Drug Treatment of Insomnia

Historically the first sedative hypnotics to be introduced were the bromides in the mid 19th century, shortly followed by chloral hydrate, paraldehyde and urethane. It was not until the early years of this century that the first barbiturate, sodium barbitone, was developed and this was shortly followed by over 50 analogues, all with essentially similar pharmacological properties. The major breakthrough in the development of selective, relatively non-toxic sedative hypnotics followed the introduction of chlordiazepoxide in 1961. Most of the benzodiazepines in current use have been selected for their high anxiolytic potency relative to their central depressant effects. Because of their considerable safety, the benzodiazepines have now largely replaced the barbiturates and the alcohols, such as chloral hydrate and trichloroethanol, as the drugs of choice in the treatment of insomnia. 

The hypnotics are some of the most widely used drugs, over 15 million prescriptions being given for this group of drugs in Britain in 1985 the number of prescriptions for hypnotics has remained fairly constant over the last decade despite the reduction in anxiolytic prescriptions by about 50% over this same period. This situation is hard to reconcile with the fact that 

Fundamentals of Psychopharmacology. Third Edition. By Brian E. Leonard 2003 John Wiley Sons, Ltd. ISBN 0 471 52178 7 

It is a well-known fact that the circadian rhythm is entrained for diurnal cues to approximately 24 hours. However, a non-entrained rhythm, which operates in the absence of external cues, lasts between 25 and 27 hours. Thus the human sleep-wake cycle normally shows a 24-hour rhythm but not all physiological processes (for example, body temperature) follow the sleep-wake cycle. 

It is now known that circadian rhythms are controlled by clock genes which are found in species as wide apart as insects and mammals. It would appear that the clock genes are activated by light falling on the retina. The activated retina neurons then stimulate the retinohypothalamic tract which projects to the suprachiasmatic nucleus and thence to the anterior pituitary. This pathway is responsible for coupling the circadian rhythm with the 

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Hartmann, P. M. Drug treatment of insomnia indications and newer agents. Am. Pam. Physician 51 (1995) 191-200. 

The two selective GABA j receptor agonists currently marketed in the United States, zaleplon and Zolpidem, are a pyrazolopyrimidine and a imidaz-opyridine, respectively. Both of these drugs are approved only for the shortterm treatment of insomnia. 

The increasing popularity of sedating antidepressants for the treatment of insomnia resulted in trazodone being the most prescribed drug in 2002.39 Other common antidepressants also... 

Eszopiclone has been approved for the treatment of patients who experience difficulty falling asleep, poor sleep maintenance, and for long-term treatment of insomnia. Clinical trials have shown that eszopiclone improved sleep onset, sleep maintenance, total sleep time, sleep quality, and daytime functioning compared with placebo. Improved wake time alertness, concentration, and sense of well-being were reported. Eszopiclone was well tolerated, with only mild adverse events reported. There was no evidence of dmg-drug interactions, tolerance, residual drowsiness or treatment-related rebound insomnia. The recommended dose to improve sleep onset and maintenance is generally between 1 and 3 mg. 

U.S. Food and Drug Administration for the treatment of insomnia, almost all benzodiazepines may be used for this purpose. Benzodiazepines are most clearly valuable as hypnotics in the hospital setting, where high levels of sensory stimulation, pain, and acute stress may interfere with sleep. The safe, effective, and time-limited use of benzodiazepine hypnotics may, in fact, prevent chronic sleep difficulties (NIMH/NIH Consensus Development Conference Statement 1985). Benzodiazepines are also used to treat akathisia and catatonia and as adjuncts in the treatment of acute mania. 

This newest non-BZD hypnotic is a pyrazolopyrimidine derivative with a fuii agonist activity on centrai BZD receptors B2 type. It is an effective hypnotic for the short-term treatment of insomnia. Because of its very short half-life (almost an hour), it may be useful for patients experiencing difficulty falling asleep and in those who wake up at night and who have trouble falling back to sleep. Zaleplon is rapidly absorbed after oral administration and its mean, apparent elimination half-life is similar to that obtained after i.v. infusion. Zaleplon is extensively metabolized in the liver by aldehyde oxidase, and to a lesser extent by CYP3A4. This drug is excreted in the urine (156). 

Melatonin is promoted commercially as a sleep aid by the food supplement industry (see Chapter 64). Ramelteon is a selective MTi and MT2 agonist that is approved for the medical treatment of insomnia. This drug has no addiction liability (it is not a controlled substance), and it appears to be distinctly more efficacious than melatonin (but less efficacious than benzodiazepines) as a hypnotic. It is metabolized by P450 enzymes and should not be used in individuals taking CYP1A2 inhibitors. It has a half-life of... 

Sedative effects, particularly with trazodone, can be quite pronounced. Thus, it is not surprising that the treatment of insomnia is currently the primary application of trazodone. The gastrointestinal effects appear to be dose-related and are less pronounced than those seen with SNRIs or SSRIs. Sexual effects are uncommon with nefazodone or trazodone treatment as a result of the relatively selective serotonergic effects of these drugs on the 5-HT2 receptor rather than on... 

The benzodiazepines are still widely prescribed for the treatment of insomnia. These agents have been extensively discussed above in terms of their mechanism of action and use in anxiety. Their mechanism of action in insomnia is the same as for anxiety (see Figs. 8—23 to 8—25). Whether a benzodiazepine is used for sedation or for anxiety is based largely on half-life, with the shorter half-life drugs preferred for insomnia because they are more likely to wear off by morning. However, in practice virtually all the benzodiazepines are used for the treatment of insomnia (Table 8-4). 

Rohypnol, developed by the pharmaceutical firm of Hoffmann-La Roche, is first sold in Switzerland as a sleeping aid for the treatment of insomnia. Reports begin surfacing that Rohypnol is abused as a recreational or party drug, often in combination with alcohol and/or other drugs. 

Many benzodiazepines have potent hypnotic activity and are useful in the treatment of insomnia. Examples include flurazepam (Dalmane, A.93), midazolam (Versed, A.94), temazepam (Restoril, A.95), and triazolam (Halcion, A.96) (Figure A.28). Flunitrazepam (Rohypnol, A.97) is a particularly notorious sedative. Often called roofie or the date rape drug, flunitrazepam causes sedation and amnesia. Because of flunitrazepam s tendency to be abused, almost all nations tightly regulate the drug s availability. 

Barbera J, Shapiro CM (2005) Benefit-risk assessment of zaleplon in the treatment of insomnia. Drug Saf 28 301-318... 

Noble S, Langtry HD, Lamb H M (1998) Zopiclone An update of its pharmacology, clinical efficacy and tolerability in the treatment of insomnia. Drugs 55 277-302... 

Heydorn WE (2000) Zaleplon - a review of a novel sedative hypnotic used in the treatment of insomnia. Exp Opin Invest Drugs 9 841-858... 

Insomnia is a common complaint in the elderly. As people age they require less sleep, and a variety of physical ailments to which the elderly are subject can cause a change in the sleep pattern (e.g. cerebral atherosclerosis, heart disease, decreased pulmonary function), as can depression. Providing sedative hypnotics are warranted, the judicious use of short half-life benzodiazepines such as temazepam, triazolam, oxazepam and alprazolam for a period not exceeding 1-2 months may be appropriate. Because of their side effects, there would appear to be little merit in using chloral hydrate or related drugs in the treatment of insomnia in the elderly. It should be noted that even benzodiazepines which have a relatively short half-life are likely to cause excessive day-time sedation. The side effects and dependence potential of the anxiolytics and sedative hypnotics have been covered elsewhere in this volume (Chapter 9). 

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