Tag Archives: insomnia

Modern Insomnia Therapeutics: Not the Barbiturates or Anxiolytic Benzodiazepines of Yore


Considering the different limitations and undesirable properties of earlier remedies used as hypnotics, such as alcohol, chloral hydrate, barbiturates and anxiolytic benzodiazepines, modern insomnia therapeutics clearly represent noteworthy improvements. In fact, the barbiturates, which were extensively used as hypnotics throughout the first half of the 20th century, are no longer in clinical use for insomnia, and the anxiolytic benzodiazepines, which were extensively used off-label following their introduction in the 1960’s, have now been mostly replaced by better designed benzodiazepines and other modern insomnia therapeutics.

Drug Approvals

A total of 11 new drug molecules have been approved for insomnia since 1970, in 5 pharmacologic classes. The first pharmacologic class, benzodiazepines, has had 5 new drugs, starting with Dalmane in 1970, which had been preceded by a few anxiolytic benzodiazepines, e.g., Librium (chlordiazepoxide, 1960) and Valium (diazepam, 1963), which have been used off-label as hypnotics. The second pharmacologic class, non-benzodiazepines, has had 3 new drug approvals, starting with Ambien in 1992, while the last 3 pharmacologic classes have had 1 new drug approval each, i.e., the melatonin receptor agonist Rozerem in 2005, the tricyclic antidepressant Silenor in 2010, and the orexin receptor antagonists Belsomra in 2014.

Refer to the accompanying chart below (click for a larger graph). In keeping with our convention, neither new formulations of approved drugs nor new combinations of previously approved drugs in that therapeutic class are included. The new molecule drug approvals are listed below:

  • Benzodiazepines: 5 new molecules, over 20 years and 8 months; Dalmane (flurazepam, 1970), Restoril (temazepam, 1981), Halcion (triazolam, 1982), Doral (quazepam, 1985), and Prosom (estazolem, 1990).
  • Non-benzodiazepines: 3 new molecules, over 12 years; Ambien (zolpidem, 1992), Sonata (zaleplon, 1999), and Lunesta (eszopiclone, 2004)
  • Melatonin Receptor Agonists: 1 new molecule; Rozerem (ramelteon, 2005).
  • Tricyclic Antidepressants: 1 new molecule; Silenor (doxepin, 2010; originally approved as Sinequan for depression in 1969).
  • Orexin Receptor Antagonists: 1 new molecule; Belsomra (suvorexant, 2014).


A few noteworthy comments and observations about this therapeutic classes are as follows:

  • Excluding alcohol, opium, and bromide salts, the earliest hypnotics included chloral hydrate, which was introduced in the 1860s, and paraldehyde, which was introduced in the 1880s.
  • While barbiturates were extensively used as hypnotics throughout the first half of the 20th century, e.g., phenobarbital, the only two barbiturates that have been approved as hypnotics are Butisol (butabarital, 1939) and Seconal (secobarbital, 1950); barbiturates are no longer in clinical use as hypnotics.
  • A few anxiolytic benzodiazepines, such as Librium (chlordiazepoxide, 1960), Valium (diazepam, 1963), and Ativan (lorazepam, 1977), have been used off-label as hypnotics. Dalmane (flurazepam, 1970), however, was the first benzodiazepine to be approved for insomnia.
  • Several sedating tricyclic antidepressants have also been used off-label as hypnotics, such as Elavil (amitriptyline, 1961), and Sinequan (doxepin, 1969). The only approved tricyclic antidepressant for insomina is Silenor (doxepin, 2010).


Until the 1970s, there had not been much progression in insomnia therapeutics for approximately a century, although different remedies were available, mostly used off-label. Since the early 1980s, there have been noteworthy improvements in this therapeutic class, with the approvals of a total of 8 new benzodiazepines and non-benzodiazepines, as well as the introduction of 2 new pharmacologic classes, a melatonin receptor agonist and a orexin receptor antagonist.

Refer to page 29 of Progression of Modern Therapeutics (2015 Report) available under Reports on this website; this report also includes a description of the methodology used.