Benzodiazepines and Z-drugs

Benzodiazepines and Z-drugs are effective as measured by the time taken to fall asleep and the duration of sleep. Combined data from four randomised clinical trials (RCTs) showed the time taken for people taking a benzodiazepine to fall asleep was 4.2 minutes shorter than for those receiving placebo (95% CI –0.7 to +9.2); pooled data from two RCTs showed that patients taking benzodiazepines slept for an average of 61.8 minutes longer than those in the placebo group (95% CI 37.4 to 86.2)6133.

However, benzodiazepines and Z-drugs do not necessarily improve the quality of sleep and daytime functioning of patients can sometimes be negatively affected95.

The effects of specific benzodiazepines are dependent upon the dose administered and the pharmacokinetic profile. Although there is variation between the estimates of elimination half-life, the BNF11 refers to loprazolam, lorazepam, lormetazepam and temazepam as having a shorter duration of action. Benzodiazepines with a longer elimination half-life (for example, diazepam and nitrazepam) tend to have prolonged effects and, if used as hypnotics, have a greater tendency to have next-day residual effects. This may affect mental function and cause psychomotor impairment, which can interfere with activities such as driving22 and working with machinery. 
 NICE does not recommend the use of the longer-acting benzodiazepines63.

A systematic review of 24 RCTs by NICE63 found no significant differences in the effectiveness of Z-drugs (zaleplon, zolpidem, zopiclone) or the shorter-acting benzodiazepines. In the absence of any compelling evidence to distinguish these hypnotics NICE recommends that the drug with the lowest purchase price (taking into account daily required dose and product price per dose) should be prescribed.

Key considerations for the pharmacological treatment of insomnia6163

  • There is good evidence for the efficacy of hypnotic drugs (benzodiazepines / Z-drugs) in short-term insomnia; however, their use is associated with adverse effects, such as daytime sedation, poor motor coordination, cognitive impairment, and related concerns about driving accidents and injuries from falls.
  • Tolerance to hypnotics (benzodiazepines / Z-drugs) may develop rapidly and reduce effectiveness. Dependence may also occur in association with long-term use, high doses, more potent or shorter-acting benzodiazepines, and a history of anxiety problems.
  • There is a lack of compelling evidence to distinguish between Z-drugs and the shorter-acting benzodiazepines and prescribing decisions should be made on a cost basis. Patients who have not responded to either a benzodiazepine or a Z-drug should not be prescribed the other. Switching between these two classes of hypnotics should only occur if the adverse effects experienced can be directly related to a specific agent.
  • Use of pharmacological/drug treatment is not generally recommended for the long-term management of insomnia. However, for people with severe symptoms or an acute exacerbation of persistent insomnia a short course of a hypnotic can help with immediate relief of symptoms.
  • For patients over 55 years of age with persistent insomnia, treatment with a modified-released melatonin should be considered.
  • Sedative drugs other than hypnotics (such as antidepressants, antihistamines, choral hydrate, clomethiazole, and barbiturates) are not recommended for the management of insomnia
  • If, after trying these drugs, the insomnia persists the patient should be referred to a sleep clinic or a specialist with expertise in sleep medicine.

The therapeutic use of other older hypnotics has also been questioned. Chloral derivatives are now considered less suitable for prescribing due to their adverse effects and abuse potential and clomethiazole is only recommended for short term treatment of severe insomnia in elderly patients11. Clomethiazole only has evidence to support its use in this age group when other hypnotics have failed, although it is rarely used now due to the risk of accidental overdose and respiratory depression11.

Hypnotics recommended for the treatment of short-term insomnia6163

  • Short-acting benzodiazepines (BZDs)
    Temazepam, loprazolam, lormetazepam.
  • Non-BZD drugs (the 'Z-drugs')
    Zopiclone, zolpidem, and zaleplon (all short acting).
  • For people over 55 years of age with persistent insomnia, consider treatment with a modified-release melatonin.

Hypnotics NOT recommended for the treatment of insomnia61

  • Diazepam, nitrazepam, and flurazepam are not recommended because their long half-life commonly gives rise to next-day residual effects, and repeated doses tend to be cumulative

School of Pharmacy and Bioengineering,
The Hornbeam, Keele University,
Keele, Staffordshire, ST5 5BG.

T: 01782 479790

© 2015 Keele University, © 2015 PDS Ltd

Supported by an unrestricted grant
from Flynn Pharma Ltd in the UK.

Flynn Pharma