A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

ANXIETY 109
Key points
• Insomnia and anxiety are common. Most patients do not
require drug therapy.
• Benzodiazepines are indicated for the short-term relief
(2–4 weeks only) of anxiety that is severe, disabling or
subjecting the individual to unacceptable levels of
distress.
• The use of benzodiazepines to treat short-term ‘mild’
anxiety is inappropriate and unsuitable.
• Benzodiazepines should be used to treat insomnia only
when it is severe, disabling or subjecting the individual
to extreme distress.
• There is no convincing evidence to support the use of
non-benzodiazepine hypnotics and anxiolytics over
benzodiazepines.
FLUMAZENIL
Flumazenil is a benzodiazepine antagonist. It can be used to
reverse benzodiazepine sedation. It is short acting, so sedation
may return. It can cause nausea, flushing, anxiety and fits, so
is not routinely used in benzodiazepine overdose which seldom
causes severe adverse outcome.
OTHERS
• Barbiturates are little used and dangerous in overdose.
• Clomethiazole – causes conjunctival, nasal and gastric
irritation. Useful as a hypnotic in the elderly because its
short action reduces the risk of severe hangover, ataxia and
confusion the next day. It is effective in acute withdrawal
syndrome in alcoholics, but its use should be carefully
supervised and treatment limited to a maximum of nine
days. It can be given intravenously to terminate status
epilepticus. It can also be used as a sedative during
surgery under local anaesthesia.
• Zopiclone, zolpidem and zaleplon – are nonbenzodiazepine
hypnotics which enhance GABA activity
by binding to the GABA–chloride channel complex at the
benzodiazepine-binding site. Although they lack structural
features of benzodiazepines, they also act by potentiating
GABA. Their addictive properties are probably similar to
benzodiazepines.
• Buspirone – is a 5HT 1A receptor partial agonist. Its use has
not been associated with addiction or abuse, but may be a
less potent anxiolytic than the benzodiazepines. Its
therapeutic effects take much longer to develop (two to
three weeks). It has mild antidepressant properties.
• Cloral and derivatives – formerly often used in paediatric
practice. Cloral shares properties with alcohol and volatile
anaesthetics. Cloral derivatives have no advantages over
benzodiazepines, and are more likely to cause rashes and
gastric irritation.
• Sedative antihistamines, e.g. promethazine, are of
doubtful benefit, and may be associated with prolonged
drowsiness, psychomotor impairment and antimuscarinic
effects.
BENZODIAZEPINES VS. NEWER DRUGS
Since the advent of the newer non-benzodiazepine hypnotics
(zopiclone, zolpidem and zaleplon), there has been much discussion
and a considerable amount of confusion, as to which
type of drug should be preferred. The National Institute for
Health and Clinical Excellence (NICE) has given guidance
based on evidence and experience. In essence,
1. When hypnotic drug therapy is appropriate for severe
insomnia, hypnotics should be prescribed for short
periods only.
2. There is no compelling evidence to distinguish between
zaleplon, zolpidem, zopiclone or the shorter-acting
benzodiazepine hypnotics. It is reasonable to prescribe the
drug whose cost is lowest, other things being equal. (At
present, this means that benzodiazepines are preferred.)
3. Switching from one hypnotic to another should only be
done if a patient experiences an idiosyncratic adverse effect.
4. Patients who have not benefited from one of these
hypnotic drugs should not be prescribed any of the others.
Case history
A 67-year-old widow attended the Accident and Emergency
Department complaining of left-sided chest pain, palpitations,
breathlessness and dizziness. Relevant past medical history
included generalized anxiety disorder following the
death of her husband three years earlier. She had been prescribed
lorazepam, but had stopped it three weeks previously
because she had read in a magazine that it was addictive.
When her anxiety symptoms returned she attended her GP,
who prescribed buspirone, which she had started the day
before admission.
Examination revealed no abnormality other than a regular
tachycardia of 110 beats/minute, dilated pupils and sweating
hands. Routine investigations, including ECG and chest
x-ray, were unremarkable.
Question 1
Assuming a panic attack is the diagnosis, what is a potential
precipitant
Question 2
Give two potential reasons for the tachycardia.
Answer 1
Benzodiazepine withdrawal.
Answer 2
1. Buspirone (note that buspirone, although anxiolytic, is
not helpful in benzodiazepine withdrawal and may
also cause tachycardia).
2. Anxiety.
3. Benzodiazepine withdrawal.
FURTHER READING
Fricchione G. Clinical practice. Generalized anxiety disorder. New
England Journal of Medicine 2004; 351: 675–82.
National Institute for Clinical Excellence. 2004: Guidance on the use of
zaleplon, zolpidem and zopiclone for the short-term management
of insomnia. www.nice.org.uk/TA077guidance, 2004.
Sateia MJ, Nowell PD. Insomnia. Lancet 2004; 364: 1959–73.
Stevens JC, Pollack MH. Benzodiazepines in clinical practice: consideration
of their long-term use and alternative agents. Journal of
Clinical Psychiatry 2005; 66 (Suppl. 2), 21–7.