Non-benzodiazepines for the treatment of insomnia

Benzodiazepine hypnotics, the mainstay of pharmacological treatment for insomnia, have been associated with altered sleep architecture, psychomotor and memory impairment, rebound insomnia, withdrawal effects, tolerance, dependence, abuse potential and respiratory depression. Non-benzodiazepines, such as zolpidem, zopiclone and zaleplon, demonstrate hypnotic efficacy similar to that of benzodiazepines along with excellent safety profiles. Non-benzodiazepines generally cause less disruption of normal sleep architecture than benzodiazepines. Psychomotor and memory impairment may be less problematic with non-benzodiazepines, especially when compared to longer-acting benzodiazepines. Rebound insomnia and withdrawal symptoms occur infrequently upon discontinuation of non-benzodiazepines and may be less common and milder than those seen upon discontinuation of some benzodiazepines. For the long-term treatment of insomnia, which is generally not recommended, zolpidem and zopiclone are particularly good options because they do not develop tolerance rapidly and have a low abuse potential. Limited data indicate that zaleplon has low tolerance and abuse potential, although further experience is needed to determine its long-term efficacy and safety profile. Since non-benzodiazepines produce minimal respiratory depression, they may be safer than benzodiazepines in patients with respiratory disorders. The choice of which hypnotic to use should be based on the patient's primary sleep complaint, health history, adverse effects and cost.     

Ro 15-1788-induced seizures in rats continually exposed to diazepam for prolonged periods

Previous reports using rats have failed to demonstrate convulsions upon withdrawal from chronic benzodiazepine (BZ) treatment. We have shown earlier that rats develop tolerance to benzodiazepines following continuous exposure to low levels of diazepam (DZ) obtained by treatment with s.c. diazepam-filled silastic capsules. This report shows that intravenous infusion of the benzodiazepine antagonist Ro 15-1788 can induce seizures in rats treated for prolonged periods (4 weeks) with such diazepam-filled capsules. Precipitated seizures are also seen in rats 24 h after the cessation of chronic diazepam exposure. This procedure may provide a useful paradigm with which to study in rats the neural changes which are related to the physical dependence and withdrawal associated with prolonged exposure to the benzodiazepines.     

Effects of zopiclone on sleep spindles studied with an improved waveform recognition method

The effects of zopiclone on sleep spindles were analyzed in six normal volunteers by using an improved waveform recognition method. The appearance rate of spindles during stage 2 of NREM sleep showed a significant increase on the drug night, which returned to the baseline on the withdrawal night. The mean duration of spindles was significantly prolonged on the drug night. No definite changes were observed in the average spindle frequency. The mean amplitude of spindles had a tendency to decrease on the drug night. On the withdrawal night, the mean amplitude decreased significantly compared with that of the baseline. Our results indicate that zopiclone is one of the spindle enhancing drugs, and that its property resembles that of benzodiazepines.     

Benzodiazepine withdrawal

As with most psychotropic sedative drugs, the potential for withdrawal reactions is present with the benzodiazepines (19). Signs suggesting the potential for withdrawal reactions can be gleaned from the clinical course of events such as the development of tolerance anc psychological and physiological dependence. If high doses are reached, the risk of withdrawal reactions increases with the length of treatment and the abruptness of cessation. The long-acting benzodiazepines have a built-in mechanism against withdrawal reactions through their active metabolites. Abrupt cessation of drug therapy in high-dose patients should be avoided to reduce the risk of withdrawal reactions.     

A withdrawal syndrome after abrupt discontinuation of alprazolam

A patient who received therapeutic doses of alprazolam for 8 weeks experienced a withdrawal syndrome beginning 18 hours after its abrupt discontinuation. Short-acting and minimally sedating benzodiazepines may have increased potential for withdrawal reactions.     

Benzodiazepine use, abuse, and dependence

Although benzodiazepines are invaluable in the treatment of anxiety disorders, they have some potential for abuse and may cause dependence or addiction. It is important to distinguish between addiction to and normal physical dependence on benzodiazepines. Intentional abusers of benzodiazepines usually have other substance abuse problems. Benzodiazepines are usually a secondary drug of abuse-used mainly to augment the high received from another drug or to offset the adverse effects of other drugs. Few cases of addiction arise from legitimate use of benzodiazepines. Pharmacologic dependence, a predictable and natural adaptation of a body system long accustomed to the presence of a drug, may occur in patients taking therapeutic doses of benzodiazepines. However, this dependence, which generally manifests itself in withdrawal symptoms upon the abrupt discontinuation of the medication, may be controlled and ended through dose tapering, medication switching, and/or medication augmentation. Due to the chronic nature of anxiety, long-term low-dose benzodiazepine treatment may be necessary for some patients; this continuation of treatment should not be considered abuse or addiction.     

Seizure following sudden zolpidem withdrawal

Zolpidem is a short acting hypnotic drug belonging to imidazopyridine family. It produces its hypnotic effects via the GABA-A benzodiazepine receptor complex, and binds preferentially to those receptors containing the alpha-1 subunit. In comparison with benzodiazepines this mechanism is thought to reduce liability to induce dependence. Several case reports of zolpidem abuse and dependence have been published along with a small number of cases demonstrating seizures after sudden zolpidem withdrawal. We describe a case of a 29-year-old Caucasian woman who developed a generalized seizure following sudden zolpidem withdrawal subsequent to drug dependence to 160mg of zolpidem. The clinical effects of zolpidem seem to be comparable to those of benzodiazepines and abuse, dependence and withdrawal seizures belong to the spectrum of its adverse drug reactions.     

Selection for pentobarbital withdrawal severity: correlated differences in withdrawal from other sedative drugs

In mice, withdrawal from agents that depress central nervous system function, such as barbiturates and benzodiazepines, results in the production of a withdrawal syndrome, one feature of which is increased severity of handling induced convulsions (HICs). High and Low Pentobarbital Withdrawal mice (HPW and LPW) were selectively bred to display severe and mild pentobarbital withdrawal HICs, respectively. These mice provide a valuable means to assess genetic correlations between withdrawal from pentobarbital and other sedative agents. We tested HPW and LPW mice for severity of HICs elicited during withdrawal from ethanol, diazepam, and zolpidem, and measured consumption of and preference for pentobarbital solutions in HPW and LPW mice. HPW mice displayed greater HICs than LPW mice during ethanol and zolpidem withdrawal, but differed less robustly during diazepam withdrawal. LPW mice consumed more pentobarbital in a solution of a moderate concentration than did HPW mice, but did not consume more pentobarbital at a higher or lower concentration. These results indicate that some of the same genes that affect the severity of withdrawal from pentobarbital also influence ethanol and zolpidem withdrawal, but that diazepam withdrawal may be less influenced by these genes.     

The Future of Anxiolytic Drug Therapy

Benzodiazepines are generally considered safer than previously used sedatives and hypnotics (e.g. opiates and barbiturates). In the past decade, however, they have generated considerable controversy. Although much of the ongoing debate about benzodiazepines tends to centre on issues related to their dependency and abuse potential, problems also may occur with their therapeutic use.

Despite a lack of study evidence demonstrating that benzodiazepines have continuing therapeutic efficacy beyond 6 months for anxiety and 4 weeks for insomnia, an unknown number of patients have taken benzodiazepines for extended periods, in some cases for up to 25 years or more. Other than increased risk of withdrawal reactions, little is known about the effects of protracted benzodiazepine use on health and cognitive function. A number of investigators, however, have reported considerable ill health, both mental and physical, in long-term users.

Short-term therapeutic use of benzodiazepines is often considered relatively risk-free. Problems, however, also may occur with brief administration of some benzodiazepines, particularly alprazolam and triazolam.

Although no new class of drugs has emerged as a clear replacement of benzodiazepines, several compounds are under investigation. In the meantime, physicians must use benzodiazepines judiciously and become adept at selecting from a range of available pharmacologic and non-pharmacologic alternatives.     

Abhängigkeit von „Non- Benzodiazepinhypnotika”Zwei Fallberichte

With the introduction of the non-benzodiazepine hypnotics zopiclone and zolpidem it was expected to have hypnotics without side effects and risks characteristically seen with benzodiazepines. We report two cases with high-dose usage and dependency of non-benzodiazepine hypnotics. Both patients were prescribed the drugs to treat sleep disturbances occurring during a depressive episode. While one patient had a polysubstance abuse there was no evidence for an abuse history in the other patient. To reduce withdrawal symptoms long-acting benzodiazepines were given to both patients. Thus, it seems that not only patients with a history of substance abuse but also patients with a psychiatric disorder are at risk for abuse of non-benzodiazepine hypnotics. Considering the increasing number of case reports with abuse and dependence of zopiclone and zolpidem it seems necessary to reevaluate the dependency risk of the currently available non-benzodiazepine hypnotics.     

Benzodiazepine withdrawal seizures: analysis of 48 case reports

Various reactions to benzodiazepine withdrawal have been widely described. Among these, seizures have occasionally occurred on abrupt withdrawal. Our own experience of 48 cases of seizures suspected to have been caused by benzodiazepine withdrawal and reported to the Adverse Drug Reaction (ADR) Monitoring Center (1979-1985) showed that a great variety of benzodiazepines with different half-lives were involved, those most frequently implicated being the most widely prescribed. The occurrence of seizures was not always related to the interruption of long-term treatment (from a few days to greater than 7 years) nor to high-dose treatment, the range of dosages being usually close to that recommended. However, in some cases, several benzodiazepines had been taken simultaneously. The time between the last intake of the drug(s) and the occurrence of the seizures was shorter when a short-life benzodiazepine had been used. Additional factors were frequently involved; these factors were present in 29 cases and were multiple in nine of them. The incidence of withdrawal seizures was related more to the presence of these additional factors than to either the pharmacokinetics of the drugs or the pattern of treatment.     

Benzodiazepine receptor binding of nonbenzodiazepines in vivo: Alpidem, zolpidem and zopiclone

Several classes of nonbenzodiazepine compounds, including imidazopyridines such as alpidem and zolpidem and cyclopyrrolones, e.g., zopiclone, have effects similar to benzodiazepines and may act at the benzodiazepine receptor in brain. We characterized the binding of these compounds to the benzodiazepine site in three brain regions using specific uptake of the high-affinity ligand [3H]Ro15-1788 (flumazenil). For alpidem, benzodiazepine binding was decreased in cortex and hippocampus with increasing drug dose. For zolpidem, receptor binding was reduced in cortex without a dose-response effect and no effect was observed on cerebellar binding. Zopiclone did not alter binding except for a decrease in binding at the lowest dose evaluated and an increase in binding above control at the highest dose. These data corroborate prior studies indicating that the imidazopyridines appear to act at the benzodiazepine receptor, but do not support receptor subtype selectivity of zolpidem. The limited effect of zopiclone except for increased binding at high doses is also consistent with prior studies suggesting that zopiclone acts at a site distinct from the benzodiazepine receptor.     

Benzodiazepines and the developing rat: a critical review

This paper reviews: the development of benzodiazepine binding-sites and the GABA system; the evidence that prenatal exposure to benzodiazepines can cause malformations; other persisting effects of developmental exposure to benzodiazepines; and the behavioral effects of benzodiazepines (and other relevant drugs) in immature animals. The review concentrates on the rat, since fundamental work in other species is scarce. The data on neurochemical development are found to be generally consistent; however, reports that the enhancement of benzodiazepine binding by GABA varies with age are controversial. The physical development of the rat is disturbed only by extremely high doses of benzodiazepines. The evidence for persisting effects after early exposure to benzodiazepines is impressive at first sight, but in most studies, confounding variables have not been eliminated. Startle and some learning tasks are affected by prenatal diazepam; submissiveness is affected by neonatal lorazepam; social behaviour and convulsions are affected by neonatal CGS 8216. Benzodiazepines inhibit chemically-induced seizures in neonatal rats, but the developmental profile of sensitivity to the convulsants is disputed. Benzodiazepines stimulate motor behavior in the neonatal rat.     

A double-blind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects

Rebound effects after withdrawal from hypnotics are believed to trigger their chronic use and to enhance the risk of tolerance and dependence. It was the purpose of this study to investigate the acute polysomnographic withdrawal effects after a 4 week treatment with standard doses of the non-benzodiazepine hypnotics zopiclone and zolpidem compared with triazolam and placebo. Healthy male subjects between 22 and 35 years of age participated in a parallel study design. They received either zopiclone 7.5 mg (n=11), zolpidem 10 mg (n=11), triazolam 0.25 mg (n=10) or placebo (n=7) over 4 weeks in randomized and double-blind order. Sleep EEG was registered during 2 nights before treatment under placebo, on days 1, 27 and 28 of treatment and on days 29, 30, 41 and 42 under placebo. Total sleep time and sleep efficiency were lower in the 1^st night after discontinuation of triazolam (p < 0.05, t-test). After withdrawal from zopiclone or zolpidem slight but not significant rebound effects concerning sleep continuity were observed. Self-rating scales showed minimal rebound insomnia after discontinuation of all three hypnotics. In the placebo group no changes of sleep parameters were observed. Assuming that rebound insomnia is part of a withdrawal reaction, this study indicates that the risks of tolerance and dependency are low when administering zopiclone or zolpidem at the recommended doses. Received: 13 September 2000 / Accepted: 7 May 2001     

The acute cognitive effects of zopiclone,zolpidem, zaleplon,and eszopiclone: A systematic review and meta-analysis

The “z-drugs” zopiclone, zolpidem, eszopiclone, and zaleplon were introduced in the 1980s for the treatment of insomnia, as it was observed that the side effect profile associated with these medications were more benign than those related to the benzodiazepines. This meta-analysis set out to ascertain which domains of cognitive function, if any, were affected by the ingestion of these medications. A total of 20 studies met the study inclusion criteria. Results revealed medium effect sizes for zopiclone and zolpidem on measures of verbal memory. An additional medium effect size was observed for zolpidem on attention. Finally, smaller effect sizes were observed for zolpidem speed of processing and for zopiclone on working memory. It is clear from these data that the use of a single dose of the z-drugs in healthy adults as measured in the morning following the exposure does produce a specific rather than a generalized negative effect on cognitive function. However, there were only enough studies to evaluate the individual cognitive effects of the zolpidem and zopiclone medications; the specific effects of zaleplon and eszopiclone cannot be ascertained because only one study met the inclusion and exclusion criteria for the review.     

Cholinergic mechanisms in physical dependence on barbiturates,ethanol and benzodiazepines

Summary The aim of this review is to summarize the effects of acute and chronic treatment with barbiturates, ethanol and benzodiazepines on cholinergic mechanisms in the brains of experimental animals. A single dose of each of these substances reduces the turnover of ACh in the brain. Long-term treatment has the opposite effect; complicated interactions including decreased content of ACh are induced. Barbiturates have been shown to bind stereospecifically to muscarinic and nicotinic receptors in the brain, but this has not been observed for ethanol or the benzodiazepines. The effects on the cholinergic system are affected by the length of treatment and choice of treatment regimen. No effect on cholinergic parameters, such as muscarinic receptors, in the brain is observed on withdrawal of ethanol or barbiturate treatment when the animals are still tolerant towards the substances. The increase in the number of muscarinic receptors observed in several brain regions on withdrawal is seen as a sign of cholinergic supersensitivity. The number of receptors returns to normal when abstinence convulsions have occurred. The assumption of a cholinergic influence is supported by the finding that atropine, given as a single dose on the day of withdrawal of barbital, can prevent the muscarinic receptor changes. Furthermore, long-term barbital or ethanol treatment can induce permanent persistent changes in the cholinergic system in the brain. Cognitive defects and a significant permanent reduction in the content of ACh can be measured in rats which have had long-term barbital treatment. Similarly, a reduced number of muscarinic receptors has been measured in different brain regions of chronic alcoholics. Accumulating data support the role of the cholinergic system in expressing symptoms of physical dependence on barbiturates, ethanol and benzodiazepines as well as in the permanent long-term effects observed after end of treatment.     

Seizures following the withdrawal of alprazolam

Seizures were observed following the withdrawal of alprazolam administered in therapeutic dose for 10 weeks. A review of available case reports suggests that seizures, like other withdrawal phenomena, are more apt to occur with short-acting benzodiazepines. To prevent their occurrence these drugs should be discontinued gradually and consideration given to substituting long-acting drugs during the withdrawal period. Physicians should remain alert to the fact that seizures may occur as early as 24 hours after the abrupt withdrawal of short-acting benzodiazepines.     

Can drug effects on anxiety and convulsions be separated?

The effects of benzodiazepines, barbiturates, a series of novel putative anxiolytic compounds and anxiogenic compounds are reviewed in animal tests of anxiety and on experimentally-induced seizures. It is clear from the data that drug effects on anxiety and convulsions are not always in the same direction; certain compounds are apparently both anxiolytic and proconvulsant, others are anxiogenic and anticonvulsant, others have varied effects depending on the test situation. It is suggested that this work necessitates considerable revision of our traditional concepts of an "anticonvulsant." The extent to which drug-induced anxiety is correlated with weak epileptiform activity in the brain is discussed. Finally, the Discussion considers a number of possible mechanisms that could underlie the separation of drug effects on anxiety and convulsions that is observed.     

Dependence on benzodiazepines

Psychotropic drugs are widely prescribed and tend to be used on a long-term basis. The barbiturates are known to induce tolerance and dependence, with a well-defined and often severe withdrawal syndrome from high doses. By contrast, the benzodiazepines are infrequently associated with tolerance and dependence at high doses. Recent work, however, has suggested that a definite withdrawal syndrome can supervene on discontinuation of long-term normal doses of benzodiazepines. In view of the widespread and chronic use of the benzodiazepines, this may represent a major problem. The theoretical implications of such normal-dose dependence are discussed.