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Hypnotic Drugs
Insomnia is a disturbance of normal sleep patterns commonly characterised by
difficulty in initiating sleep (sleep onset latency) and / or difficulty in maintaining sleep
(sleep maintenance). 1 The prevalence of insomnia has been estimated to be between
10 and 48% and has been reported to be higher in women, with increasing age and in
those with concurrent physical or mental health conditions. 2 NHS Clinical Knowledge
Summaries (CKS) recommend the early identification and management of any
psychiatric or medical comorbid disorder as essential as up to 80% of insomnia is
associated with a comorbidity. 3 For all people with insomnia, healthcare professionals
should first offer advice on good sleep hygiene and stimulus control: 3
Avoid caffeine, nicotine and alcohol within 6 hours of going to bed (alcohol may
encourage sleep onset but tends to fragment sleep)
Exercise regularly during the day but not within a few hours of bedtime
Avoid large meals before bedtime, although a light snack may be helpful
Get up at the same time each day regardless of the amount of sleep achieved
the previous night and avoid sleep in the day
Avoid using the bedroom for working or for watching television
Maintain a comfortable sleeping environment: not too hot, cold, noisy or bright
Avoid watching or checking the clock throughout the night
Try to relax before going to bed
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Trends in Prescribing of Hypnotics in General Practice in England (Chart 1)
3.0
2.5
Items (Millions)
2.0
1.5
1.0
0.5
0.0
Sep-10
Jun-10
Melatonin
Mar-10
Dec-09
Lormetazepam
Sep-09
Jun-09
Mar-09
Dec-08
Zolpidem
Sep-08
Jun-08
Nitrazepam
Mar-08
Dec-07
Sep-07
Zopiclone
Jun-07
Mar-07
Dec-06
Temazepam
Sep-06
Jun-06
Mar-06
Dec-05
Sep-05
Quarter to
Others
Trends in Spending on Hypnotics in General Practice in England (Chart 2)
12
10
NIC (£ Millions)
8
6
4
2
0
Sep-10
Jun-10
Melatonin
Mar-10
Dec-09
Sep-09
Lormetazepam
Jun-09
Mar-09
Dec-08
Zolpidem
Sep-08
Jun-08
Mar-08
Nitrazepam
Dec-07
Sep-07
Zopiclone
Jun-07
Mar-07
Dec-06
Temazepam
Sep-06
Jun-06
Mar-06
Dec-05
Sep-05
Quarter to
Others
Hypnotics used for the management of insomnia include; benzodiazepines, the
commonly called ‘Z-drugs’ - zaleplon, zolpidem and zopiclone which act on the
benzodiazepine receptor; and drugs acting on the melatonin receptor. The risks
associated with the long term use of hypnotic drugs have been well recognised for
many years but the overall prescribing is not decreasing (chart 1). In the quarter to
September 2010 the prescribing of hypnotics (BNF chapter 4.1.1) was 2.6 million
items, an increase of 5% in the last five years. In the same time frame the spending
has doubled to £10.9 million. Sedative drugs such as tricyclic antidepressants,
antihistamines, chloral hydrate, clomethiazole and barbiturates are not recommended
for the management of insomnia by CKS.
In 1988 the Committee on Safety of Medicines advised that benzodiazepine hypnotics
should be used only if the insomnia was severe, disabling or causing the patient
extreme distress. The lowest dose that controls symptoms should be used for a
maximum of four weeks and intermittently if possible. In addition a gradual tapering off
towards the end of the course of treatment in order to avoid rebound insomnia and
withdrawal effects is recommended. 4
In April 2004 the National Institute for Health and Clinical Excellence (NICE) provided
guidance on the use of zaleplon, zolpidem and zopiclone for the short-term
management of insomnia 1 and advised:
•
No compelling evidence of a clinically useful difference between the Z-drugs and
shorter acting benzodiazepines from the point of view of their effectiveness,
adverse effects, or potential for dependence or abuse
•
The drug with the lowest purchase cost should be prescribed
•
Switching from one of these hypnotics to another should only occur if a patient
experiences adverse effects considered to be directly related to a specific agent.
These are the only circumstances in which the drugs with the higher acquisition
cost are recommended
•
Patients who have not responded to one of these hypnotic drugs should not be
prescribed any of the others
NICE recommend that hypnotics should be prescribed for short periods of time only, in
strict accordance with their licensed indications, when insomnia is severe and
interfering with normal daily life and the usual non-pharmacological measures have
been considered. Chart 3 shows the quantity of nitrazepam, temazepam and Z-drugs
prescribed on FP10 prescriptions in primary care for the quarter to September 2010.
Although there has been a reduction in the percentage of prescriptions for quantities
of more than 28 tablets/capsules compared to the same quarter four years ago
(September 2006) there were still 32% of all prescriptions for nitrazepam for a quantity
of 29+ (compared to 39% four years ago), 21% of all prescriptions for temazepam
(compared to 27%) and 11% of all prescriptions for Z-drugs (compared to 13%). This
suggests that the duration of supply of prescribed hypnotics is commonly 4 weeks or
longer. A report from the NHS Information Centre assessed the variation in use of 26
medicines positively approved by NICE in 13 technology appraisals which included the
Z-drugs for the short term management of insomnia. 5 The report provides a
comparison of England and Strategic Health Authority predicted versus observed
uptake of medicines expressed as defined daily doses (DDD). The prescribing of Zdrugs, per expected patient by PCT in 2008, ranged from about 2 to 16 times (average
7.4) of the expected use of 28 DDDs (four weeks supply). The report suggested that
the reclassification of temazepam as a controlled drug may have led to increased
prescribing of the Z-drugs.
Quantities of Selected Hypnotics (Tabs/Caps) Prescribed in General Practice in England
(Quarter to September 2010) (Chart 3)
800,000
"Z" drugs
Temazepam
Nitrazepam
700,000
600,000
Items
500,000
400,000
300,000
200,000
100,000
0
> 84
78 to 84
71 to 77
64 to 70
57 to 63
50 to 56
43 to 49
36 to 42
29 to 35
22 to 28
15 to 21
8 to 14
1 to 7
Quantities on Prescriptions
In 2005 the results of a meta-analysis (24 RCTs, n =2,417) 6 looking at the potential
benefits and risks of hypnotics in people aged 60 years or more with primary insomnia
who took hypnotics for at least 5 consecutive nights concluded that these drugs confer
only a modest benefit in a small minority of people at the expense of a greater number
of side effects. Whilst there were limitations in this meta-analysis the numbers needed
to treat (NNT) and the numbers needed to harm (NNH) are represented pictorially as a
decision aid to assist health professionals in consultations explain the harms and
benefits of hypnotic treatment to patients and are available to download from the
patient decision aid rooms on the insomnia and mental health floor of the NPCi:
http://www.npci.org.uk/therapeutics/cns/insomnia/room_insomnia.php .
In addition leaflets for patients explaining the causes, symptoms and prevention of
insomnia can be found on the CKS website;
www.cks.nhs.uk/patient_information_leaflet/Insomnia
A further meta-analysis of RCTs in 2007 7 considered the efficacy and safety of drugs
for chronic insomnia in adults (benzodiazepines – 52 RCTs, Z-drugs – 48 RCTs and
antidepressants – 8 RCTs). Sleep onset latency was significantly decreased, but only
a small average improvement was achieved. When measured by polysomnography
the weighted mean difference was:
Benzodiazepines: - 10.0 minutes (95% CI -16.6 to -3.4), Z-drugs: - 12.8 minutes (95%
CI -16.9 to -8.8), Antidepressants: -7.0 minutes (95% CI -10.7 to -3.3)
When assessed by sleep diaries the weighted mean difference was:
Benzodiazepines: - 19.6 minutes (95% CI -23.9 to -15.3), Z-drugs: - 17.0 minutes
(95% CI -20.0 to -14.0), Antidepressants: -12.2 minutes (95% CI -22.3 to -2.2).
Melatonin is a hormone produced by the pineal gland that regulates circadian rhythms
and sleep. In 2008 a prolonged-release 2mg tablet (Circadin®) was licensed for the
short-term monotherapy treatment of primary insomnia in patients aged 55 years or
older. In 2008, a review by the National Prescribing Centre (NPC) of modified-release
melatonin for the short term treatment of primary insomnia, concluded that there was a
lack of evidence to demonstrate clinically significant benefits over prescription
hypnotics. 8 In the summer of 2010 the licensed recommended duration of treatment
of Circadin® was increased from three weeks to up to thirteen weeks. 9 In the last two
years prescribing of and spending on melatonin has more than doubled to 44,000
items (£3.4 million). Two years ago (quarter to September 2008) licensed melatonin
accounted for 5% of prescribing of all melatonin (1,000 items) and 1% of the cost
(£15,000). At present licensed melatonin (quarter to September 2010) accounts for
33% of prescribing (14,000 items) of all melatonin and 10% of the cost (£350,000).
The most commonly prescribed melatonin presentation is the generically written
licensed preparation, melatonin 2mg m/r tablets, at 8,800 items costing £210,000 with
the brand Circadin® at 5,400 items, (£140,000) with an average cost per prescription
of around £25. The second most commonly prescribed presentation is the unlicensed
melatonin 3mg capsules 6,500 items costing £611,000 and an average cost per
prescription of £94, followed by melatonin 2mg capsules 5,800 items costing £603,000
(average cost per prescription £104). Prescribing of the melatonin 5mg/5ml liquid
special is 4,400 items costing £708,000 (average cost per prescription of over £160).
Prescribing Data
(Reporting quarter = July-September 2010, Index quarter = July- September
2005)
Prescribing of Z-drugs (zaleplon, zolpidem and zopiclone) has increased by 33% to
1.5 million items whereas costs have fallen 16% to £2.5 million. Z-drugs account for
59% of prescribing of hypnotics (BNF 4.1.1) and 23% of the cost. Prescribing of
benzodiazepines (nitrazepam, temazepam, loprazolam, lormetazepam and
flurazepam) has fallen by 22% to 993,000 items whilst the cost has more than doubled
to £4.5 million. These drugs represent 39% of all prescribing of hypnotics and 41% of
the cost.
The most commonly prescribed hypnotic is zopiclone which has increased by 38%
over the last 5 years to 1.3 million items at a cost of £2.2 million (a fall of 11%).
Prescribing of temazepam has fallen by 18% to 700,000 items whilst costs have risen
169% to £2.7 million. Prescribing of nitrazepam fell by 25% to 257,000 with costs
falling by just 3% to £393,000. Zolpidem accounts for 185,000 items (an increase of
11%) and £321,000 (a 36% decrease). Prescribing of lormetazepam has fallen by
61% to 15,000 items whereas the cost has tripled to £936,000.
Cost for 7 Days (£)
Temazepam
1 x 20mg tab at night
0.55
Zopiclone
1 x 7.5mg tab at night
0.34
Nitrazepam
1 x 5mg tab at night
0.24
Zolpidem
1 x 10mg tab at night
0.36
Lormetazepam
1 x 1mg tab at night
12.43
Circadin®
1 x 2mg mr tab at night
3.59
Loprazolam
1 x 1mg tab at night
4.50
Zaleplon
1 x 10mg cap at night
1.88
0
3
6
9
12
Cost (£)
Prices based on Drug Tariff February 2011 and the NHS dictionary of medicines and
devices. Dose based on WHO DDDs where possible, otherwise BNF stated dose. The
WHO DDD is a unit of measurement based on the assumed average maintenance dose
in adults. It may not necessarily reflect the actual dose used.
15
1. NICE. Guidance on the use of zaleplon, zolpidem, and zopiclone for the shortterm management of insomnia. Technology Appraisal 77; April 2004
2. NPCi - http://www.npci.org.uk/therapeutics/cns/insomnia/room_insomnia.php
3. CKS. Insomnia. Clinical Knowledge Summaries http://cks.nhs.uk/insomnia#
4. Committee on Safety of Medicines. Current Problems. January 1988 No 21
5. NHS Information Centre. Use of NICE appraised medicines in the NHS in
England – experimental statistics. September 2009.
www.ic.nhs/pubs/niceappmed
6. Glass J, Lanctot KL, Herrmann et al. sedative hypnotics in older people with
insomnia: meta-analysis of risks and benefits. BMJ 2005; 331:1169-1175.
7. Buscemi N et al. The Efficacy and Safety of Drug Treatments for Chronic
Insomnia in Adults: A Meta-analysis of RCTs. J Gen Intern Med 2007; 22:
1335-50
8. National Prescribing Centre. Prolonged-release melatonin (Circadin®). NPCi
Rapid Review blog 137.
9. Circadin. Summary of Product Characteristics.
Summary
•
Identify and address any underlying cause of insomnia or associated
comorbidities
•
Offer advice on good sleep hygiene and stimulus control
•
Hypnotics should be prescribed for short periods of time in strict accordance
with their licensed indications, when insomnia is severe and interfering with
normal daily life
Prescribing and Spending on Hypnotic Drugs in England for Quarter to December 2010
ITEMS
NIC
693,614
Temazepam
£2,242,354
252,732
Nitrazepam
£323,925
Lormetazepam
14,016
£898,526
1,347,440
Zopiclone
£1,809,429
185,441
Zolpidem
Melatonin
£266,686
45,854
£3,532,048
Temazepam
Zopiclone
Nitrazepam
Melatonin
Quarter to December 2010
National
ITEMS/1000
NIC/1000
PUs
PUs
9.49
£30.61
18.39
£24.70
3.45
£4.42
0.62
£48.22