title: Update on the safety considerations in the management of insomnia with hypnotics: incorporating modified-release formulations into primary care.
abstract: 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.
  
  
  METHODS
  Publications relevant to the subject of this review were identified by a PubMed search (conducted without date restrictions; search terms: insomnia WITH safety OR tolerability OR side effects OR tolerance OR dependence OR abuse OR residual effects AND benzodiazepines OR non-benzodiazepines OR zolpidem OR eszopiclone OR zaleplon OR ramelteon OR melatonin OR trazodone OR antihistamines OR alcohol OR alternative therapies), and additional articles (selected by the author on the basis of his experience) were included.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
authors.affiliation: Jefferson Medical College, Thomas Jefferson University, Hockessin, DE, USA. jlieberman@jalmd.com
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Lieberman