The need for flexibility in dosing of hypnotic agents

Although a variety of medical and psychiatric disorders are known to cause insomnia, there are many patients for which a cause cannot be determined. When the etiology is unknown, treatment of insomnia must be symptomatic. Epidemiologic studies suggest that insomnia does not occur on a regular basis in most people. In addition, the presentation of insomnia relative to the time of night is often variable, with waking in the middle of the night and initiating sleep upon going to bed being the most common. The intermittent occurrence of most insomnia suggests that treatment is best accomplished by using hypnotics on an "as needed" basis when difficulties with sleep occur. When pharmacological treatment of insomnia is warranted, benzodiazepine receptor agonists (BzRAs) are often the preferred class of agents. Agents with a shorter duration of action and rapid onset of action are preferred for flexible administration, providing an option for middle of the night dosing if this is when insomnia occurs. Of the available hypnotic agents in the BzRA class, triazolam, zolpidem, and zaleplon have rapid onsets of action and short half-lives. However, with a half-life of 1 hour, only zaleplon appears to be suited for middle of the night administration. Other important factors that affect selection of an agent for the treatment of intermittent insomnia include psychomotor or cognitive impairment and rebound insomnia after discontinuation of therapy. In one placebo-controlled trial, residual sedation was seen after flurazepam, but not with zaleplon, following middle-of-the-night administration. In addition, rebound insomnia was not apparent in a 4-week, placebo-controlled trial of zaleplon. In this same study, transient rebound insomnia was apparent with zolpidem compared to placebo. More data are needed on long-term therapy with hypnotic agents given intermittently on nights during which insomnia occurs.