Management of Insomnia -- The Role of Zaleplon
Medscape General Medicine. 2002;4(1)
Context: Insomnia is the most frequently reported sleep symptom, severely affecting up to 15% of the US population. The need to effectively treat this disorder is underscored by the significant adverse consequences on the productivity, safety, overall health, and quality of life of the affected individual. Pharmacologic intervention has traditionally involved the use of benzodiazepine receptor agonists (BzRAs), for which efficacy and general safety have been established. Objective: The purpose of this paper is to examine the potentially unique role of zaleplon in the treatment of insomnia. Data Source: The clinical experience of the authors was critically applied to peer-reviewed published papers or abstracts regarding zaleplon, which were identified via MEDLINE (1995-September 2000). Results: Adverse effects, usually related to residual sedation, impose limits on the use of older BzRAs and have prompted the development of new sleep medications with advantageous adverse event profiles. Zaleplon demonstrates a very rapid onset and offset of effect that permits symptomatic rather than prophylactic administration, resulting in comparable efficacy and reduced risk of the adverse effects associated with longer half-life agents. Conclusions: The characteristics of zaleplon may translate into distinct and significant clinical advances in the treatment of insomnia.
Insomnia is characterized by difficulty in initiating or maintaining sleep, possibly including frequent or prolonged nocturnal awakenings, and is associated with suboptimal quality of sleep. Approximately 50% of adult Americans experience symptoms of insomnia in any given year.[1,2] It is more common in women than in men, and its prevalence increases with age and with the presence of predisposing underlying conditions such as psychiatric illness.[3] The disorder is often transient or of short duration, typically occurring in response to acute life stresses, but insomnia can also be a ongoing problem. Chronic insomnia has been described by healthcare organizations[4,5] to include the following: subjective report of poor sleep, sleep latency of greater than 30 minutes, sleep efficiency (time asleep/time in bed) less than 85%, sleep difficulty on 3 or more nights per week for more than 6 months, and a subjective impression of at least 1 adverse result (ie, performance impairment [social/work], moodiness, fatigue).[6] Regardless of its duration, this sleep difficulty can have profound adverse effects on mental, physical, social, and occupational performance.[7] The substantial morbidity of insomnia, then, includes not just the symptomatic disruption of sleep, but also the subsequent impairment of daytime function.
Insomnia adversely affects the physical and mental health of an afflicted individual,[8-10] and it interferes with the attainment of restorative sleep. Historically, both pharmacologic and behavioral treatments for insomnia have focused on nighttime difficulties. Recognizing the broader morbidity of this disorder, more recent therapies have been sought to address or improve the daytime functioning of patients with insomnia. Ongoing efforts to optimize the management of insomnia need to focus on improving patients' overall health and quality of life by targeting both nocturnal and diurnal aspects of insomnia, using objective end points in assessment.
Although behavioral approaches to insomnia treatment (eg, relaxation therapy or cognitive therapy) have been shown to be effective,[11] the costs and time commitments involved in applying them restrict their use. As a result, pharmacotherapy for insomnia has undergone a series of evolutionary developments, each one attempting to improve upon the previous generation of agents. In the 1970s, long half-life benzodiazepines (eg, flurazepam) replaced barbiturates as the preferred hypnotic agent, offering an improved therapeutic index and a reduced propensity for drug dependence and interactions with other medications. The problem of residual daytime sedation, however, which was particularly troublesome in elderly patients, soon was considered the most important adverse effect of these drugs.[12,13] Consequently, benzodiazepines with shorter half-lives (eg, triazolam) were developed and became the first-line treatment for insomnia in the 1980s. However, from 1987 to 1991, the use of triazolam declined dramatically as a result of reports of paradoxic reactions, memory impairment, and rebound insomnia occurring in association with this drug.[14,15] Typically, these adverse events occurred with excessive doses, prompting a reduction in the recommended dose. Still, concern remained that rebound effects occurring after abrupt discontinuation of triazolam could involve increased anxiety and an exacerbation of insomnia worse than the initial problem (ie, rebound insomnia).
In the 1990s, medications that bind to the benzodiazepine receptor but that are chemically unrelated to benzodiazepines became available as therapeutic options for the treatment of insomnia. The first of these drugs available in the United States, zolpidem, has a half-life similar to that of triazolam. At low doses, zolpidem proved to be effective and relatively free of side effects, a profile hypothesized to reflect its specificity for the type-1 benzodiazepine receptor.[16] At equipotent doses, however, one comparison of zolpidem and triazolam demonstrated little difference between the 2 agents in terms of their pharmacokinetic profiles, efficacy, and safety, thus failing to support the therapeutic advantage of receptor selectivity alone.[17] In addition, evidence that patients with insomnia were often taking medication during the night (ie, later than bedtime) led to concern that the short half-lives of zolpidem and triazolam were not short enough to prevent possibly dangerous daytime carryover effects.[18,19]
More recently, a novel nonbenzodiazepine, zaleplon, was approved for the treatment of insomnia. Efficacy of zaleplon in the treatment of insomnia has been established in several studies.[20-25] In adults with primary insomnia, data gathered by Walsh and colleagues[20] from 132 patients showed that objective and subjective improvements in sleep onset latency and total sleep time were comparable during 14 days of treatment with 10-mg doses of zaleplon. Similar results were noted in open-label follow-up studies (N = 284) reported by Scharf,[26] who found that time to sleep onset decreased from a median baseline of 82 minutes to approximately 30 minutes and was maintained at that level throughout 1 year of nightly use. Moreover, continued monitoring during placebo washout periods revealed no evidence of rebound effects or a withdrawal syndrome.[26] Long-term efficacy was shown in a double-blind study in which zaleplon 10 mg was administered nightly for 35 nights.[25] This study also produced no evidence of tolerance to the sleep-improving effect of zaleplon throughout the 5 weeks of administration nor rebound insomnia following discontinuation.
As described above, comparison with zolpidem and triazolam shows that zaleplon has both a more rapid onset of effect and a shorter elimination half-life,[27] properties that allow for more versatility in zaleplon administration than other agents.[28-30] A study comparing the pharmacokinetics and pharmacodynamics of zaleplon and zolpidem in 10 healthy subjects demonstrated that each drug was rapidly absorbed, producing linear pharmacokinetic values with both 10- and 20-mg doses.[31] Zaleplon may be administered at bedtime, later at night after difficulty falling asleep becomes evident, or upon awakening in the middle of the night.
Residual daytime sedation after bedtime administration may occur with hypnotic agents that have intermediate and long half-lives. Such residual sedation is generally undesirable and may predispose patients to dangerous daytime impairment. These unwanted effects are not evident in studies with zaleplon. Administration of zaleplon facilitates sleep but, because of rapid elimination, does not produce persistent sedation or psychomotor or cognitive impairment upon awakening.[28,29] Two studies described by Zammit,[29] in which patients with sleep maintenance insomnia were examined by an objective polysomnographic measurement of daytime sleepiness (Multiple Sleep Latency Testing), showed that zaleplon caused no next-day sedation within 4 hours after a 10-mg dose, whereas zolpidem 10 mg was associated with significantly greater next-day sedation for as long as 7 hours after administration. Importantly, subjective reports by patients in these studies generally supported the objective evaluations.
Residual sedation occurs even when older "short-acting" hypnotic agents are administered after an awakening during the night, because although they have short half lives, their residual effects may still last 6 to 8 hours. The shorter half-life of zaleplon permits middle-of-the-night dosing. A study by Hindmarch and colleagues[32] compared zaleplon 10 or 20 mg and zolpidem 10 mg with placebo when administered in healthy subjects during the night at 5 hours, 3 hours, and 1 hour before morning awakening. Residual effects were evaluated by performance on psychomotor and memory tests immediately after awakening. The degree of effects in the zaleplon 10 mg-treated patients was similar to that in the placebo patients except for 1 small but significant psychomotor effect 1 hour after dosing; zaleplon 20 mg (twice the recommended dose) caused significant impairment only at the 1-hour time point. However, zolpidem 10 mg not only produced more marked impairment than zaleplon 20 mg in alertness 1 hour after administration, but also impaired information processing and working memory for at least 3 hours after administration, and reaction time and long-term memory for at least 5 hours after administration.
Other studies have also reported a lack of residual sedation with zaleplon after middle-of-the-night use as measured by psychomotor and memory testing[32,33] and automobile driving performance.[34-36] The active comparators in these studies included zolpidem 10 mg[32,33,36] and zopiclone 7.5 mg,[34,35] a nonbenzodiazepine agent not marketed in the United States.
Recent research has documented that zaleplon also produces less cognitive and psychomotor impairment even within the window of its therapeutic action.[32,33] At 1.25 hours after administration (ie, at peak plasma concentration), zaleplon produces minimal impairment on measures of these functions relative to other benzodiazepine-receptor hypnotics, despite producing equivalent reductions in sleep latency.[32] This differential lack of adverse effects on function cannot be attributed solely to its more rapid elimination, but instead may be a consequence of other distinctive features of the pharmacology of zaleplon (ie, markedly lower affinity for the benzodiazepine receptor).[37-39] This has been evidenced by evaluations of cognitive and psychomotor function at the time of peak concentrations. Pooled data from 15 double-blind, placebo-controlled trials have demonstrated that cognitive and psychomotor function were not significantly altered at or around the time of peak plasma concentrations in healthy subjects given 10-mg doses of zaleplon.[38,39] In a controlled trial comparing the effects of 10 mg of zaleplon to 10 mg of zolpidem, psychomotor and word-recall abilities tested at the time of peak concentrations were significantly impaired in the patients receiving zolpidem but not in those treated with zaleplon, compared with placebo.[32] The absence of a negative effect of zaleplon on these parameters at a time when both have equivalent hypnotic effect provides the first evidence that impairment effect is separable from the therapeutic sleep-inducing effect of the individual agent.
Insomnia is a highly prevalent sleep problem that affects multiple aspects of daily life. Zaleplon, a novel nonbenzodiazepine sleep medication, represents a therapeutic advance by virtue of its distinct pharmacokinetic and pharmacodynamic profiles. Its rapid elimination and receptor-binding profile allow it to be used more flexibly (ie, for symptomatic treatment of insomnia, rather than just as a prophylactic agent taken at the beginning of the night). Thus, zaleplon is well suited for individuals with variable sleep patterns, such as long-distance travelers, shift workers, or patients with middle-of-the-night awakenings. Regardless of the individual patient's insomnia complaints, the absence of residual daytime effects and a wider margin of safety permit more versatile administration with zaleplon than is possible with previously available agents.
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