Benzodiazepines

Benzodiazepines act by binding to gamma-aminobutyric acid (GABA) receptors in the brain. The duration of their action is variable:

• Long acting (diazepam, chlordiazepoxide, alprazolam, clobazam)
• Medium acting (nitrazepam, flurazepam)
• Short acting (Lorazepam, temazepam, loprazolam, lormetazepam, oxazepam)

Shorter-acting compounds may be preferred in hepatic impairment but carry a greater risk of withdrawal symptoms. The effects of specific benzodiazepines vary, due to dose and pharmacokinetic profile.¹

• Short-term relief of anxiety (2-4 weeks only)
• Insomnia, when severe
• Muscular spasm or spasticity
• Status epilepticus
• Febrile convulsions
• Alcohol withdrawal (to prevent seizures and delirium tremens)
• Opiate withdrawal
• Short-term adjunct to anti-depressant (to prevent initial anxiety

The IM route has no advantage over the oral route. Diazepam is available as a rectal solution. Midazolam is widely used as a subcutaneous infusion in palliative care. Diazepam (as a non-irritant emulsion) and lorazepam are occasionally given IV for control of panic attacks.

(see individual drugs for full list)

• Respiratory depression
• Phobic or obsessional states
• Chronic psychosis
• Myasthenia gravis
• Severe hepatic insufficiency
• Sleep apnoea syndrome
• Pregnancy, labour and lactation

(see individual drugs for full list)

• Potentiated by CNS depressants, eg alcohol, anticonvulsants, opioids, antidepressants, antihistamines and muscle relaxants
• Plasma levels increased by cimetidine and rifampicin, (and other inhibitors of cytochrome P450)

• Side-effects are worse with higher dosages, longer-acting benzodiazepines, the elderly and with renal and/or hepatic impairment.
• Benzodiazepines may impair judgment and increase reaction time, and affect ability to drive or operate machinery.
• Evidence of an increased risk of hip fracture is conflicting.² However, these potential risks need to be considered when prescribing for older people.
• Tolerance develops to some of the unwanted actions (sedation, ataxia and memory impairment).
• Common side effects include:
  • Drowsiness, light-headedness "hang-over" effect
  • Hypotension
  • Impaired alertness
  • Psychomotor impairment
  • Falls (in elderly)
  • Confusion, ataxia (in elderly)
  • 'Floppy' baby or withdrawal reaction if mother taking benzodiazepines

See individual drugs for a full list.

Benzodiazepines are usually safe in overdose if taken alone, except when ingested with large quantities of alcohol or other CNS depressants. Coma, hypotension and respiratory depression occasionally occur.
Flumazenil (Anexate), a benzodiazepine antagonist, is available to treat severe CNS depression in benzodiazepine overdose. It has a short half life (~1 hour) and should not be used in mixed overdoses (particularly tricyclics and other drugs that reduce seizure threshold) or as a diagnostic test. It should only be used on the advice of an expert.¹

CSM in 1988 advised benzodiazepines should only be used to treat insomnia when it is severe, disabling, or subjecting the individual to extreme distress.³ A meta-analysis of short-term benzodiazepine use (1-7 days of treatment) for insomnia showed an increase in sleep by an average of 61.8 minutes compared with placebo, and time to fall asleep was decreased by an average of only 4.2 minutes. More patients reported adverse effects with benzodiazepines than placebo, though dropout rates were similar.⁴A meta-analysis of 24 randomised studies of benzodiazepines showed they do improve sleep in patients over 60, but the effect is small and adverse events (such as ataxia, memory impairment or falls) are twice as likely as enhanced quality of sleep.⁵ Cognitive behavioural therapy is as effective as drug therapy for insomnia in the elderly.⁶

Benzodiazepines can reduce the symptoms of anxiety, but should not be used for more than about 4 weeks because of the risk of dependence. Treatment should be limited to the lowest possible dose fore the shortest possible time.

is increased by long-term use, high doses, alcohol dependency and use without medical supervision. Dependence is particularly likely in patients with a history of alcohol or drug abuse and in patients with marked personality disorders.

Withdrawal symptoms are common if benzodiazepines have been taken for 6 months or longer. Symptoms can develop anytime 3 weeks after stopping (or within a few hours with short-acting ones). Withdrawal should be gradual because abrupt withdrawal may produce confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens.

• Reduce by one-eighth of the daily dose every 2 weeks, e.g. reduce diazepam dose in fortnightly steps of 2 or 2.5 mg.
• If withdrawal symptoms occur, maintain this dose until symptoms improve.
• Counselling may help and beta-blockers can be tried.
• Antidepressants should be used only for clinical depression or panic disorder.
• Avoid anti-psychotics (which may aggravate withdrawal symptoms).
• The following may continue for weeks or months after stopping benzodiazepines:
  • Insomnia
  • Anxiety
  • Nausea
  • Loss of appetite
  • Tremor
  • Perspiration
  • Tinnitus
  • Depression
  • Perceptual disturbances