Benzodiazepine Hypnotics Research Articles

The mechanism of action of zopiclone

The mechanism of action of the cyclopyrrolone hypnotic drug zopiclone involves allosteric modulation of the GABAA receptor. Zopiclone displaces the binding of [(3)H]-flunitrazepam with an affinity of 28 nM, and enhances the binding of the channel blocker [(35)S]-TBPS. The binding of zopiclone, unlike that of hypnotic benzodiazepines, is not facilitated by GABA. Zopiclone does not distinguish between GABAA receptors containing different alpha-subunits (BZ(1) and BZ(2) phenotype). Studies with protein-modifying agents (eg diethylpyrocarbonate) and photoaffinity labelling suggest that cyclopyrrolones bind to a domain on the GABAA receptor different from the benzodiazepine binding domain. The consequence of this interaction with the GABAA receptor is to potentiate responses to GABA, as can be demonstrated by electrophysiological methods. Subchronic treatment of mice with high doses of zopiclone does not produce the changes in sensitivity of the GABAA receptor that are observed with hypnotic benzodiazepines.

Falls and fractures in nursing home patients receiveing psychotropic drugs

AbstractFalls in 44 matched control patients (average age 87.1) were statistically compared to 38 patients (average age 85.3) who received scheduled or as needed (prn) single‐agent psychotropics over a 6‐month period. Prospective assessments of psychotropic drug therapy were made on a monthly basis, and data on falls and fractures were retrospectively gathered. Both scheduled and prn single‐agent usage of benzodiazepine (BZ) hypnotics, and scheduled usage of BZ anxiolytics and thioridazine increased the incidence and episodes of falls over the frequency of falls found in the control group. Fractures were more prevalent in the treatment group over the 6‐month period, but half the falls in the control group resulted in fractures. Longer‐acting BZs, both prn and scheduled, resulted in a greater rate of falls than the shorter‐acting BZs, but even the shorter‐acting (SA) BZs given on a scheduled basis more often than three times a week had a greater rate of falls than the control group. When not more than 3 SABZ doses per week were given, no falls were noted for the follow‐up 6‐month period. It appears that most single psychotropics, except the SABZs given no more often than three times a week, haloperidol and desipramine, increase the risk of falls and fractures in a very old frail nursing home population.

A Comparative Study of Benzodiazepine Hypnotics and Zopiclone in Schizophrenia: Effects on Polysomnograms and BPRS Scores

Abstract: Sleep variables and psychiatric symptoms during benzodiazepine (BZD) hypnotic therapy and during zopiclone (ZPC) treatment were investigated in 6 male chronic schizophrenics. The amount of stage 1 was smaller and that of stage 2 was larger during treatment with ZPC than BZDs. However, no significant difference was shown in the amount of slow‐wave sleep (SWS) between the treatments. Both the total and negative‐symptom scores in the Brief Psychiatric Rating Scale (BPRS) were lower, and the soundness of sleep in the subjective sleep assessments was better evaluated during treatment with ZPC than BZDs. These results suggest that ZPC may be more beneficial in treating schizophrenic insomnia than BZDs.

Effects of chronic treatment with triazolam on operant responding in rats

The aims of the present study were to investigate the effect of the benzodiazepine antagonist, flumazenil, on operant responding in rats treated chronically with the short-acting hypnotic triazolam and to study the consequence of chronic triazolam treatment on the time course of effects of triazolam and zolpidem. Zolpidem is an imidazopyridine with a pharmacological and behavioral profile that differs from that of the benzodiazepine hypnotics. Rats were treated with saline or triazolam (1 or 3 mg/kg) twice daily for 5 days and were tested daily 1, 3, 5.5 or 7.5 h after injection. In addition, on the 5th day of chronic treatment all rats were injected with flumazenil (10 mg/kg) 10 min before session. The time course of effects of triazolam and zolpidem was determined after cessation of repeated saline or triazolam treatment. Tolerance to the depressant effect of 1 mg/kg of triazolam developed during long-term administration. Flumazenil decreased operant responding in rats pretreated with triazolam. The effect was statistically significant when rats had received 1 mg/kg of triazolam 3 h before the session or 3 mg/kg of triazolam 3, 5.5 or 7.5 h before the session. After cessation of chronic treatment, rats pretreated chronically with 3 mg/kg of triazolam displayed decreased sensitivity to triazolam and to 10 mg/kg but not 3 mg/kg of zolpidem. The present results indicate that chronic treatment with triazolam induces tolerance to the rate-decreasing effect of the drug and dependence as measured by flumazenil-induced disruption of operant responding. The limited degree of cross-tolerance between zolpidem and triazolam may suggest that their pharmacological mechanisms of action are distinct.

Systemic absorption and abuse liability of snorted flunitrazepam

Benzodiazepine hypnotics are widely abused as part of a polydrug misuse culture. This study set out to investigate some pharmacokinetic and pharmacodynamic characteristics of a novel method of abuse, snorting, of flunitrazepam. Twenty healthy volunteers took part: three took 0.5 mg, three took 1 mg, three took 1.5 mg, six took 2 mg and five took placebo. Blood was sampled and ratings of mood, bodily symptoms, strength and liking of drug effect were completed pre- and at 5, 15, 30, 60, 90, 120 and 240 minutes and at 24 hours post-drug. It was found that flunitrazepam could be detected in venous blood 5 minutes after intake. As the dose increased, the peak plasma concentration was higher but also occurred progressively later, the levels reached being comparable to oral or intramuscular administration at 110 minutes. Subjects reported sedation but complained of few side-effects. They liked the drug effects and subjective ratings of strength were correlated with liking and with plasma drug levels.

Effects of zopiclone on sleep and symptoms in schizophrenia: Comparison with benzodiazepine hypnotics

1. Sleep variables and psychiatric symptoms were investigated in 6 male chronic schizophrenic outpatients. 2. The patients were being treated with benzodiazepine(BZD) hypnotics for more than 8 weeks, and BZDs were replaced with zopiclone (ZPC) 15 mg/day. 3. Polysomnographic examinations, subjective sleep assessments and BPRS scoring were performed during BZD therapy and at the end of 8 weeks of ZPC therapy. 4. The doses of neuroleptics and anticholinergic agents remained fixed throughout the study. 5. The amount of slow-wave sleep (SWS) was markedly small and that of stage 1 sleep was moderately large during BZD therapy. 6. The amount of stage 1 was smaller and that of stage 2 was larger during treatment with ZPC than BZDs. 7. There were no significant change in the amount of SWS between the treatment. 8. Half of the patients exhibited a sleep-onset REM period (SOREMP) during ZPC therapy. 9. Both total BPRS score and negative symptom score were lower during treatment with ZPC than BZDs. 10. These results suggest that ZPC may be more beneficial in treating schizophrenic insomnia than BZD hypnotics and that reduced SWS and SOREMP may be partly involved in the pathophysiology of schizophrenia.

Nifedipine Blocks Effects of Triazolam Injected into the Dorsal Raphe Nucleus on Sleep

In previous studies, the author has reported both in vitro and in vivo sleep studies in which there were complex interactions between benzodiazepine hypnotics and the dihydropyridine calcium channel blocker nifedipine. The author has also reported that microinjections of triazolam into the dorsal raphe nucleus of the rat result in enhancement of wakefulness. In the present study, nifedipine and triazolam were coadministered into this site. As previously was observed, triazolam produced a dose-dependent increase in sleep latency and a decrease in total sleep, primarily by reducing non-rapid-eye-movement sleep. Nifedipine had no effect on sleep when given by itself but prevented the alterations in sleep by triazolam. These various sleep effects were not associated with alterations in core temperature. These data are consistent with the view that aspect of the sleep-altering activity of triazolam involves interaction with voltage-dependent calcium channel activity.

Anxiety or depression during withdrawal of hypnotic treatments

The prescription of hypnotics, mostly benzodiazepines, continues at a high level, long-, medium- and short-acting compounds all being used. The indication for these hypnotics is the symptom of insomnia which is often secondary to a primary anxiety or depressive disorder. One problem with the use of hypnotics, particularly shorter-acting ones, is rebound insomnia in that discontinuation may be followed by sleep which is worse than pretreatment levels. Anxiety, which may well have been assuaged by the hypnotic treatment, may also rebound but depression, usually not really helped by the hypnotic, does not alter much. A second problem, on discontinuation of long-term treatment, particularly longer-acting hypnotics, is a physical withdrawal syndrome characterized by general malaise, and perceptual symptoms as well as marked increases in anxiety and insomnia. In some patients, however, depressive symptoms predominate. These may be an exaggeration of an on-going depressive disorder or it may appear to arise de novo in patients hitherto free of such an illness. The depression can be quite severe and need rigorous treatment in its own right. It is always useful to enquire about hypnotic/anxiolytic withdrawal in patients presenting with a depressive disorder. Depression is also a prognostic indicator of poor outcome (failure to withdraw successfully) in patients taking benzodiazepine hypnotics chronically.

Erratum to Zopiclone review

Synopsis Zopiclone is a cyclopyrrolone which is chemically unrelated to the benzodiazepines and is thought to act on the GABAA receptor complex at a site distinct from, but closely related to, the benzodiazepine binding site. The hypnotic efficacy of zopiclone administered as single oral doses has been demonstrated in patients undergoing next-day surgery and in patients with insomnia, and these studies have established an optimal dose of 7.5mg for elderly patients. Using this dose, clinical studies have shown that zopiclone improved sleep in elderly patients to a similar extent as triazolam 0.125 to 0.5mg, flurazepam 15mg, and nitrazepam 5mg. Studies that also included younger patients have shown that zopiclone 7.5mg is at least as effective as triazolam 0.25 or 0.5mg, and on most sleep parameters is comparable to temazepam 20mg, nitrazepam 5mg, flunitrazepam 2mg, and flurazepam 20mg. Zopiclone causes minimal impairment to psychomotor performance and mental alertness the morning after night-time administration. The drug is generally well tolerated by patients of all ages; the most frequently reported adverse effects being bitter taste and dry mouth. Treatment withdrawal due to adverse effects is seldom required and reports of rebound insomnia after zopiclone withdrawal are rare. While symptoms of physical dependence have not been observed in clinical studies, there have been isolated reports of physical dependence in patients with a history of substance abuse. Although the latter finding should be kept in mind, it appears that zopiclone has a low dependence liability. Thus, with its short duration of action and good tolerability profile, zopiclone is a well established alternative to the benzodiazepine hypnotics and may be particularly beneficial in those patients unable or unwilling to tolerate the residual effects associated with many other hypnotic agents.

Hypnotics as concurrent medication in depression: A placebo-controlled, double-blind comparison of flunitrazepam and lormetazepam in patients with major depression, treated with a (tri) cyclic antidepressant

The addition of benzodiazepine hypnotics to a treatment with tricyclic antidepressants has received little systematic study. In a double-blind placebo-controlled design, the effects on mood and on sleep of two benzodiazepine hypnotics (lormetazepam and flunitrazepam) were studied in patients with major depression who were also treated with maprotiline or nortriptyline. After 4 weeks of combined treatment, lormetazepam resulted in a significantly greater decrease in the score on the Hamilton Depression Subscale than placebo, while there was a non-significant trend in favour of lormetazepam in comparison with flunitrazepam. With respect to sleep EEGs, lormetazepam resulted in a significantly greater suppression of REM sleep. The differences between lormetazepam and flunitrazepam may be partly explained by the shorter half-live of lormetazepam.

Acute effects of zolpidem, triazolam and flunitrazepam on arterial blood gases and control of breathing in severe COPD

Patients with severe chronic obstructive pulmonary disease (COPD) commonly complain of insomnia, but hypnotic drugs are generally not recommended due to their depressant effect on the respiratory centres. The aim of this study was, therefore, to compare the effects of a single dose of the benzodiazepine hypnotics, triazolam 0.25 mg and flunitrazepam 1 mg, and a new imidazopyridine compound, zolpidem 10 mg, in hypercapnic COPD patients. Twelve stable COPD patients (mean +/- SD arterial oxygen tension (PaO2) 9.3 +/- 0.8 kPa and arterial carbon dioxide tension (PaCO2) 5.9 +/- 1.9 kPa) were included in the study. The following measurements were performed before and 2 h after drug administration: PaO2 and PaCO2, minute ventilation (VE), mouth occlusion pressure (P0.1), rebreathing CO2 tests with ventilatory response to carbon dioxide stimulation (delta VE/delta PACO2) and mouth occlusion pressure response to carbon dioxide stimulation (delta P0.1/delta PACO2). The measurements were performed in a randomized, double-blind fashion, each patient receiving a single dose of each drug on three different days, separated by a one week interval. No difference was noted between control measurements and those taken 2 h after administration of zolpidem in the following parameters: PaCO2, PaCO2, VE, P0.1, delta VE/delta PACO2 and delta P0.1/PACO2. Two hours after administration of triazolam and flunitrazepam, a significant difference was noted in VE for triazolam and for flunitrazepam. After flunitrazepam administration, a significant decrease in PaCO2 (6 +/- 1.8 at baseline versus 7 +/- 0.4 kPa), and delta VE/PACO2 (0.44 +/- 0.20 at baseline versus 0.31 +/- 0.21 l.min-1 x kPa) were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence and treatment of insomnia in general practice. A longitudinal study.

The aim of the study was to assess prevalence and treatment modalities of insomnia in general practice. To investigate the course of insomnia, a longitudinal study design was adopted. Two thousand five hundred and twelve patients (age 18-65 years) were investigated with a questionnaire in general practice (T1). Four months later (T2) and again 2 years later (T3) a questionnaire was sent to all patients who had complained about severe insomnia at the time of the first inquiry. To assess insomnia, operationalized diagnostic criteria were applied (DSM-III-R). Eighteen point seven percent suffered from severe, 12.2% suffered from moderate and 15% suffered from mild insomnia. In the course of 2 years insomnia appeared as a chronic health problem. A high comorbidity of severe insomnia was found with chronic somatic and psychiatric disorders, especially with depression. Of the severely insomniac patients, 23.9% used prescribed hypnotics habitually, mainly benzodiazepines. The use of prescribed hypnotics remained rather stable during the whole study period. More than half of the patients reported a daily use of the hypnotics for 1-5 years or longer, but only 22% of the severely insomniac patients reported at the time of the third inquiry a significant improvement of insomnia due to the administration of sleeping pills. Thus, the long-term administration of benzodiazepine hypnotics seems to be an inadequate treatment strategy in chronic insomnia. Whether the occurrence of rebound insomnia after benzodiazepine withdrawal may be one of the main factors for chronic hypnotic use requires discussion.(ABSTRACT TRUNCATED AT 250 WORDS)

Classification of benzodiazepine hypnotics in humans based on receptor occupancy theory.

Benzodiazepine (BZP) hypnotics are now classified into four groups according to their plasma elimination rates: ultrashort-, short-, intermediate-, and long-acting drugs. Since the specific binding affinities for the BZP receptor vary widely among the BZPs and their active metabolites, it may be more reasonable to correlate their pharmacological activities with the BZP receptor occupancy rather than with their plasma concentrations. The time courses of total plasma concentrations of BZPs and their active metabolites after a single oral administration were obtained from the literature, and their unbound concentrations (Cu) were calculated from the reported values of their plasma unbound fractions. The data of the receptor binding affinities of the BZPs, reported as dissociation constants (Kd) determined by in vitro binding experiments, were also obtained from the literature. Using these values, the time courses of receptor occupancies [Cu/(Kd + Cu) x 100%] were calculated for the various BZPs. A mutual competitive inhibition was considered in the case of the drugs that had active metabolites. Although plasma total and unbound concentration time profiles of the BZPs showed a wide variation, similar patterns were obtained for the time courses of the receptor occupancy among the BZPs in each group, indicating that the BZP hypnotics can be classified more conveniently based on receptor occupancy theory.

睡眠薬とエタノールを併用したときの体内動態に関する検討 ベンゾジアゼピン誘導体とそのプロドラッグについて

睡眠薬とエタノールを併用したときの体内動態に関する検討 ベンゾジアゼピン誘導体とそのプロドラッグについて

Zopiclone. A review of its pharmacological properties and therapeutic efficacy as an hypnotic.

Zopiclone is a cyclopyrrolone which is chemically unrelated to the benzodiazepines and is thought to act on the GABAA receptor complex at a site distinct from, but closely related to, the benzodiazepine binding site. The hypnotic efficacy of zopiclone administered as single oral doses has been demonstrated in patients undergoing next-day surgery and in patients with insomnia, and these studies have established an optimal dose of 7.5mg for elderly patients. Using this dose, clinical studies have shown that zopiclone improved sleep in elderly patients to a similar extent as triazolam 0.125 to 0.5mg, flurazepam 15mg, and nitrazepam 5mg. Studies that also included younger patients have shown that zopiclone 7.5mg is at least as effective as triazolam 0.25 or 0.5mg, and on most sleep parameters is comparable to temazepam 20mg, nitrazepam 5mg, flunitrazepam 2mg, and flurazepam 20mg. Zopiclone causes minimal impairment to psychomotor performance and mental alertness the morning after night-time administration. The drug is generally well tolerated by patients of all ages; the most frequently reported adverse effects being bitter taste and dry mouth. Treatment withdrawal due to adverse effects is seldom required and reports of rebound insomnia after zopiclone withdrawal are rare. While symptoms of physical dependence have not been observed in clinical studies, there have been isolated reports of physical dependence in patients with a history of substance abuse. Although the latter finding should be kept in mind, it appears that zopiclone has a low dependence liability. Thus, with its short duration of action and good tolerability profile, zopiclone is a well established alternative to the benzodiazepine hypnotics and may be particularly beneficial in those patients unable or unwilling to tolerate the residual effects associated with many other hypnotic agents.

Benzodiazepine receptor binding of benzodiazepine hypnotics: Receptor and ligand specificity

Benzodiazepine (BDZ) hypnotics bind at a specific receptor located on postsynaptic neurons. Some data support specificity of binding for several hypnotics to receptor subtypes. We evaluated BDZ receptor binding in cerebral cortical membranes using agonist, antagonist, and subtype-specific ligands for commonly used hypnotics and their metabolites. All hypnotics competed similarly at BDZ1 and BDZ2 receptor subtypes except quazepam and its metabolite 2-oxo-quazepam and to a lesser extent hydroxyethyl flurazepam (EtOH) flurazepam. These compounds had relative specificity for the BDZ1 site. Triazolam, estazolam, and flurazepam bound equally to sites labeled by agonists but kesalkylflurazepam, EtOH flurazepam, temazepam, quazepam, and 2-oxo-quazepam did not; in addition, these four compounds did not bind to the “peripheral” BDZ site labeled by Ro 5-4864. BDZ hypnotics differ in their receptor subtype and ligand binding characteristics.

Sleep apneas and high altitude newcomers.

Sleep and respiration data from two French medical high altitude expeditions (Annapurna 4,800 m and Mt Sajama 6,542 m) are presented. Difficulties in maintaining sleep and a SWS decrease were found with periodic breathing (PB) during both non-REM and REM sleep. Extent of PB varied considerably among subjects and was not correlated to the number of arousals but to the intercurrent wakefulness duration. There was a positive correlation between the time spent in PB and the individual hypoxic ventilatory drive. The relation between PB, nocturnal desaturation, and mountain sickness intensity are discussed. Acclimatization decreased the latency toward PB and improved sleep. Hypnotic benzodiazepine intake (loprazolam 1 mg) did not worsen either SWS depression or apneas and allowed normal sleep reappearance after acclimatization.

Pharmaco-EEG profile of intravenous zolpidem in healthy volunteers

The mechanism of action and the pharmacokinetics of hypnotic drugs are key determinants of their clinical effects in patients with primary or comorbid insomnia. Accordingly, the sedation and sleep-promoting properties of drugs acting as positive allosteric modulators of the GABAA receptor depend upon their selective binding to the α1 receptor subtype. The additional binding to other receptor subtypes conditions the occurrence of adverse events. The absorption rate has been emphasized as a determinant of onset of action, and the elimination half-life (t1/2) and distribution as key factors of duration of action of hypnotic drugs in clinical use. Benzodiazepine and nonbenzodiazepine hypnotics improve sleep induction, and depending on their t1/2 and presence of active metabolites, they improve sleep maintenance. In this respect, the pyrazolopyrimidine derivative zaleplon does not affect total sleep time. On the other hand, the increase of total sleep time that follows the administration of the benzodiazepine and imidazopyridine derivatives midazolam, triazolam, and zolpidem immediate-release, is limited to the first half of the night. In order to circumvent this limitation, a zolpidem extended-release preparation has been made available. The benzodiazepine hypnotics, temazepam, flunitrazepam, and flurazepam, and the cyclopyrrolone derivatives, zopiclone and eszopiclone, increase total sleep time beyond the first half of the night. The effect of the melatonin agonist ramelteon on sleep variables is limited to a decrease of the latency to sleep onset. The benzodiazepine derivatives induce a further reduction of slow-wave sleep (SWS) and rapid eye movement (REM) sleep in patients with an insomnia complaint. Furthermore, during the administration of the nonbenzodiazepine derivatives, zaleplon, zolpidem, zopiclone, and eszopiclone, and the melatonin agonist ramelteon, SWS and REM sleep do not regain normal levels or can even be further suppressed.

Rebound insomnia and newer hypnotics.

The prescription of hypnotics, mostly benzodiazepines, continues at a high level. One problem with their use is rebound insomnia: upon discontinuation sleep worsens compared with pretreatment levels. Factors influencing rebound include the type of subject, the duration of action of the hypnotic, the dosage and perhaps duration of treatment. The detection of rebound requires both sleep-laboratory and clinical studies with night-by-night analyses of individual patient data. This review concentrates on the newer compounds, (quazepam and zolpidem) which act selectively on subtypes of benzodiazepine receptors or bind atypically (zopiclone). It concludes that present evidence, while limited, is consistent with claims of less rebound potential than older benzodiazepine hypnotics of equivalent duration of action. Nevertheless, further rigorous studies are essential before these claims can be totally accepted.

Psychoactive drug prescribing in the Tasmanian community

To gather data on the prescribing of psychoactive drugs (benzodiazepines, antidepressants and antipsychotics) using a network of Tasmanian community pharmacies. The prescribing of psychoactive drugs in the community was studied during 1989 using data retrospectively obtained from computerised dispensing systems in 11 community pharmacies in Tasmania. The data collection procedure included all prescriptions dispensed in the pharmacies, irrespective of supply under the Pharmaceutical Benefits Scheme, the Repatriation Pharmaceutical Benefits Scheme or as a private prescription. Results of the pooled data were quantified by both the number of prescriptions and the defined daily doses (DDDs) dispensed for the psychoactive drugs. When extrapolated to the population of Tasmania, the estimated annual prescribing rates for the benzodiazepines, antidepressants and antipsychotics (including lithium) were 853.3, 316.2 and 54.8 prescriptions per 1000 persons, respectively. Prescriptions for the psychoactive drugs accounted for 13.2% of all prescriptions dispensed. In terms of DDDs, the estimated prescribing rates for the total Tasmanian population for the benzodiazepines, antidepressants and antipsychotics were 47.8, 12.5 and 2.1 DDDs per 1000 persons per day, respectively. The rate of benzodiazepine prescribing appeared to be high in comparison with the limited Australian data available. The relative prescribing rates of the long acting benzodiazepine hypnotics, flunitrazepam and nitrazepam, were also disturbingly high. This study has demonstrated the potential value of comprehensive pharmacoepidemiological data obtained from a network of community pharmacists and will form the basis for future studies using an expanded collection procedure.