Hypnotic and anxiolytic drugs
The pharmacology of drugs with anxiolytic, sedative, and hypnotic effects overlaps significantly, with different doses of the same drug having effects ranging from sedation to loss of consciousness. So it can be difficult to ascribe just one function to each drug. The job of the prescriber is to identify the drug which offers the best therapeutic outcome for their patient.
Benzodiazepine class drugs are the most commonly used anxiolytics and hypnotics. They act selectively on gamma-aminobutyric acid-A (GABAA) receptors in the brain. Benzodiazepines enhance response to the inhibitory neurotransmitter GABA, by opening GABA-activated chloride channels, thereby rendering neurons resistant to excitation. Benzodiazepine family drugs are similar in pharmacological action but vary in potency and clinical efficacy in treatment of particular conditions. Benzodiazepines are used as sedatives, hypnotics, anxiolytics, anticonvulsants and muscle relaxants.
In clinical practice, benzodiazepines are indicated only for short-term relief (two to four weeks) of severe, disabling or distressing anxiety.
Note that:
- It is considered inappropriate to prescribe benzodiazepines for short-term ‘mild’ anxiety.
- Benzodiazepine use to treat insomnia should only be considered when the insomnia is severe, disabling, or is causing extreme distress.
Hypnotics prescribed for insomnia
Benzodiazepine hypnotics
Benzodiazepines used as hypnotics include the long-acting drugs nitrazepam and flurazepam. However, these may cause residual effects the following day and repeated doses are cumulative.
Loprazolam, lormetazepam, and temazepam are shorter acting drugs with little or no hangover effect. Unfortunately, the short-acting benzodiazepines are more commonly associated with withdrawal symptoms. Short-acting hypnotics are preferable in patients with sleep onset insomnia, when hangover sedation is undesirable.
In patients whose insomnia is associated with daytime anxiety, use of a long-acting benzodiazepine anxiolytic such as diazepam given as a single dose at night may effectively treat both symptoms.
Note that:
- Chronic insomnia rarely benefits from hypnotic administration.
- Routine prescribing is undesirable, and use should be reserved for short-term acutely distressed patients.
- Prescribing of hypnotics to children, except for use in rare patients suffering night terrors and somnambulism, is not justified.
- Benzodiazepines and the Z–drugs (see below) should be avoided in the elderly, because they are at greater risk of becoming ataxic and confused, potentially leading to increased falls and injury.
Non-benzodiazepine hypnotics
Z-drugs: zaleplon (very short-acting), zolpidem tartrate and zopiclone (both short-acting drugs) are non-benzodiazepine hypnotics, which bind to a different site on GABAA receptors compared to the benzodiazepines, although they produce the same receptor activation. Dependence has been reported in a small number of patients. In the UK, NICE guidance recommends that Z-drugs use be restricted to the short-term management of severe insomnia that interferes with normal daily life, and should be prescribed for the shortest period of time possible. These drugs are not licensed for long-term use.
Buspirone hydrochloride is thought to act at serotonin 5-HT1A receptors. Response to treatment may take up to 2 weeks. The dependence and abuse potential of buspirone hydrochloride is low. Although it is licensed only for short-term use, specialists occasionally use it for several months.
The use of chloral hydrate and derivatives as hypnotics is now very limited, mainly due to the lack of evidence supporting clinical efficacy.
Clomethiazole may be a useful hypnotic for elderly patients because of its freedom from hangover effects, but as with all hypnotics, routine administration is undesirable and dependence occurs.
Some antihistamines such as promethazine hydrochloride and diphenhydramine are available over-the-counter for managing occasional insomnia.
The pineal hormone melatonin is licensed for the short-term treatment of insomnia in adults over 55 years.
Barbiturates
Barbiturates are a group of drugs derived from barbituric acid. They suppress central nervous system activity and are effective anxiolytics, antiepileptics, sedatives and hypnotics. Barbiturates act as positive allosteric modulators of GABAA receptors to enhance the action of neuroinhibitory GABA. They are classified according to their duration of action; short-, medium- or long-acting. As they have the tendency to cause tolerance and psychological and physical dependence, they are now rarely used as anxiolytics. Barbiturates are currently used principally for their hypnotic actions (in anaesthesia) and in rare cases as antiepileptics. The use of barbiturates as sedatives has been superceded by safer and more effective benzodiazepine drugs in routine clinical practice.
The intermediate-acting barbiturates amobarbital sodium, butabarbital (butobarbital), and secobarbital should only be used for the treatment of severe intractable insomnia in patients already taking barbiturates. Their use should be avoided in the elderly.
The long-acting barbiturate phenobarbital is still sometimes of value in epilepsy but its use as a sedative is unjustified.
The very short-acting barbiturate thiopental sodium is used in anaesthesia.
Older non-benzodiazepine drugs such as meprobamate and the barbiturates are not recommended as hypnotics as they have more side-effects and interactions (especially with alcohol) than benzodiazepines and are much more dangerous in overdose.