The Pharmacotherapy of Insomnia: Efficacy and Rebound With Hypnotic Drugs

Currently prescribed hypnotics (i.e., benzodiazepines and benzodiazepine-like compounds) are commonly categorized according to pharmacokinetic profile, which is primarily distinguished by long, intermediate, or short elimination half-life. Hypnotics with a long elimination half-life (flurazepam and quazepam) maintain efficacy over prolonged periods of nightly use and their discontinuation does not usually result in rebound insomnia, but they have the major drawback of causing unwanted potent daytime sedative effects. Use of intermediate half-life hypnotics (estazolam, flunitrazepam, lormetazepam, nitrazepam, and temazepam) is associated with carryover effects of moderate intensity and varying degrees of tolerance and rebound insomnia. Rapidly eliminated benzodiazepine (brotizolam, midazolam, triazolam) and nonbenzodiazepine (zaleplon, zolpidem, and zopiclone) hypnotics are practically devoid of carryover effects, making them appropriate for use in the majority of cases of insomnia, but they are generally associated with relatively rapid development of tolerance and rather frequent occurrence of rebound insomnia upon their discontinuation. Contrary to previous beliefs, tolerance and rebound insomnia vary considerably among the rapidly eliminated hypnotics: tolerance is intense with triazolam and slight with midazolam and zolpidem, while rebound insomnia is intense with triazolam, variable with midazolam, and quite mild with zolpidem. For brotizolam, zaleplon, and zopiclone, existing relevant research findings are still inconclusive; brotizolam and zopiclone, however, appear to have a marked potential for the development of tolerance and/or rebound insomnia, which does not seem to be the case with zaleplon.