Conventional Pharmacologic Treatment
One of the most common types of OTC sleep medications are antihistamines, such as doxylamine (Unisom®) and diphenhydramine (Benadryl®). Antihistamines block the receptors that respond to histamine; this reduces congestion, sneezing, coughing, and allergy symptoms. Centrally, blockade of histamine receptors causes sedation; thus antihistamines can be used as sleep aids.
Despite the widespread use of these OTC drugs, there are significant concerns regarding their efficacy and safety. Although some studies have found that these OTC drugs can improve sleep, there are few well designed trials to definitively determine their efficacy (Randall 2008). Diphenhydramine can remain in the body for long periods of time, resulting in sedation the following day. In addition, the human body can build up a tolerance to the effects of antihistamines. Evidence appears to suggest that antihistamines may be useful for insomnia for short periods of time, but not efficacious in treating chronic insomnia (Randall 2008).
Benzodiazepines (e.g., alprazolam [Xanax®], clonazepam [Klonipin®], and diazepam [Valium®]) were the cornerstone for the treatment of insomnia until the 1990s. These medications enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA), which is one of the main inhibitory neurotransmitters in the brain (Lieberman 2007). Studies have found that benzodiazepines are able to reduce the amount of time users need to fall asleep (Buscemi 2007; Holbrook 2000).
Benzodiazepines can be classified based on their duration of action. Short-acting benzodiazepines are more likely to cause withdrawal symptoms, whereas long-acting are more likely to leave users feeling groggy and produce a "hangover" feeling (Lieberman 2007), as well as paradoxical rebound anxiety.
Non-benzodiazepines, also called benzodiazepine-like drugs, such as zalelplon (Sonata®), zolpidem (Ambien®), and eszopiclone (Lunesta®), are the next generation of sleep aids (Lieberman 2007). Zaleplon, one of the first non-benzodiazepines developed for the treatment of insomnia, has been proven to be effective in reducing the amount of time it takes to fall asleep (Ancoli-Israel 1999; Cluydts 2002). Its short half-life (1 hour) also reduces the risk of lasting effects the following morning. However, this may make it less useful for people who wake up during the night (Ancoli-Israel 1999). Zolpidem's half-life (about 2.5 hours) may make it more effective at reducing the amount of time it takes to fall asleep and stay asleep. In order to improve zolpidem's effectiveness for maintaining sleep, "modified release" and "extended release" formulations have been designed. Studies have found that modified release forms are very effective at improving sleep, with over 92% of individuals reporting that zolpidem helped them sleep when taken three to seven nights per week; also, that it may not affect performance the next day (Hindmarch 2006; Krystal 2008). Eszopiclone has also been shown to be effective at improving sleep (Roth 2005; Ancoli-Israel 2010).
There are some significant risks associated with taking these drugs. For example, zolpidem can cause sleep-walking, sleep-driving, and eating while sleeping (Hoque 2009). In addition, sedative hypnotics increase the risk of depression, and long-term effects on the brain are not known (Kripke 2007). Moreover, in 2012, a well-controlled study revealed an association between popular hypnotic sleep aids, such as zolpidem (Ambien®), eszopiclone (Lunesta®), and temazepam (Restoril®), and a more than three-fold increased risk of death (Kripke 2012). We should note, however, that those using hypnotic sleep aid drugs often have poor overall sleep quality, which could be the factor causing the sharply increased risk of death. Hypnotic sleep aids are by no means a cure for chronic insomnia, despite ads run on national TV claiming miraculous sleep improvement.
Many antidepressants such as doxepin (Silenor®), a histamine receptor antagonist with tricyclic antidepressant properties, trazodone (Desyrel®), a serotonin antagonist and reuptake inhibitor, and amitriptyline (Elavil®), a tricyclic antidepressant, are used to treat insomnia because they have sedative properties (Weber 2010; Aurón Zaltzman 1976; Galecki 2010). Doxepin has been found to increase sleep time without causing significant adverse effects (Roth 2007; Krystal 2010). Some data have shown that trazodone, functioning as a mild hypnotic, may temporarily help people fall asleep (Walsh 1998). However, there are few well-designed studies that demonstrate its effectiveness. Trazodone can cause significant side effects such as dizziness as well as slowed thinking and movement the next day. Therefore, its risks may outweigh its benefits, particularly in those more susceptible to these side effects (e.g., the elderly) (Mendelson 2005). Although amitriptyline is commonly prescribed by physicians as a sleep aid, data regarding its effectiveness for the treatment of primary insomnia is limited (Schweitzer 2010).