Pharmacological profile and clinical effect of zolpidem (Myslee tablets), a hypnotic agent

Zolpidem is a non-benzodiazepine hypnotic agent with a chemical structure of imidazopyridine. In vitro and in vivo binding studies, zolpidem exhibits selectivity to omega 1 receptors (GABAA-receptor subtypes containing alpha 1 subunits). Unlike benzodiazepines, zolpidem produces sedative effects in preference to anxiolytic, anticonvulsant and myorelaxant effects in behavioral experiments using mice. Double-blind comparative studies with reference drugs such as triazolam and zopiclone show that zolpidem is an effective and highly safe drug for the treatment of insomnia. In addition, zolpidem does not produce next-day residual effects, rebound insomnia and tolerance. This clinical profile of zolpidem may be related to its selectivity and high intrinsic activity for omega 1 receptors.     

Benefit-risk assessment of zaleplon in the treatment of insomnia.

Insomnia is a heterogeneous, highly prevalent condition that is associated with a high level of psychiatric, physical, social and economic morbidity. The treatment of insomnia involves pharmacological and non-pharmacological interventions. The mainstay of pharmacological treatment of insomnia has been the benzodiazepines, the introduction of which represented a significant improvement over the barbiturates and chloral hydrate. Although benzodiazepines have been shown to be efficacious in treating insomnia, they have also been associated with a number of adverse effects including tolerance, dependence, withdrawal and abuse potential, impairment in daytime cognitive and psychomotor performance (including an increased risk of accidents and falls), adverse effects on respiration and the disruption of normal sleep architecture with reduction in both slow wave sleep and rapid eye movement. In the last decade, the treatment of insomnia has been supplemented by the introduction of a number of non-benzodiazepine hypnotics including zolpidem, zopiclone and, most recently, zaleplon. Zaleplon possesses a unique pharmacological profile, with an ultra-short half-life of about 1 hour, and selective binding to the BZ1(omega1) receptor subtypes of the GABA(A) receptor. This unique pharmacological profile predicts a number of pharmacodynamic properties that account for a unique benefit-risk profile. Consistent with these predictions, zaleplon has been shown in a number of studies to be efficacious in promoting sleep initiation, but less so in promoting sleep maintenance. The adverse effects associated with zaleplon have been shown to be more rapidly resolved and/or lesser in magnitude than those associated with benzodiazepines (including triazolam) and the longer acting non-benzodiazepine hypnotics (zolpidem and zopiclone). This improved risk profile includes: the effects of zaleplon on psychomotor and cognitive performance; tolerance, withdrawal and rebound; respiratory depression; sleep architecture; and other treatment-emergent adverse effects. The unique benefit-risk profile of this agent may be particularly suitable for certain patients with insomnia and provides yet another option in the management of this impairing condition.     

A comparative assessment of the risks and benefits of zopiclone: a review of 15 years' clinical experience.

Zopiclone is a cyclopyrrolone hypnosedative that is chemically unrelated to the benzodiazepines but nevertheless potentiates gamma-aminobutyric acid-mediated neuronal inhibition, and has demonstrated proven efficacy and good tolerability in the treatment of insomnia over 15 years of use. Zopiclone is indicated for short term use, and should not be prescribed for more than 4 weeks. This review compares the efficacy of zopiclone with that of a number of commonly used short-, medium- and long-acting benzodiazepines. Zopiclone at dosages of 7.5 mg/day has demonstrated efficacy equivalent and in some cases greater to that of flurazepam 30 mg/day, nitrazepam 5 mg/day, flunitrazepam 1 to 2 mg/day, temazepam 20 mg/day, triazolam 0.125 to 0.5 mg/day and midazolam 15 mg/day. Zopiclone-treated patients reported themselves to be less impaired by daytime sedation than patients treated with the medium- and long-acting hypnosedatives flurazepam, nitrazepam and flunitrazepam. Zopiclone and temazepam showed similar effects on daytime behaviour while zopiclone appeared to have somewhat better effects on daytime well-being than the short-acting triazolam and midazolam. There has been no clinical comparison with the frequently used medium-acting benzodiazepines lormetazepam and brotizolam and the imidazopyridine hypnosedative zolpidem. Data from clinical trials, pooled analyses and postmarketing surveillance including over 30,000 patients showed that with the exception of bitter taste (reported by <10% of zopiclone recipients), the tolerability profile of zopiclone is similar to that of placebo. Clinical trials found no evidence for significant rebound insomnia and indicated that the risk of withdrawal reactions with therapeutic doses of zopiclone is very low. In addition, to date, dependency appears very low, although abuse potential should be considered following a history of addiction or psychiatric illness. Evaluation of the accumulated evidence from over 2.5 billion units dispensed in more than 30 countries indicates that zopiclone is effective, well tolerated and an excellent alternative to benzodiazepines in the short term treatment of insomnia.     

Clinically important drug interactions with zopiclone,zolpidem and zaleplon

Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted. Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H(2) receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs. Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The fact that these drugs are newer to the market and have not been as extensively studied as the conventional benzodiazepines may be the reason for this. Another explanation may be a difference in CYP metabolism. While triazolam and midazolam are biotransformed almost entirely via CYP3A4, the newer hypnosedatives are biotransformed by several CYP isozymes in addition to CYP3A4, resulting in CYP3A4 inhibitors and inducers having a lesser effect on their biotransformation.     

Double-blind study on the hypnotic and antianxiety effects of zopiclone compared with nitrazepam in the treatment of insomnia

The effects of zopiclone (7.5 mg/per os/day), a new non-benzodiazepine drug, on anxiety levels, time of sleep induction, hours of sleep, number of nocturnal arousals, quality of sleep and of daytime arousal were evaluated by using psychometric ratings. A random double-blind cross-over study versus nitrazepam (5.0 mg/per os/day) was performed on 20 patients affected by insomnia and generalized anxiety disorder (DSM III-R). The effects were evaluated by using the Hamilton Rating Scale for Anxiety, the Toulouse-Pieron Attention Test and a time-signed quantitative scale for anxiety. The results of the trial confirmed the effectiveness of zopiclone in the treatment of insomnia with effects similar to nitrazepam on the quality and duration of sleep and number of nocturnal arousals, but with an improvement in all the other parameters.     

Zopiclone, a cyclopyrrolone hypnotic: review of properties

Zopiclone is a non-benzodiazepine hypnotic with a pharmacological spectrum of activity which resembles that of the benzodiazepines (BZD), but it binds to the GABA complex at a site different from the BZD receptor. Pharmacokinetic properties class ZPC in the category of hypnotics with intermediate-short half-life (5-7 hours) and explain the low incidence of unwanted effects reported. The influence of zopiclone 7.5 mg on sleep architecture is minimal. In healthy volunteers, the amount of deep sleep is increased. No depressant effect on respiratory function and no rebound effect has been demonstrated.     

Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia

Zolpidem is an imidazopyridine agent that is indicated for the short term (< or = 4 weeks) treatment of insomnia (recommended dosage 10 mg/day in adults and 5 or 10 mg/day in the elderly or patients with hepatic impairment). Data have shown that the hypnotic efficacy of zolpidem is generally comparable to that of the benzodiazepines flunitrazepam, flurazepam, nitrazepam, temazepam and triazolam as well as nonbenzodiazepine hypnotic agents such as zopiclone and trazodone in the treatment of elderly and adult patients with insomnia. The comparative efficacy of a recently available nonbenzodiazepine hypnotic zaleplon and zolpidem has yet to be established. There was no evidence of tolerance developing to the hypnotic effects of zolpidem in a number of studies of up to 6 months' duration. However, tolerance has been described in a few patients taking the drug at high dosages for periods of up to several years. Zolpidem is well tolerated in patients with insomnia and the most common adverse events are generally nausea, dizziness and drowsiness. Although zolpidem produced some psychomotor and memory impairment over the first few hours after administration, it had few next-day effects (including effects on daytime well-being and morning coordination). In this respect, it was comparable or superior to flunitrazepam and flurazepam and comparable to other benzodiazepines in patients with insomnia. Zolpidem appears to have a low potential for abuse. Conclusions: Zolpidem is effective and well tolerated in patients with insomnia, including the elderly. Studies have shown that zolpidem generally has similar efficacy to other hypnotics including benzodiazepines and zopiclone. Zolpidem appears to have minimal next-day effects on cognition and psychomotor performance when administered at bedtime. In addition, there is little evidence of tolerance to the hypnotic effects of zolpidem, or rebound insomnia or withdrawal symptoms after discontinuation of the drug when it is given as recommended (10 mg/day for < 1 month) or over longer periods.     

Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone

Benzodiazepines have historically been the mainstay of treatment for sleeping disorders, yet they have many shortcomings. A new group of sedative hypnotic agents has been developed for this purpose. Similar to the benzodiazepines, zaleplon, zolpidem and zopiclone have activity at the GABA receptor complex, yet they appear to have more selectivity for certain subunits of the GABA receptor. This produces a clinical profile that is more efficacious with fewer side effects. Zaleplon, zolpidem and zopiclone are structurally distinct. Due to variation in binding to the GABA receptor subunits, these three compounds show subtle differences in their effect on sleep stages, and as antiepileptics, anxiolytics and amnestics. The duration of action of zaleplon, zolpidem and zopiclone can be related to their individual pharmacokinetic profile, which subsequently determines the time course of drug effect. Each of these compounds has a unique pharmacokinetic profile with different bioavailability, volume of distribution and elimination half-lives. Zaleplon has a rapid elimination so there are fewer residual side effects after taking a single dose at bedtime. By comparison, zolpidem and zopiclone have a more delayed elimination so there may be a prolonged drug effect. This can result in residual sedation and side effects but may be useful for sustained treatment of insomnia with less waking during the night. There are also differences in potency based on plasma concentrations suggesting that there are differences in binding to the GABA receptor complex. Although zaleplon has a much lower bioavailability (30%), the treatment dose is similar to zolpidem and zopiclone (bioavilaibility of 70%) because of the increased potency of zaleplon. The pharmacokinetics and pharmacodynamics of zaleplon, zolpidem and zopiclone are significantly different from benzodiazepines. The new drugs are sufficiently unique from each other to allow customisation of treatment for various types of insomnia. While zaleplon may be best indicated for the delayed onset of sleep, zolpidem and zopiclone may be better indicated for maintaining a complete night's sleep. Only the patient's symptoms and response to treatment will dictate the best course of treatment.     

The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents

The new generation hypnotic drugs, zolpidem, zopiclone and zaleplon, are at least as efficacious in the clinic as benzodiazepines and may offer advantages in terms of safety. These drugs act through the BZ binding sites associated with GABAA receptors, but show some differences from benzodiazepines in pharmacological effects and mechanisms of action. Of particular interest is the finding that zolpidem shows a wide separation between doses producing sedative effects and those giving rise to other behavioural actions, and induces less tolerance and dependence than benzodiazepines. Zolpidem also demonstrates selectivity for GABAA receptors containing alpha1 subunits. Recent studies using genetically modified mice have confirmed that receptors containing alpha1 subunits play a particularly important role in mediating sedative activity, thus providing an explanation for the pharmacological profile of zolpidem.     

Zolpidem. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential

Zolpidem is an imidazopyridine, a chemically novel nonbenzodiazepine hypnotic agent which acts at the benzodiazepine omega 1-receptor subtype in the brain. With a rapid onset of action and short elimination half-life, it reduces the latency to and prolongs the duration of sleep in patients with insomnia, yet has no major effects on sleep stages when given in dosages of 5 to 20 mg nightly. Rebound effects on withdrawal of the drug have not been observed. Unlike benzodiazepines, zolpidem has no myorelaxant or anticonvulsant effects and its effects on anxiety appear to be minor. While zolpidem aids sedation, and may reduce memory or psychomotor function within the first 2 hours after administration of single oral doses, its use as a surgical premedicant remains to be established. Adverse effects are predominantly CNS and gastrointestinal in nature. Altered pharmacokinetics may lead to an increase in dose-proportionate adverse effects in the elderly and in patients with renal dysfunction. Limited evidence to date suggests that the dependence liability of zolpidem is minimal. Thus, zolpidem is an interesting alternative to benzodiazepines in the treatment of insomnia, with properties that potentially offer worthwhile advantages in this therapeutic area if they are confirmed with wider clinical experience.     

Behavioral analysis of zopiclone on the basis of their discriminative stimulus properties in the rat

Zopiclone is a new cyclopyrrolone derivative which exerts pharmacological activities similar to those of benzodiazepines in behavioral and biochemical studies. In order to clarify the discriminative stimulus properties of zopiclone, 8 rats were trained to discriminate the interoceptive stimulus induced by zopiclone (3.2 mg/kg, i.p.) from those of saline. Following discrimination acquisition, administration of zopiclone resulted in drug-appropriate responding with an ED50 of 1.3 (1.0-1.8) mg/kg. The zopiclone discriminative stimulus generalized to the benzodiazepines diazepam (1.8 mg/kg), nitrazepam (10 mg/kg) and alprazolam (10 mg/kg). A non-benzodiazepine, suriclone, at 3.2 mg/kg, generalized to the zopiclone stimulus in 5 out of 7 rats, but meprobamate, hydroxyzine, tracazolate and muscimol did not. The benzodiazepine antagonist Ro 15-1788 (1 mg/kg) completely blocked zopiclone stimulus. In contrast, however, bicuculline and pentetrazol failed to antagonize it. The serotonin antagonist cinanserin and ritanserin neither generalized to the zopiclone stimulus nor did they exhibit antagonism. These results suggest that the zopiclone discriminative stimulus is mediated by binding to benzodiazepine receptors and appears not to be related to GABAergic or serotonergic system.     

Zopiclone produces effects on human performance similar to flurazepam, lormetazepam and triazolam.

The cognitive function and psychomotor performance of 10 healthy male volunteers were measured following single oral doses of: zopiclone (7.5 mg), flurazepam (15 mg), lormetazepam (1 mg), triazolam (0.25 mg) and placebo. The performance tests selected (stroop task, five choice serial reaction time, memory span, logical reasoning, mood and saccadic eye movement analysis) were thought to reflect aspects of normal daily activity. The tests demonstrated a clear reduction of performance for all active treatments. No drug emerged as the most potent sedative overall, as each of the tests was affected to a different degree by each drug. Drug effects were not qualitatively different between active treatments so that zopiclone was indistinguishable from the three benzodiazepines with which it was compared.     

Prescribing short-acting hypnosedatives. Current recommendations from a safety perspective.

The duration of action of hypnosedative drugs is mainly determined by their pharmacokinetic properties. The ideal drug should induce sleep within 30 min and maintain a normal pattern of sleep for 6 to 8h, with little or no residual effects the next morning. Clinically, 4 types of insomnia can be distinguished: prolonged latency, 1 to 2 long periods of wakefulness, frequent short awakenings and early morning awakening. An ultra-short-acting drug (2 to 3h), such as triazolam, is useful for prolonged latency. Temazepam, lormetazepam and loprazolam provide more prolonged effects (8 to 10h). These benzodiazepines are not free of daytime adverse effects, particularly drowsiness, dependency potential, rebound insomnia and habituation to the drug effect. Zopiclone and zolpidem are new nonbenzodiazepine hypnotics that are as effective as benzodiazepines but without the problems associated with the latter. They produce a more normal electroencephalogram sleep pattern and so would seem to approach to the ideal hypnosedative for the future. However only further clinical trials and widespread use in practice will determine whether they will live up to this potential.     

New drug evaluations. Triazolam

Triazolam is a sedative/hypnotic triazolobenzodiazepine, structurally related to alprazolam. Recently, it has been approved for the short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. Triazolam is metabolized with a half-life of 1.5-5.0 hours. Its one active metabolite, which appears in low concentrations and is inactivated rapidly, is not thought to contribute to its pharmacologic activity. Triazolam has been shown to decrease sleep latency and the number of nocturnal awakenings while increasing total sleep time in patients with insomnia. Sleep electroencephalogram studies show that triazolam has no effect on delta-sleep (Stages 3 and 4) and has variable effects on rapid-eye-movement sleep. Nighttime administration of triazolam increases daytime alertness in insomniacs and improves or has no effect on performance. The reported side effects are similar to those of other benzodiazepines and include drowsiness, dizziness, and dry mouth. The recommended dosage of triazolam is 0.25-0.5 mg hs. A reduced initial dose of 0.125 mg should be used in geriatric patients.     

Overview of the therapeutic management of insomnia with zolpidem

Benzodiazepine hypnotic agents were the mainstream pharmacotherapy for insomnia from the 1960s to the 1980s, but their safety profile proved to be not quite as perfect as originally expected with regard to daytime performance and cognition, and above all the risk of dependence. These risks are substantially diminished in the non-benzodiazepine hypnotic agents developed and marketed during the past two decades, but the fears engendered by certain benzodiazepines still greatly influence the attitude of both physicians and the general public to the treatment of insomnia. For this reason, as well as in the interests of matching the pharmacotherapy of insomnia more closely to the often fluctuating nature of this disorder, the possibility of the discontinuous or 'as needed' use of hypnotic drugs has attracted increasing attention in recent years. Current recommendations strongly favour the use of hypnotic drugs for a limited period of time. However, some insomniac patients need sleep medication for longer periods in spite of a non-pharmacological approach, whereas other patients become dependent on drugs as a result of rebound insomnia, withdrawal symptoms, or the recurrence of insomnia. The pharmacological properties of zolpidem make it feasible for non-nightly use. A double-blind, randomized, parallel-group study of continuous treatment with either zolpidem or estazolam, followed by an observation of the discontinuation of drug treatments combined with the non-pharmacological management of primary insomnia, showed a carry-over benefit for zolpidem treatment.     

Pharmacodynamic profile of Zaleplon,a new non-benzodiazepine hypnotic agent

The challenge in developing hypnotic agents for the treatment of insomnia is to balance the sedative effect needed at bedtime with the residual sedation on awakening. Zaleplon is a novel pyrazolopyrimidine hypnotic agent that acts as a selective agonist to the brain omega(1) receptor situated on the alpha(1) subunit of the GABA(A) receptor complex. Zaleplon was proven to be an effective hypnotic drug as it consistently and significantly reduced latency to persistent sleep in insomniac patients for doses of 10 mg and above in polysomnography studies. The pharmacodynamic profile of zaleplon on psychomotor performance, actual driving and cognitive function, including memory, was assessed in several randomized, double-blind, placebo-controlled studies in healthy young subjects as well as insomniac patients by using various positive controls (zolpidem, zopiclone, triazolam and flurazepam). The recommended hypnotic dose of zaleplon in young adults (10 mg) produced minimal or no impairment of psychomotor and memory performance even when administered during the night as little as 1 h before waking. No impairment of actual driving was observed when zaleplon 10 mg was administered either at bedtime or in the middle of the night as little as 4 h before waking. Zaleplon 20 mg, twice the recommended dose, generally produced significant impairment of performance and cognitive functions when these functions were measured at the time of peak plasma concentration, i.e. 1 h after dose administration, and no impairment of driving abilities was observed 4 h after a middle-of-the-night administration. In contrast, consistent detrimental residual effects on various aspects of psychomotor and cognitive functions were observed with the therapeutic doses of the various commonly prescribed hypnotic agents used as comparators, e.g. zolpidem 10 mg up to 5 h after dose administration, zopiclone 7.5 mg up to 10 h after, flurazepam 30 mg up to 14 h after and triazolam 0.25 mg up to 6 h after. Also, zolpidem 10 mg and zopiclone 7.5 mg were also shown to significantly impair driving ability the next morning when this was measured 4 h and up to 10 h after dose administration, respectively. The present review shows that zaleplon 10 mg has little or no residual effect when administered in the middle of the night, as late as 1 h before waking, and is devoid of impairment of driving abilities as assessed by actual driving 4 h after dose administration. The lack of clinically significant or minimally statistically significant residual effects of zaleplon even at its peak concentration may be explained by its unique pharmacokinetic (rapid elimination half-life) and pharmacodynamic (low affinity, and specific binding profile to various subunits of the GABA(A)receptor) profiles. These properties allow zaleplon to be used for treatment of symptoms only when they occur, either at bedtime or later in the night, without incurring significant risk of developing next-day impairment of psychomotor and cognitive functioning. Copyright 2001 John Wiley & Sons, Ltd.     

Ramelteon: profile of a new sleep-promoting medication

To date the mainstay of the pharmacological treatment of insomnia has involved the modulation of the gabaminergic system via benzodiazepines or the Z-drugs, zolpidem, zopiclone or zaleplon. A new approach has explored the melatoninergic system, namely activation of MT1 and MT2 receptors in the suprachiasmatic nucleus of the hypothalamus. Ramelteon (TAK-375) is a novel sleep-promoting agent that acts as an agonist at these receptors; its preclinical pharmacology, mode of action, pharmacokinetics, drug interactions, clinical efficacy, and safety and tolerability are reviewed here.     

Eszopiclone stimulates the hypothalamo-pituitary-adrenal axis in the rat

Eszopiclone (Lunesta?) is used for the treatment of insomnia. It is the S (+)-enantiomer of racemic zopiclone, a cyclopyrrolone with no structural similarity to the hypnotic drugs zolpidem and zaleplon or to the benzodiazepines and barbiturates. Although eszopiclone interacts with the gamma-aminobutyric acid A-type (GABA(A)) receptor complex, it has a different binding profile than other sedative/hypnotic agents and modulates the receptor complex in a unique manner. Thus, eszopiclone might produce different pharmacological effects compared to other sedative/hypnotic agents. Beside their behavioral properties, sedative/hypnotic drugs affect the hypothalamo-pituitary-adrenal (HPA) axis. In general, low doses of benzodiazepine-type drugs decrease, whereas high doses increase the activity of the HPA axis. Furthermore, benzodiazepines reduce stress-induced increases in HPA axis activity. The goal of the present study was to characterize the effects of eszopiclone on the HPA axis in the rat. Male rats were injected with saline or eszopiclone and trunk blood was collected for the measurement of plasma levels of adrenocorticotropin (ACTH) and corticosterone by radioimmunoassay. The acute administration of eszopiclone produced dose-dependent increases in plasma levels of ACTH and corticosterone, and tolerance developed to these effects after repeated drug administration. Pretreatment with eszopiclone did not affect stress-induced stimulation of the HPA axis. These results show that eszopiclone and the benzodiazepine-type drugs differentially affect the HPA axis.