Rebound insomnia and rebound anxiety: a review

Rebound insomnia and rebound anxiety are clinical conditions related to withdrawal of certain benzodiazepine drugs. Numerous studies of benzodiazepine and nonbenzodiazepine hypnotics conducted in our sleep laboratory demonstrated that rebound insomnia developed following withdrawal from benzodiazepines with a rapid or intermediate elimination rate. Several studies conducted by other investigators also indicated the development of rebound insomnia under similar conditions. Rebound insomnia and rebound anxiety are discussed in terms of their interrelationship, clinical implications, and receptor mechanisms. Evidence suggests that drugs producing rebound insomnia and rebound anxiety also show a more rapid development of tolerance and greater potential for drug dependence than benzodiazepines where the parent compound or its metabolites have a long elimination half-life.     

New hypnotic agents: clinical studies in general practice

The type of sleep problem should be determined so that the most appropriate hypnotic can be used, and in this respect duration of action is an important property. The benzodiazepine hypnotics are adequate for this purpose, but problems may arise due to daytime after-effects and the possibility of dependence developing. Non-benzodiazepine hypnotics may be useful alternatives and our group has undertaken double-blind comparative trials with two such compounds, namely zopiclone and zolpidem. Zopiclone was compared to temazepam in a cross-over trial on 36 patients and similar hypnotic effects were recorded. In a parallel group study, zolpidem 10 mg was compared to zolpidem 20 mg and placebo in 88 patients. Both doses of zolpidem were significantly better than placebo on a number of the parameters recorded, side-effects were negligible and there was no evidence of any rebound insomnia during the final control week.     

Tolerance and rebound insomnia with rapidly eliminated hypnotics: a meta-analysis of sleep laboratory studies.

Differences in development of tolerance and occurrence of rebound insomnia have been well established between rapidly and slowly eliminated benzodiazepine hypnotics. Based on meta-analytic methodology, this study assesses whether there are such differences among the rapidly eliminated benzodiazepine and benzodiazepine-like hypnotics (brotizolam, midazolam, triazolam, zolpidem and zopiclone). All sleep laboratory studies of these drugs (n = 137) published from 1966 to 1997 were obtained, mainly through a MEDLINE search. Rigorous selection criteria resulted in the inclusion of 75 studies employing 1276 individuals (804 insomniacs and 472 healthy volunteers). Using a mixed effects regression model, reliable estimation of the effects on insomniacs of the recommended dose of each drug could be obtained. All five rapidly eliminated hypnotics showed statistically significant initial efficacy. Tolerance with intermediate and long-term use was clearly developed with triazolam and was only marginal with midazolam and zolpidem; it could not be estimated for brotizolam or zopiclone because of insufficient data. Rebound insomnia on the first withdrawal night was intense with triazolam and mild with zolpidem; data were unavailable for brotizolam and inadequate for midazolam and zopiclone. In conclusion, there are differences among the rapidly eliminated hypnotics with respect to tolerance and rebound insomnia suggesting that, in addition to short elimination half-life, other pharmacological properties are implicated in the mechanisms underlying these side-effects.     

Rebound insomnia: a critical review

Rebound insomnia, a worsening of sleep compared with pretreatment levels, has been reported upon discontinuation of short half-life benzodiazepine hypnotics. This paper reviews the existing sleep laboratory studies for the presence or absence of rebound insomnia following treatment with triazolam, temazepam, and flurazepam in insomniac patients or poor sleepers and, when possible, in normals. The results indicate that rebound insomnia is a distinct possibility after discontinuation of triazolam in both insomniacs and normal controls. Compared with baseline, disturbed sleep was reported in insomniacs or poor sleepers for the first 1 or 2 nights of withdrawal in seven of nine polygraphically recorded sleep studies following triazolam 0.5 mg and in one of two studies following triazolam 0.25 mg. In one study conducted in normal volunteers, rebound insomnia was observed following triazolam 0.5 mg but not triazolam 0.25 mg. In another study, which used subjective reports of sleep rather than polygraphic recordings, rebound insomnia was significantly attenuated after triazolam 0.5 mg by tapering the dose over 4 nights. The risk of rebound insomnia after temazepam 15 or 30 mg was low. In keeping with its long elimination half-life, flurazepam (30 mg) continued to exert beneficial effects for the first 2-3 withdrawal nights, but the possibility of a mild rebound insomnia cannot be dismissed during the intermediate withdrawal period (nights 4-10) following prolonged, consecutive, nightly administration (more than 30 nights). The benzodiazepine hypnotics are generally preferred over other types (barbiturates or nonbenzodiazepine, nonbarbiturate), but there are advantages and disadvantages related to half-life of the benzodiazepines. The risk of rebound insomnia is greater with the short half-life as compared with the long half-life benzodiazepines.     

Temazepam (Restoril, Sandoz Pharmaceuticals)

Temazepam is a benzodiazepine derivative indicated for the treatment of insomnia. Pharmacokinetic studies of the hard capsule formulation indicate that the mean time to peak is 2.99 hours and the mean elimination half-life is 14.7 hours. Sleep laboratory studies have demonstrated improvements in all sleep parameters except sleep onset latency. Clinically, patients report improvements in all sleep parameters including sleep onset latency. The efficacy of temazepam compares favorably with barbiturates, glutethimide, nitrazepam, lorazepam, oxazepam, and flurazepam. It has not been compared with diazepam in the clinical setting. Side effects include drowsiness, dizziness, and lethargy. The incidence of hangover effects from 15- and 30-mg doses is relatively low. Temazepam has no proven advantages over other benzodiazepine hypnotics. The major issues that need further clarification include temazepam's sleep induction properties and the relative incidence of hangover and rebound insomnia when compared with longer-acting benzodiazepines.     

Rebound insomnia induced by abrupt withdrawal of hypnotics in sleep-disturbed rats

The present study was performed to examine whether or not rebound insomnia is caused by an abrupt withdrawal of benzodiazepine hypnotics and tandospirone in rats. Etizolam and triazolam caused a significant shortening of sleep latency, increase in non-REM sleep time, and decrease in wake time in a dose-dependent manner. Etizolam and triazolam caused a significant shortening of sleep latency during drug administration (for 7 days), whereas a significant prolongation of sleep latency was observed by the abrupt withdrawal of these drugs. Tandospirone caused a shortening of sleep latency, whereas no effect was observed on non-REM sleep time and wake time during drug administration (for 7 days). On the other hand, tandospirone showed no significant effect on sleep latency through its abrupt withdrawal, differing from etizolam and triazolam. From these findings, a rebound phenomenon in terms of sleep latency was confirmed with etizolam and triazolam in rats. Furthermore, the 5-HT(1A) agonist, tandospirone, caused no rebound phenomenon regarding sleep latency in rats.     

Rebound insomnia and elimination half-life: assessment of individual subject response

Following abrupt withdrawal of five benzodiazepine hypnotics, the presence of rebound insomnia on individual subject nights was evaluated in comparison to a placebo group. During the first three nights of withdrawal, the frequency of occurrence of rebound insomnia for drugs with relatively rapid rates of elimination (triazolam, midazolam, and lormetazepam) was significantly higher than that for the placebo control group. In contrast, the frequency of withdrawal sleep difficulty for two slowly eliminated hypnotics (flurazepam and quazepam) was similar to that of the placebo control group during each of five successive three-night segments of a 15-night withdrawal period. These findings, based on individual subject-night data, confirm and extend previous reports using group mean values that demonstrate a frequent, immediate, and intense degree of rebound insomnia following abrupt withdrawal of relatively rapidly eliminated hypnotic drugs and an infrequent, delayed, and milder degree of sleep difficulty following withdrawal of slowly eliminated drugs.     

1996-2006年广州市精神病医院催眠药物的应用分析及趋势预测

目的考察广州市精神病医院(下称我院)1996~2006年催眠药物的应用状况及变化趋势。方法采用WHO推荐的限定日剂量作为基本指标的分析方法,对我院催眠药物的用药频度、日用药金额等进行统计分析并排序。结果苯二氮卓(benzodiazepine,BZ)药物的日用金额一般都明显低于非苯二氮卓(non-benzodiazepine,NBZ)药物。除个别年份外,催眠药物的年销售金额有小幅增长的趋势,但年度总DDDs的增减趋势并不明显。其中,BZ类药物所占的年销售金额比例虽有下降的趋势,但仍占绝大多数;BZ类药物的年度总DDDs比例仍占98%以上,所有NBZ药物的排名均在末位。结论目前BZ类药物仍是精神科临床中改善失眠症状的主力,NBZ类药物逐渐被临床所接受。预测今后这种趋势会进一步明显。     

Does improvement in the benzodiazepine prescribing indicator reflect more appropriate prescribing of hypnotics?

The benzodiazepine prescribing indicator included in the NHS performance indicator set for health authorities (HAs) has shown decreased prescribing of benzodiazepines, ie, improved performance National data show that use of hypnotics has not decreased due to increased prescribing of newer non‐benzodiazepine hypnotics Analysis of change in prescribing across HAs for October to December 1999 and 2001 shows that use of temazepam and nitrazepam has decreased in each HA but only one HA has shown a decrease in prescribing of zopiclone, zolpidem and zaleplon In 10 HAs overall prescribing of these 5 hypnotics has increased suggesting that prescribing of these drugs is not well managed in these HAs A high score on the health deprivation and disability index is associated with a higher prescribing rate for hypnotics therefore tackling the root causes of health inequalities may eventually lead to less demand for hypnotics     

Zopiclone in elderly patients: Efficacy and safety

Zopiclone is an hypnotic medication belonging to the cyclopyrrolone family of drugs. It is chemically unrelated to the benzodiazepines and binds to a specific site of the GABA_A receptor complex. Zopiclone has been found to be effective as an hypnotic for the elderly: single doses of 7.5 mg have been found to decrease sleep onset Latency and the number of nocturnal awakenings: to improve sleep duration and sleep quality, and to cause minimal impairment of psychomotor performance and mental alertness the morning after a normal bed-time dose. Importantly, the drug has been shown to have little or no effect on short-term memory, a function that is often impaired by earlier hypnotic drugs particularly in elderly patients. Furthermore, there is little evidence of dependency or rebound insomnia on withdrawal of the medication after continued use. The drug is well tolerated by patients of all ages, and adverse effects are infrequently reported, the majority of side-effects being taste disturbance (3.6 per cent in the largest trial to date) and dry mouth (1.6 per cent). Zopiclone is now a well-established alternative to the benzodiazepine hypnotics.     

Interaction of the hypnotic lormetazepam with central benzodiazepine receptor subtypes omega 1, omega 2 and omega 3]

To clarify the action of lormetazepam, 3-hydroxybenzodiazepine, on the benzodiazepine (BZ) receptor subtypes, effects of lormetazepam on motor performance in the traction test and hexobarbital-induced loss of righting reflex in mice and the binding to BZ receptor subtypes were investigated in comparison with those of other BZ hypnotics. Lormetazepam prolonged the duration of hexobarbital-induced loss of righting reflex. The minimal effective dose (1 mg/kg, p.o.) was higher than that of flunitrazepam, lower than those of diazepam and zopiclone, and the same as those of triazolam and brotizolam. Lormetazepam showed the ataxic effect at 10 mg/kg, p.o., but the separation between its effective doses for the hypnotic and ataxic effects was the largest among the hypnotics tested. In the displacement study on [3H]flumazenil binding to cerebellar and spinal cord membranes, lormetazepam bound with a higher affinity to omega 1 receptor (Ki = 10 nM) than to omega 2 receptor (Ki = 29 nM). The GABA-ratios of lormetazepam to omega 1 and omega 2 receptors were 3.9 and 4.0, respectively; and they were higher and lower than those of flunitrazepam to omega 1 and omega 2 receptors, respectively. In the displacement study on [3H] Ro5-4864 binding to kidney membranes, lormetazepam bound with a lower affinity to the omega 3 receptor (Ki = 213 nM) than flunitrazepam. Thus, lormetazepam was suggested to be a potent hypnotic with weaker ataxic effects than other BZ hypnotics, which may be due to its selective and potent agonistic action on central omega 1 receptors.     

Pharmacokinetic properties of benzodiazepine hypnotics

The kinetic properties of three benzodiazepine hypnotics are reviewed. Flurazepam serves as a precursor for at least two rapidly appearing and rapidly cleared metabolites that may contribute to sleep induction and are nonaccumulating. The final metabolite of flurazepam (N-desalkylflurazepam), however, has a long half-life and accumulates during repeated dosage. Temazepam has a relatively slow rate of absorption and an intermediate half-life in the range of 10 to 20 hours. Triazolam has an intermediate rate of absorption; due to its ultrashort half-life (1.5 to 5 hours), triazolam is a non-accumulating hypnotic. Taken together with sleep laboratory studies and clinical trials, knowledge of the kinetic profile of benzodiazepine hypnotics can assist in evaluating their clinical benefits and disadvantages.     

Assessment of hypnotic effects in the rat: Influence of the sleep-awake cycle

The influence of the sleep-awake cycle of the rat on the apparent hypnotic effects of two benzodiazepine hypnotics, triazolam (short half-life) and flurazepam (long half-life), was assessed. Cortical electroencephalographic recordings from freely moving animals were used to determine whether the rats were awake or asleep. When tested during the dark phase of the light-dark cycle, when rats sleep approximately 50% of each hour, both agents increased sleep, with flurazepam having a longer duration of action than triazolam. In contrast, when tested during the light phase of the light-dark cycle, when rats sleep approximately 70–90% of each hour, the sleep-inducing effects of the two agents could not be distinguished. These data emphasize the importance of baseline levels of sleep in assessing hypnotic-drug effects.     

Effects of three hypnotics on the sleep-wakefulness cycle in sleep-disturbed rats

Rationale New sleep disturbance model in rats is useful for estimating the characteristics of some hypnotics.Objectives The present study was undertaken to investigate the utility of a sleep disturbance model by placing rats on a grid suspended over water using three kinds of hypnotics, that is, short-acting benzodiazepine (triazolam), intermediate-acting benzodiazepine (flunitrazepam) and long-acting barbiturate (phenobarbital).Methods Electrodes for measurement of EEG and EMG were implanted into the frontal cortex and the dorsal neck muscle of rats. EEG and EMG were recorded with an electroencephalogram. SleepSign ver.2.0 was used for EEG and EMG analysis. Total times of wakefulness, non-REM and REM sleep were measured from 0900 to 1500 hours.Results In rats placed on the grid suspended over water up to 1 cm under the grid surface, not only triazolam but also flunitrazepam and phenobarbital caused a shortening of sleep latency. Both flunitrazepam and phenobarbital were effective in increasing of total non-REM sleep time in rats placed on sawdust or the grid, and the effects of both drugs in rats placed on the grid were larger than those in rats placed on sawdust. Measurement of the hourly non-REM sleep time was useful for investigating the peak time and duration of effect of the three hypnotics. Phenobarbital showed a decrease in total REM sleep time in rats placed on the grid, although both triazolam and flunitrazepam were without effect.Conclusions The present insomnia model can be used as a sleep disturbance model for testing not only the sleep-inducing effects but also the sleep-maintaining effects including non-REM sleep and REM sleep of hypnotics.     

Benzodiazepines,amnesia and sedation: Theoretical and clinical issues and controversies

The amnestic effect of benzodiazepines, first described in 1965, and the subsequent attempts to identify the precise nature of this effect, are reviewed. The difficulty in deciding to what extent this effect is secondary to the sedative action of these drugs is shown by the lack of agreement between studies. Nevertheless, it is concluded that, given the right experimental design, all benzodiazepines can be shown to cause an anterograde amnesia which is probably primarily a result of reduced attention or rehearsal and secondary to sedation. Its onset, degree and duration are influenced by dose, rate of absorption, route of administration, potency and the receptor occupancy rate of the particular benzodiazepine involved, but plasma elimination t_½ appears to be relatively unimportant. The clinical relevance of this for the long-term use of hypnotics and anxiolytics is not clear. Tolerance appears to be greater than for the anxiolytic but less than the sedative or anticonvulsant effect of benzodiazepines. It seems that transient amnestic effects could occur in chronic users related to post-dose, peak benzodiazepine levels. The great variability in individual response means that transient amnesia is a potential adverse drug reaction in certain individuals taking benzodiazepines.     

Evaluation of anxiolytic-like effects of some short-acting benzodiazepine hypnotics in mice

Anxiolytic-like effects of some short-acting benzodiazepine hypnotics were examined with experimental paradigms of anxiety using an elevated plus-maze in male ICR mice. Diazepam was used as a positive control. The drug at a dose of 1 mg/kg significantly increased the percentage of time spent in the open arms and percentage of the number of open arm entries in the elevated plus-maze. Triazolam, brotizolam, rilmazafone, and lormetazepam also showed an anxiolytic-like effect as indicated by the significant increase in the percentage of time spent in the open arms and percentage of the number of open arm entries. Effects of short-acting benzodiazepine hypnotics used in the study were more potent than those of diazepam. In addition, the doses affecting the elevated plus-maze by benzodiazepine hypnotics were much smaller than those that showed muscle-relaxant activity measured by the rotarod test, indicating that anxiolytic-like effects of benzodiazepine hypnotics had high specificity and selectivity.     

Quazepam. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in insomnia

Quazepam is a trifluoroethyl benzodiazepine hypnotic with a half-life of 27 to 41 hours, which has been shown to induce and maintain sleep in the short to long term (up to 4 weeks) treatment of patients with chronic or transient insomnia. Although its hypnotic efficacy has been well characterised against placebo, there are few clinical studies in comparison with established hypnotics, particularly over long term administration. However, preliminary evidence suggests that quazepam 15 to 30 mg is as effective as flurazepam and triazolam in usual therapeutic doses, and causes minimal rebound insomnia following its withdrawal, unlike rapidly eliminated benzodiazepines such as triazolam. The lack of rebound phenomena is likely to be attributable to the 'carryover' effects occurring after discontinuation of quazepam, which has pharmacologically active metabolites with half-lives of elimination similar to or longer than that of the parent drug. Probably because of the long half-lives of quazepam's metabolites, daytime sedation, fatigue and lethargy are the most frequently reported side effects. These side effects are most intense with the 30 mg dose and least with the 7.5mg dose, which has not been studied extensively. Hence, quazepam is an effective hypnotic which may be particularly suitable for short or medium term use in patients in whom withdrawal effects or rebound insomnia may be especially bothersome. Further definition of certain characteristics of its profile--such as its long term use and potential for development of tolerance or dependence, effects on psychomotor skills, efficacy of the 7.5mg dose, and suitability in elderly patients and patients with chronic organic diseases--will assist in more clearly defining its ultimate place in therapy.     

Loprazolam. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in insomnia

Loprazolam is a 1,4-benzodiazepine with hypnotic properties, advocated for use in acute or chronic insomnia. As loprazolam has a half-life of 7 to 8 hours in healthy adults it may have advantages over longer-acting hypnotics, particularly when residual sedative effects on the day after ingestion are undesirable, although at doses greater than 1 mg residual sedation may occur. In addition, it may reduce daytime anxiety, following a hypnotic dose the night before, more effectively than the short-acting drug, triazolam. In short term comparative studies loprazolam was clearly superior to placebo, and was at least as effective as triazolam, flurazepam, nitrazepam, flunitrazepam or temazepam in hastening sleep onset, reducing nocturnal awakenings and increasing total sleep duration and quality. In the small number of patients with chronic insomnia who have received extended treatment with loprazolam, no evidence of tolerance has occurred, although rebound insomnia was evident 3 days after drug withdrawal in several studies. Thus, with its 'intermediate' elimination half-life, loprazolam would appear to have some potential advantages over both long- and short-acting hypnotics in selected patients, although further studies are needed to fully elucidate its place in therapy.