodt, Merck, Organon, Pfizer, Pharmacia, ResMed, sanofi-aventis, Schwarz Pharma, and Takeda; and owns stock in Cephalon, Forest, Merck, Neurocrine, Pfizer, sanofi-aventis, and Sepracor.

“That we are not much sicker and much madder than we are is due exclusively to that most blessed and blessing of all natural graces, sleep.” —A. Huxley

Current practice for treating insomnia is often different from the recommendations of various professional bodies and sleep authorities, including the recommendations of the National Institute of Health State of the Science Panel.¹ For example, the benzodiazepine receptor agonists are effective in the treatment of insomnia. They have been widely used throughout the world for >40 years and have demonstrated a remarkable safety record.

Introduction

Despite their well-documented efficacy and safety records, physicians elect to use agents from a number of pharmaceutical classes to treat insomnia, despite absent safety and efficacy data to support their use. Although antidepressants are the most widely-used agents used “off-label” to treat insomnia, antipsychotics, antihistamines, anticonvulsants, and drugs from other classes are routinely prescribed for insomnia, with little consideration given to risks of side effects associated with their use.

γ-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the central nervous system. All approved hypnotic medications except ramelteon have their effects on the basis of their actions at the benzodiazepine recognition site on the GABA_A receptor complex.

Two types of compounds approved for the treatment of insomnia are included within the benzodiazepine receptor agonist (BZRA) category. Agents with a classical benzodiazepine chemical structure can be described as BZRAs on the basis of their agonist properties at this receptor site. Five benzodiazepine hypnotic compounds are approved for use in the United States and include flurazepam, quazepam, estazolam, temazepam, and triazolam (Table 1).^2-6 Quazepam and flurazepam have very long elimination half-lives (up to 100 hours); as a result, they may promote next-day “hangover” effects, as sedation persists beyond a desired 7–8 hours of sleep time and impacts on waking function. Estazolam and temazepam are best thought of as intermediate half-life agents, but each has a half-life of >8 hours and may promote residual sedation, especially at high doses or if taken without the opportunity to sleep for a full 8 hours. Basic pharmacokinetics are detailed in Figure 1.^7,8

Triazolam is a very effective and very potent hypnotic agent, with a relatively short half-life and duration of action. It was widely used in the 1970s and 1980s;  however, during the late 1980s questions were raised about its association with possible serious side effects, mostly psychological and usually at high dosage levels.

The benzodiazepines have been demonstrated to be safe and effective in the treatment of insomnia, but are restricted to short-term use and have a higher frequency and severity of adverse effects than the newer BZRAs.¹ The term BZRA is usually utilized to refer to newer “non-benzodiazepine” agents (zolpidem, zaleplon, and eszopiclone; Tables 2 and 3).^9-11 These agents do not have a benzodiazepine chemical structure, but, like the benzodiazepines, promote sleep on the basis of their agonist effects at this benzodiazepine recognition site of the GABA_A complex. Unlike benzodiazepines, zaleplon and zolpidem bind at the α₁ subunit of the GABA receptor. These medications, like the classic benzodiazepines, are classified as Schedule-IV agents by the Drug Enforcement Administration. This classification reflects a low risk of abuse potential. The BZRAs have demonstrated little to minimal abuse risk during their many years of widespread use in this country.

The three BZRAs  that have been available have half-lives and durations of action that cover a broad spectrum. Zaleplon has an extremely short half-life of approximately 1 hour, and is effective for treatment of sleep initiation problems. However, likely due to its short half-life, it does not increase total sleep time or improve sleep maintenance. Zolpidem immediate release, with a half-life of approximately 2.5 hours, has demonstrated efficacy in sleep promotion and the capacity to increase total sleep time. However, it does not have an indication for sleep maintenance.

 
Eszopiclone, with a half-life of approximately 6 hours, has demonstrated a longer duration of action than zaleplon or zolpidem. Consequently, it is approved for treatment of both sleep initiation and sleep maintenance difficulties. However, its longer half-life and duration of action increases the risk that some patients will experience residual sedation with this medication.

As a group, the BZRA agents share properties of safety, efficacy, and low abuse potential. They have also demonstrated safety and efficacy in association with treatment over periods of time of up to 6 months, without development of tolerance or rebound insomnia when discontinued. For example, Krystal and colleagues¹² compared eszopiclone to placebo in a 6-month, double-blind study of approximately 800 primary insomniacs. The results were dramatic, with eszopiclone providing immediate and sustained improvements in multiple sleep parameters compared with placebo. The results were sustained for the 6-month period of evaluation without development of tolerance.

Efficacy of non-nightly use of zolpidem 10 mg has been demonstrated by Perlis and colleagues¹³ in a double-blind study lasting 12 weeks. Subjects were instructed to take medication (zolpidem 10 mg or placebo) between 3 and 5 nights/week, and rated sleep from various perspectives on nights when medication was used or not used. In these studies, ratings of sleep latency, total sleep time, number of awakenings, and sleep quality were all improved on nights when zolpidem was taken, compared to results of subjects taking placebo.

Until recently, hypnotic agents were available only as immediate-release formulations. The only way to lengthen hypnotic duration of action was to select an agent with a longer half-life (Figure 2)⁸ or to increase the dose of the drug being used (Figure 3).⁸ Using a hypnotic agent with a longer half-life will typically promote greater sedation through the night, but with increased risk of next-day residual effects.

Dose escalation of hypnotic agents can increase the duration of time that a medication is above a minimum effective concentration threshold, which may promote better sleep maintenance. However, this may increase the risk of side effects as a consequence of increases in maximal concentrations (Figure 3).⁸

A modified-release formulation has been developed to provide altered pharmacokinetic profiles for hypnotic agents. In its most ideal form, such an agent would have an immediate onset, sustained effects, and stable concentrations for the desired therapeutic period, as well as a rapid offset of effects (Figure 4).^7,8 Such an agent is a practical impossibility, but use of techniques to modify the release of and availability of a hypnotic agent has led to the development of zolpidem controlled release (CR). This compound combines immediate release and modified-release components to achieve initial plasma levels and peak concentrations similar to those seen with immediate-release formulations, while maintaining higher plasma levels for a longer of time, extending the duration of efficacy. This technology allowed zolpidem CR to be approved for treatment of both sleep initiation and maintenance complaints. 

Zolpidem CR has been evaluated in a 6-month, double-blind, placebo-controlled study of 3–7 nights use.¹⁴ Results of this study demonstrated that zolpidem CR differentiates from placebo with regard to its capacity to improve sleep initiation, maintenance, and satisfaction with sleep quality over this 24-week study, without development of tolerance (Table 3).^9-11,14 PP

References

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14. Erman M, Krystal A, Zammit G, et al. Zolpidem extended-release 12.5 mg, taken for 24 weeks “as needed” up to 7 nights/week, improves subjective measures of therapeutic global impression, sleep onset, and sleep maintenance in patients with chronic primary insomnia. Int J Neuropsychopharmacol. 2006;9(suppl 1):S256.