Before the benzodiazepines, both anxiety and sleep problems were treated with sedatives. The emergence of the benzodiazepines led to distinctions between anxiolysis and sedation, and to the discovery of the idea of an anxiolytic. It also led to distinctions between sedatives and hypnotics. The hypnotics were supposed to induce a truer sleep than older sedatives did. The concerns about the overprescription of benzodiazepines in the 1980s led some prescribers to look at alternative agents. This has meant either a return to older sedatives, such as the barbiturates or chloral agents, or the use of antidepressants or antipsychotics with a sedative profile, or more recently the use of melatonin or related compounds. There are a number of problems with any of these options.
MELATONIN AND ITS ANALOGUES
It has been known for decades that the circadian system in the brain is regulated by the hormone melatonin. 2 This naturally occurring agent has been used for conditions like jet-lag without any great evidence that its use convincingly speeds up the resolution of jet-lag. But its use has been helpful in jet-lag because, particularly in larger doses, the compound is sedative. This led to its widespread use in many countries as an over-the-counter sleeping pill. In the doses used the effects have very little to do with modulation of the circadian system, although the sales pitch will often emphasise how natural melatonin is compared to other hypnotics. The doses are supraphysiological – that is, they are considerably higher than would occur naturally.
From over-the-counter use, melatonin spread to child psychiatry, where it was used for a number of years as a supposedly gentle sleeping pill – something to use where child psychiatrists would be reluctant to give a benzodiazepine.
From a company point of view, however, melatonin has been a problem. As a natural product, it cannot be patented and many companies can produce versions of it. This led companies to produce versions of it that differ from the natural product and therefore could be patented. This led to the marketing of ramelteon as a hypnotic and agomelatonin as an antidepressant (Table 16.1).
Table 16.1 Melatonin compounds
Generic drug name
Trade names
Melatonin
Melatonin
Ramelteon
Rozerem
Agomelatonin
Valdazoxan
The side effects of these remain uncertain at present, aside from sedative effects and, in the case of agomelatonin, weight gain.
CHLORAL COMPOUNDS
Chloral compounds (Table 16.2) were first produced in 1869. 8 Their sedative effects were quickly recognised. A number of factors militated against their widespread use. One was the difficulty in making them in other than foul-tasting liquid formats. The subsequent discovery of the barbiturates around 1900 led to a decline in their use.
Table 16.2 Chloral compounds
Generic drug name
UK trade name
Chloral hydrate
Noctec/Welldorm elixir
Chloral betaine
Welldorm tablets
Triclofos sodium
–
The chloral compounds are now produced in tablet and liquid form. They are popular with some prescribers as they do not appear to give the buzz sometimes obtained from benzodiazepines and are, therefore, considered by some less likely to be abused. For this reason they are used in some hospitals as the sedative of choice for illicit drug users. They are also popular with hospital pharmacies in that they cost pennies rather than pounds. A chloral prescription may cost the pharmacy as little as 5p per week.
Chloral compounds, however, cause dependence, as well as gastric irritation, heartburn and rashes. They are hazardous in overdose. These compounds are contraindicated where there is a coexisting disorder of almost any sort – cardiac, renal or gastric.
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