The physiological mechanisms regulating the sleep-wake rhythm are not completely known. There is evidence that histaminergic, cholinergic, glutamater-gic, and adrenergic neurons are more active during waking than during the NREM sleep stage. Via their ascending thalamopetal projections, these neurons excite thalamocortical pathways and inhibit GABA-ergic neurons. During sleep, input from the brain stem decreases, giving rise to diminished tha-lamocortical activity and disinhibition of the GABA neurons (A). The shift in balance between excitatory (red) and inhibitory (green) neuron groups underlies a circadian change in sleep propensity, causing it to remain low in the morning, to increase towards early afternoon (midday siesta), then to decline again, and finally to reach its peak before midnight (B1).
Treatment of sleep disturbances. Pharmacotherapeutic measures are indicated only when causal therapy has failed. Causes of insomnia include emotional problems (grief, anxiety, "stress"), physical complaints (cough, pain), or the ingestion of stimulant substances (caffeine-containing beverages, sympa-thomimetics, theophylline, or certain antidepressants). As illustrated for emotional stress (B2), these factors cause an imbalance in favor of excitatory influences. As a result, the interval between going to bed and falling asleep becomes longer, total sleep duration decreases, and sleep may be interrupted by several waking periods.
Depending on the type of insomnia, benzodiazepines (p. 226) with short or intermediate duration of action are indicated, e.g., triazolam and brotizolam (ti/2 ~ 4-6 h); lormetazepam or temaze-pam (t1/2 ~ 10-15 h). These drugs shorten the latency of falling asleep, lengthen total sleep duration, and reduce the frequency of nocturnal awakenings. They act by augmenting inhibitory activity. Even with the longer-acting benzodiaz-epines, the patient awakes after about
6-8 h of sleep, because in the morning excitatory activity exceeds the sum of physiological and pharmacological inhibition (B3). The drug effect may, however, become unmasked at daytime when other sedating substances (e.g., ethanol) are ingested and the patient shows an unusually pronounced response due to a synergistic interaction (impaired ability to concentrate or react).
As the margin between excitatory and inhibitory activity decreases with age, there is an increasing tendency towards shortened daytime sleep periods and more frequent interruption of nocturnal sleep (C).
Use of a hypnotic drug should not be extended beyond 4 wk, because tolerance may develop. The risk of a rebound decrease in sleep propensity after drug withdrawal may be avoided by tapering off the dose over 2 to 3 wk.
With any hypnotic, the risk of suicidal overdosage cannot be ignored. Since benzodiazepine intoxication may become life-threatening only when other central nervous depressants (etha-nol) are taken simultaneously and can, moreover, be treated with specific ben-zodiazepine antagonists, the benzo-diazepines should be given preference as sleep remedies over the all but obsolete barbiturates.
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