Addiction Treatment Blog

Benzodiazepine Structure

What is the place for hypnotics in this scheme of things? Basically the same place that alcohol has occupied for centuries. Most of us every so often, if we are anxious, worked up or have a lot of things on our mind will have on occasion resorted to alcohol to knock ourselves out. This it doers effectively on an episodic basis. There are drawbacks to alcohol, however. One is that it may produce a rebound insomnia – it knocks you out but also wakes you up several hours later as the effects wear off. It may also wake you up to pass urine or because of dehydration.

Hypnotics do roughly the same thing, with similar benefits and side effects. Judiciously used, they are wonderful. Taken in the early stages of a problem they may abort the later development of habitual anxiety-based insomnia. Taken too regularly or chronically, they may produce their own problems.

The place for the hypnotics lies in the management of sleeplessness rather than in the management of insomnia. Where there is genuine sleeplessness stemming from jet lag or an underlying physical condition, or problems with falling asleep in what may be uncomfortable circumstances or situations of stress, a hypnotic may be of great benefit. The presumption in these cases is that there is a transient sleeplessness and the condition is being managed until normality returns. In certain circumstances, such as where a chronic physical condition regularly compromises sleep, it would seem that hypnotics can be used chronically without causing much in the lines of dependence or other problems. Under the side effects section below, problems such as the risks posed to driving from sedative effects of these drugs will be outlined but it should also be borne in mind that the fatigue consequent on sleeplessness is seen as a rather trivial issue.

The hypnotics in current use include a number of benzodiazepines and newer, non-benzodiazepine compounds which act at different sites on the GABA receptor. These bind to a ‘benzodiazepine’ receptor and modulate the action of GABA therapy. At present, distinctions are drawn between BZ-1, BZ-2 and BZ-3 receptors within this family. The BZ-1 receptor it is thought is primarily responsible for sedative effects, the BZ-2 myorelaxant and anticonvulsant effects and BZ-3 for anxiolytic effects. The older benzodiazepines bind to all three types and are therefore, sedative, anxiolytic, muscle relaxant and anticonvulsant. It is claimed that newer agents such as zolpidem bind primarily to the BZ-1 site and are accordingly hypnotic only.

Any of the benzodiazepines listed in Benzodiazepine Anxiolytics article may be used as a hypnotic, in addition to those given in the table below.

Table of Contents

• Benzodiazepine Hypnotics
  • Zopiclone
  • Zolpidem
• Side Effects
  • Tolerance
  • Rebound Insomnia
  • Broken Sleep
  • Hangover
  • Inappropriate Sedation
  • Others
  • Dependence
• Reference

Benzodiazepine Hypnotics

The benzodiazepine hypnotics are essentially the same as the benzodiazepines that are used for anxiolytic purposes. To some extent, calling one compound an anxiolytic and another a hypnotic is a marketing convenience, although a compound is likely to have greater potential as a hypnotic if it penetrates the brain quickly, and it was this that underlay the success of temazepam gels. The same compound in tablet form is simply not as effective a hypnotic.

Zopiclone

This is technically a cyclopyrrolone. Much is made of the fact that it is a non-benzodiazepine hypnotic, that it gives a more natural sleep, that it is free of hangover effects and that it will not produce dependence. Its profile of binding to BZ receptors suggests it binds to BZ-1 and BZ-2, but not BZ-3. It is not clear, however, whether clinically this conveys significant advantages – the clinical ambiguities will be dealt with further below.

It has one advantage in that its half-life is short; this means that in older individuals, for instance, who are slower to excrete hypnotic drugs from their system, zopiclone and zolpidem are the only sleeping pills that are not likely to accumulate. For this reason, it may be better than some of the currently available benzodiazepine hypnotics for this age group. Among side effects reported with zopiclone are a metallic taste, heartburn and a lightening of sleep on withdrawal.

Zolpidem

This agent is an imidazopyridine, which it is claimed binds preferentially to BZ-1 receptors and because of this gives a more natural sleep and is less likely to produce dependence, rebound, insomnia or some of the other problems associated with benzodiazepine hypnotics. If it only binds to BZ-1 receptors, it should have little in the line of anxiolytic or myorelaxant effects. Whether it does or not is uncertain. Side effects include drowsiness, fatigue, depression, falls and amnesia. In addition, as this agent is comparatively new, there is little knowledge of possible interactions with other medications that may be concomitantly prescribed, such as cimetidine, etc.

Side Effects

The side effects of both benzodiazepine and non-benzodiazepine hypnotics resemble those of benzodiazepine tranquillisers, outlined in Benzodiazepine Anxiolytics article, with the following additional problems.

Tolerance

Within 2-4 weeks of continuous use, tolerance is likely to develop to hypnotics. This means that they will not be as sedating after this length of treatment. Little further sedative benefit will be gained by continuing with them. But continuing may be helpful in that they may continue to be anxiolytic, which might help, and the psychological effect of getting into the habit of falling asleep on these drugs, as mentioned in the last chapter, might also help to promote sleep even though the truly sedative effect of the drug has worn off.

Rebound Insomnia

This effect probably relates to the development of tolerance as shown by the example of taking coffee to bed. Once the habit is created of sleeping on hypnotics, their absence may make sleep difficult, until the new habits are established. Rebound insomnia may be shown within 2 weeks of continuous hypnotic ingestion. In practice, it means that people who stop taking sleeping pills sleep poorly for several nights, which confirms their worst fears that they need the pills.

Broken Sleep

As with alcohol, modern hypnotics induce sleep but may also cause a waking from sleep as their effects wear off. This is particularly likely with the shorter-acting compounds – temazepam and lormetazepam. The extent of the problem with zolpidem and zopiclone is less certain.

Hangover

The shorter half-life hypnotics were synthesised in order to avoid the clear hangover effects produced in some individuals by the older benzodiazepines. This was a state of muzziness, with slowing of cognitive functioning and impairment of reaction times, which is sometimes quite marked. It may occur with compounds such as nitrazepam or flurazepam, the morning after the night before. In occasional individuals, this can last most of the next day. However, taking the pills regularly usually reduces the severity of this effect as tolerance develops. In controlled clinical trials, the shorter-acting compounds appeared to eliminate this problem. But in real life, they may also cause a similar problem if people resort to having another short-acting sleeping pill on waking up at 3 or 4 am.

There is a further problem with elderly people, who are most likely to be such pills chronically. Often, sometimes for the benefit of carers, the dose of a hypnotic will be pushed up in an elderly person and then traces of the drug begin to build up in the system as if the patient had been put on a longer half-life compound. If the original dose fails to work, (for elderly people the dose should be lower than for younger people) management should involve methods other than increasing the dose.

Inappropriate Sedation

There is some indication on packaging of hypnotics that after taking a hypnotic driving or operating machinery may be hazardous. In practice, with shorter-acting compounds, if the individual does not feel unduly affected, they are likely to take a risk and drive or work. It is difficult to calculate what the effects on the economy might be if everyone on any psychotropic drug were to refrain from driving or operating machinery. The problem is that some people have reactions that are more impaired than they are aware of and there is increasing evidence to suggest that a significant number of road traffic accidents happen to individuals who are taking psychotropic medication (although much less than are caused by alcohol).

At present no blood tests for hypnotics or other psychotropic drugs are likely to be done if one is stopped by the police for careless driving. But doctors, nurses and others are being encouraged to warn takers of hypnotics of the risks of driving so that any accidents that may occur while driving are clearly the responsibility of the taker. As always, however, the issues are complex in that as mentioned above the consequences of sleeplessness produce their own hazards.

Others

All of the other side effects of benzodiazepines listed the previous articles apply to these hypnotics. Amnesia is less of a problem, as the person sleeps it off. This does not apply if the pill is taken during the day, as the intravenous abuse of temazepam has clearly indicated. When taken in large amounts either intravenously or orally, on of the notable side effects of temazepam abuse has been a profound amnesia. Abusers who present at clinics often appear to have no recollection of visits they may have made to same clinic several days before.

In contrast to amnesia, dissociation may be a greater problem when these compounds are used as hypnotics, precisely because the confused overactivity that result may be more at odds with the tranquil sleep that is being sought than it would have been with anxiety if the pills had been given during the day. Dissociation is more likely with the elderly but as with antidepressants or neuroleptics a range of problems from confusion to hallucinations are possible.

Dependence

The use of benzodiazepines as hypnotics raises the issue of possible dependence: an issue that also clouds the use of zolpidem and zopiclone, in that they act on an adjacent receptor moiety to the benzodiazepines, which raises a natural suspicion that in time they too will be shown to produce dependence.

The risks of dependence with modern hypnotics, however, stem not just from the pills but from the marketing process that distinguishes hypnotics from benzodiazepine anxiolytics. When benzodiazepines were used widely as anxiolytics, it was common to find individuals on a benzodiazepine anxiolytic, such as lorazepam or diazepam, and a benzodiazepine hypnotic. Such combinations promote a more rapid tolerance, a greater likelihood of dependence and a more general scrambling or overriding of the body prompts that might otherwise be used to come to grips with the problem of insomnia, as well as that of anxiety. In the past decade the prescription of benzodiazepine anxiolytics has dropped substantially, which makes it much less likely that the more recently introduced hypnotics will be implicated in the widespread production of dependence, although not necessarily because they are intrinsically less dependence producing.

Where individuals have been taking hypnotics for years, there is no food argument for forcing them to discontinue. There is substantial evidence that for a great number of subjects, chronic hypnotic intake, provided there is no concurrent daytime use of benzodiazepines, does not cause significant physical dependence / withdrawal. This is because taken once at night, rather than regularly during the 24-hour period, the drug may not build up in the system to any great extent. At the correct dose, there may be little more harm in taking hypnotics for such individuals than in taking Ovaltine or a night-cap. The harm is more likely to come from the levels to which the dose of the drug has been pushed by prescribers than from the intrinsic properties of the drug. At high doses, these hypnotics will cause sedation the next day, confusion, amnesia and possible ataxia.

Despite the relative safety of these compounds, the current climate is such that the future of hypnotics may depend on limiting their use to a regime of something like 10 pills per month (1). Many takers are likely to find increasing pressure on them to stop the continuous use of these compounds. Where discontinuation is indicated or desired a regime like that for the withdrawal of benzodiazepine anxiolytics is indicated, with supplementary education about sleep hygiene and the likely misperceptions the person is likely to experience on halting a hypnotic after some months or years of intake.

References

1. Lader M, ed. The medical management of insomnia in general practice. Royal Society of Medicine Round Table Series no 28. Oxford: Alden Press; 1992.