Sleep Therapy: New Generation Pharmacologic Agents for Managing Insomnia

Abstract

Disturbed sleep is the most commonly reported sleep complaint,1,2 affecting about one third of the population of the United States; about 10%–15% suffer from chronic insomnia.3 Chronic insomnia occurs more frequently in women, older adults, and patients with chronic medical and psychiatric disorders.4–6 In the vast majority of cases (around 90%), insomnia is comorbid with other conditions. Whether it is a primary disorder or comorbid with other conditions, chronic insomnia is often associated with numerous daytime consequences, including fatigue, mood disturbances, diminished functioning at home, occupational difficulties, increased incidence of accidents, a reduced quality of life, and increased risk for depression.7 Additionally, increased health care costs reported by individuals experiencing insomnia ultimately result in a significant economic burden to society due to lost productivity. The chronic and non-remitting nature of insomnia suggests that short-term treatments are less than optimal. Historically, insomnia has been treated with a variety of pharmacologic agents, typically the benzodiazepine receptor agonists, whose benefits must be considered in the context of their adverse events, including ataxia, amnesia, daytime somnolence, and rebound insomnia. More recently, the treatment of insomnia includes agents that act at benzodiazepine receptors but have a nonbenzodiazepine structure (eg, eszopiclone, zolpidem, and zaleplon). Results from randomized clinical trials indicate that these agents are effective in the management of insomnia.8 Melatonin-receptor agonists, a new class of drugs that promote sleep by targeting the regulation of sleep by the suprachiasmatic nucleus (SCN), have shown benefit in randomized trials.9,10 Ramelteon is the first approved sleep-promoting medication with this novel mechanism of action. To address the recent exciting developments in the use of medications in the treatment of insomnia, a symposium was held at the 25th Congress of the Collegium Internationale Neuropsychopharmacologicum in July 2006. The goal of this symposium was to provide a comprehensive overview of the prevalence and impact of sleeplessness, a review of the influence of circadian processes in the normal sleep-wake cycle, and the pharmacologic options for the successful management of insomnia as well as insights into future therapeutic directions. In the first paper, “Insomnia: Definition, Prevalence, Etiology, and Consequences,” Thomas Roth, PhD, from the Sleep Disorders and Research Center at Henry Ford Health System, sets the stage in discussing the definition and diagnosis of insomnia. Dr. Roth notes that insomnia is defined as difficulty initiating sleep, problems with sleep maintenance, or waking too early despite adequate sleep opportunity. He describes the brain regions involved in sleep-wake regulation. Dr. Roth also discusses the prevalence of sleep disturbances in the general population and the various risk factors associated with increased prevalence of chronic insomnia occurring in individuals of older age, female gender, and those suffering from comorbid medical and psychiatric conditions. In the next paper, “The Evolution and Development of Insomnia Pharmacotherapies,” David N. Neubauer, MD, from Johns Hopkins University School of Medicine, focuses on the pharmacological characteristics and clinical value of medications and related substances that currently are used to help patients fall asleep or remain asleep. The efficacy of these compounds ranges from negligible to well established, and several have significant safety issues. Dr. Neubauer discusses the historical evolution of the array of pharmacologic sleep-promoting agents, describing the early use of benzodiazepine medications for the treatment of insomnia in the early 1970s, the introduction of nonbenzodiazepine hypnotics in the 1990s, followed by the recent release of the first melatonin receptor agonist, ramelteon. In the final paper of the supplement, Karl Doghramji, MD, from the Jefferson Medical College, discusses “Melatonin and Its Receptors: A New Class of Sleep-Promoting Agents.” Dr. Doghramji discusses how the role of melatonin in synchronizing the circadian clock by its direct action on the SCN has led to the investigation of melatonin as a remedy for treating disordered circadian rhythms that occur in jet lag, shift work, and insomnia. However, conflicting results on melatonin's effectiveness in clinical trials have prompted the development of melatonin receptor agonists for the treatment of sleep disturbances. Dr. Doghramji describes the efficacy and safety of ramelteon as well as other melatonin receptor agonists that are currently being investigated for the treatment of sleep disorders. The purpose of this supplement is to provide a resource that clinicians may use to recognize and understand the descriptive paradigms, prevalences, and risk factors for insomnias, as well as to identify the currently available pharmacologic options for the treatment of insomnia.