Chloral hydrate, clomethiazole and barbiturates also enhance GABA function but at high doses have the additional capacity directly to open the membrane chloride channel (see Figure 19.4); this may lead to potentially lethal respiratory depression and explains their low therapeutic ratio. These drugs also have a propensity for abuse/misuse and are very much second-line treatments.

Chloral hydrate has a fast (30-60 min) onset of action and duration of action 6-8 h. It is a prodrug, being rapidly metabolised by alcohol dehydrogenase into the active hypnotic trichloroethanol (t^ 8h). Chloral is dangerous in serious hepatic or renal failure and aggravates peptic ulcer. Interaction with ethanol is to be expected since both are metabolised by alcohol dehydrogenase. Ethanol also appears to induce the formation of trichloroethanol which attains higher plasma concentrations if alcohol is co-administered, increasing sedation. Triclofos (Tricloryl) and cloral betaine (Welldorm) are related compounds.

Clomethiazole is structurally related to vitamin B 1 (thiamine) and is a hypnotic, sedative and anticonvulsant. It is comparatively free from hangover; it can cause nasal irritation and sneezing. Dependence occurs and use should always be brief. When taken orally, it is subject to extensive hepatic firstpass metabolism (which is defective in the elderly and in liver damaged alcoholics who get higher peak plasma concentrations), and the usual 1is 4 h (with more variation in the old than the young); it may also be given i.v.

Barbiturates have a low therapeutic index, i.e. relatively small overdose may endanger life; they also cause dependence and have been popular drugs of abuse. The use of intermediate-acting drugs

(amylobarbital, butobarbital, secobarbital) is now limited to severe intractable insomnia in patients already taking barbiturates (they should be avoided in the elderly). The long-acting phenobarbital is used for epilepsy (see Chapter 20), and very short-acting thiopental for anaesthesia (see p. 353). Overdose following self-poisoning by hypnotic barbiturates may have severe features including hypotension (may lead to renal failure), hypothermia, respiratory depression and coma. Supportive measures may suffice with i.v. fluid to restore central venous pressure and so cardiac output and, if that fails, using a drug with cardiac inotropic effect (see p. 457). A good urine volume (e.g. 200 ml/h) promotes elimination of the drug. Urine alkalinisation accelerates removal of phenobarbital (an acid, pKa 7.2) as do repeated doses of activated charcoal. Active elimination by haemoperfusion or dialysis may be needed in particularly severe and complicated cases.

Other drugs used in insomnia

Antihistamines. Most proprietary (over the counter) sleep remedies contain antihistamines. Promethazine (Phenergan) has a slow (1-2 h) onset and long (t'/2 12 h) duration of action. It reduces sleep onset latency and awakenings during the night after a single dose but there have been no studies showing enduring action. It is sometimes used as a hypnotic in children. There are no controlled studies showing improvements in sleep after other antihistamines. Trimeprazine (alimemazine) is used for short-term sedation in children. Most antihistamine sedatives have a relatively long action and may cause daytime sedation.

Antidepressants. In the depressed patient, improvement in mood is almost always accompanied by improvement in subjective sleep and therefore choice of antidepressant should not usually involve additional consideration of sleep effects. Nevertheless, some patients are more likely to continue with medication if there is a short-term improvement, in which case mirtazapine or nefazodone provide an effective antidepressant together with sleep-promoting effects.

Antidepressant drugs, particularly those with 5HT2-blocking effects, may occasionally be effective in long-term insomnia (but see Table 19.6).

Antipsychotics have been used to promote sleep in resistant insomnia occurring as part of another psychiatric disorder, probably due to a combination of 5HT2-receptor, a,-adrenoceptor and histamine Hj-receptor antagonism, in addition to their primary dopamine antagonist effects. Their long action leads to daytime sedation and extrapyramidal movement disorders may result from dopamine receptor blockade (see p. 380, Antipsychotics). Nevertheless, modern antipsychotics, e.g. quetia-pine, have been occasionally used for intractable insomnia.

Melatonin, the hormone produced by the pineal gland during darkness, has been investigated for insomnia but it appears to be ineffective. The impressive nature of the diurnal rhythm in melatonin secretion has stimulated interest in its use therapeutically to reset circadian rhythm to prevent jet-lag on long-haul flights and for blind or partially sighted people who cannot use daylight to synchronise their natural rhythm. There is controversy about dose and timing of treatment and in most countries pharmaceutical preparations are not generally available.

Herbal preparations. Randomised clinical trials have shown some effect of valerian in mild to moderate insomnia, and hops, lavender and other herbal compounds show promise in pilot studies that are presently being pursued more fully.

Summary of pharmacotherapy for insomnia

• Drug treatment may be effective for a short period (2-4 weeks).

• Some patients may need long-term medication.

• Intermittent medication, i.e. taken only on nights that symptoms occur, is preferable and may often be possible with modern, short-acting, compounds.

• Discontinuing hypnotic drugs is usually not a problem if the patient knows what to expect. There will be a short period (usually 1-2 nights) of rebound insomnia on stopping hypnotic drugs which can be ameliorated by phased withdrawal.

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