P> Objective: From a safety perspective, several issues require assessment when a decision is made to prescribe a sleep medication, including next-day residual effects, the potential for abuse, tolerance, and dependence. This article aims to provide an update of the safety profile of agents commonly used in the management of insomnia, with an emphasis on newly approved hypnotics.

Data Sources: Publications relevant to the subject of this review were identified by a PubMed search (conducted without date restrictions; search terms:insomnia WITHsafety ORtolerability ORside effects ORtolerance ORdependence ORabuse ORresidual effects ANDbenzodiazepines ORnon-benzodiazepines ORzolpidem OReszopiclone ORzaleplon ORramelteon ORmelatonin ORtrazodone ORantihistamines ORalcohol ORalternative therapies), and additional articles (selected by the author on the basis of his experience) were included.

Study Selection and Data Extraction:Publications relevant to the objective of this article were obtained, and the key safety data relating to adverse events, next-day residual effects, tolerance, and withdrawal were summarized.

Data Synthesis: The non-benzodiazepines (eszopiclone, zolpidem, zolpidem extended-release, and zaleplon), which have largely replaced the benzodiazepines for insomnia treatment, have a lower risk of tolerance, dependence, abuse, and residual effects compared with benzodiazepines. The modified-release formulation of zolpidem demonstrates a comparable safety profile to that of original zolpidem but has an additional sleep maintenance benefit. Ramelteon, a novel melatonin receptor agonist, is indicated for sleep-onset difficulties and is not scheduled. Over-the-counter agents, alternative therapies, and the prescription of off-label drugs, such as trazodone, have a lack of controlled clinical efficacy and safety studies in the treatment of insomnia and as a result should be used with caution.

Conclusions: Overall, published studies report that the safety of insomnia treatments has improved considerably over the past 10 years with the introduction of agents that provide improved safety, particularly with regard to next-day residual effects and abuse liability.

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