Drug Safety

, Volume 26, Issue 4, pp 261–282 | Cite as

New Drugs for Insomnia

Comparative Tolerability of Zopiclone, Zolpidem and Zaleplon
  • Mario Giovanni Terzano
  • Mariano Rossi
  • Vincenzo Palomba
  • Arianna Smerieri
  • Liborio Parrino
Review Article


Insomnia affects 30–35% of people living in developed countries. The impact of insomnia on daytime functioning and its relationship with medical and psychiatric illnesses necessitate early treatment to prevent insomnia becoming persistent and to avoid the development of complications. However, pharmacological strategies must achieve a balance between sedative and adverse effects.

In the last 30 years, benzodiazepines have been the preferred drugs for the treatment of insomnia. Benzodiazepines act nonselectively at two central receptor sites, named ω1 and ω2, which are located in different areas of the CNS. The sedative action of benzodiazepines is related to ω1 receptors, whereas ω2 receptors are responsible for their effects on memory and cognitive functioning. According to their pharmacokinetic profile, benzodiazepines can be classified into three groups: short half-life (<3 hours), medium half-life (8–24 hours) and long half-life (>24 hours).

The newer non-benzodiazepine agents zopiclone, zolpidem and zaleplon have a hypnosedative action comparable with that of benzodiazepines, but they display specific pharmacokinetic and pharmacodynamic properties. These three ‘Z’ agents all share a short plasma half-life and limited duration of action. In addition, these agents are selective compounds that interact preferentially with ω1 receptors (sedative effect), whereas benzodiazepines also interact with ω2 receptors (adverse effects on cognitive performance and memory). Zaleplon is characterised by an ultrashort half-life (approximately 1 hour). Zolpidem and zopiclone have longer half-lives (approximately 2.4 and 5 hours, respectively). These properties, together with the low risk of residual effect, may explain the limited negative influences of these agents on daytime performance. Psychomotor tasks and memory capacities appear to be better preserved by non-benzodiazepine agents than by benzodiazepines. When present, cognitive deficits almost exclusively coincide with the peak plasma concentration. In particular, impairment can emerge in the first hours after drug administration, whereas psychomotor and memory tests carried out 7–8 hours later (i.e. in the morning) generally show no relevant alterations.

As with benzodiazepines, the three ‘Z’ non-benzodiazepine agents should be used for a limited period, even in chronic relapsing conditions. Further evaluation is needed of the safety of hypnosedative medications in the long-term management of insomnia.


Zolpidem Triazolam Zopiclone Flunitrazepam Zaleplon 
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No sources of funding were used to assist in the preparation of this manuscript. The authors have no potential conflicts of interest that are directly relevant to the contents of this manuscript.


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Copyright information

© Adis International Limited 2003

Authors and Affiliations

  • Mario Giovanni Terzano
    • 1
  • Mariano Rossi
    • 1
  • Vincenzo Palomba
    • 1
  • Arianna Smerieri
    • 1
  • Liborio Parrino
    • 1
  1. 1.Sleep Disorders Center, University of Parma, Istituto di Neurologia - UniversitàParmaItaly

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