Transcript 02-20121007+Revised+02+安眠.鎮靜藥物之安全使用+桃園醫師公會

安眠、鎮靜藥物之安全使用
林為文醫師
心 寧 診 所
慈濟醫院台北分院身心醫學科
國防醫學院醫學系精神學科
心寧診所 http://peacefulmindclinic.com/
部落格 http://wwlin-psy.kingnet.com.tw/index.html
E-mail: [email protected]
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1
Sedative & Hypnotics
Sedative : Drugs that clam the patient and
reduce anxiety without inducing normal sleep.
Hypnotic : Drugs that initiate and maintain the
normal sleep.
簡史
•
•
•
•
Bromide: 20世紀初上市; 1930s淘汰
Barbiturate: 1930s~1950s
Meprobamate: 1955 in USA
Benzodiazepine: 1957 Sternbach:
chlordiazepoxide, 1961上市; 合成:3000s;
通過動物或人體試驗: 120s;上市: 40s
Sedative-Hypnotics
•
•
•
•
Benzodiazepines
Benzo-like
Barbiturates
Miscellaneous
SEDATIVE-HYPNOTIC DRUGS
SEDATIVE-HYPNOTICS
Benzodiazepines
Short
action
Intermediate
action
Long
action
Barbiturates
Miscellaneous agents
Ultra
action
Short
action
Long
action
Buspirone
Chloral hydrate
Zaleplon
Zolpidem
Zopliclone
Eszopliclone
Classification of Hypnotic Drugs
1.Benzodiazepines ( BDZ )
2. Barbiturates
3. Miscellaneous ( non BDZ, non barbiturate drugs).

Zolpidem

Zaleplon

Zolpiclone

Eszopiclone
BENZODIAZEPINES (BZD)
Benzodiazepines Mechanism of Action
• Binds to the benzodiazepine receptors on
GABA neuron
• GABA is the major inhibitory neurotransmitter
in the CNS
• Benzodiazepines relieve anxiety through
enhancement of the inhibitory activity of
GABA
• No antipsycotic, No analgesic, Not affect ANS
9
Mechanism of Action
Bzs binding to BZ receptors (BZ1 or BZ2) to facilitate
GABA-induced chloride channels hyperpolarization =
GABA-mediated inhibitory neurotransmission.
Bzs  facilitation of GABA action on GABA receptors
 chloride channels opening 
chloride influx to the cell 
cell membrane hyperpolarization 
inhibition of propagation of action potential 
inhibitory effect on different sites of the brain especially
motor cortex, and limbic system.
Diagram of mechanism of action of the natural neurotransmitter
GABA (gamma-aminobutyric acid) and benzodiazepines on nerve
cells (neurons) in the brain
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Kinetics
• Most well absorbed PO
• Metabolism
– Most have active metabolites
– Duration is wildly different among agents
– Example
• Flurazepam: 2-3 hour half-life; metabolite 50 hours
• Safer and lower abuse potential that other CNS
depressants (barbiturates)
• Mechanism
– Potentiate GABA (CNS neurotransmitter)
– Bind to GABA-chloride gate receptors and
enhance the natural action of GABA
– Finite action
• All are controlled substances
• Effects
– CNS
•
•
•
•
Reduce anxiety
Promote sleep
Muscle relaxation
Anterograde amnesia
– CV: PO none; IV hypotension, cardiac arrest
– Resp: weak depressants alone
According to Duration of Action :
- Short acting: (3-5 hours).
Triazolam
- Intermediate: (6-24 hours).
Alprazolam
Lorazepam
Estazolam
Oxazepam
Temazepam
(ALEOT)
Long acting: ( 24-72 hours):
Chlorazepate
Diazepam
Quazepam
Nitrazepam
Chlordiazepoxide
Flurazepam.
Prazepam
According to uses
Sedative (Anxiolytics)
Alprazolam
Diazepam
Chlordiazepoxide
Prazepam
Hypnotics
Triazolam
Lorazepam Estazolam Temazepam
Flurazepam Nitrazepam Quazepam
Preanesthetics
Diazepam
- Midazolam
Clinical Uses
•
•
•
•
•
•
•
Anxiety
Insomnia
Seizure
Muscle Spasm
Alcohol withdrawal (DT prevention)
Panic Disorder
Surgery
– Induction of anesthesia
– Conscious sedation
THERAPEUTIC ACTIONS OF
BENZODIAZEPINES (IN SHORT-TERM USE)
Action
Clinical Use
Anxiolytic - relief of anxiety
- Anxiety and panic disorders,
phobias
Hypnotic - promotion of sleep
- Insomnia
Myorelaxant - muscle relaxation
- Muscle spasms, spastic disorders
Anticonvulsant - stop fits,
convulsions
- Fits due to drug poisoning, some
forms of epilepsy
Amnesia - impair short-term
memory
- Premedication for operations,
sedation for minor surgical
procedures
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Half-life (hrs)1
[active metabolite]
Market Aim2
Approximately Equivalent
Oral dosages (mg)3
Alprazolam (Xanax)
6-12
a
0.5
Bromazepam (Lexotan, Lexomil)
10-20
a
5-6
5-30 [36-200]
a
25
Clobazam (Frisium)
12-60
a,e
20
Clonazepam (Klonopin, Rivotril)
18-50
a,e
0.5
[36-200]
a
15
Diazepam (Valium)
20-100 [36-200]
a
10
Estazolam (ProSom)
10-24
h
1-2
18-26 [36-200]
h
1
Flurazepam (Dalmane)
[40-250]
h
15-30
Halazepam (Paxipam)
[30-100]
a
20
30-100 [36-200]
a
15-30
Loprazolam (Dormonoct)
6-12
h
1-2
Lorazepam (Ativan)
10-20
a
1
Benzodiazepines5
Chlordiazepoxide (Librium)
Clorazepate (Tranxene)
Flunitrazepam (Rohypnol)
Ketazolam (Anxon)
anxiolytics (a), hypnotics (h) or anticonvulsants (e).
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Half-life (hrs)1
[active metabolite]
Market
Aim2
Approximately Equivalent
Oral dosages (mg)3
Lormetazepam (Noctamid)
10-12
h
1-2
Medazepam (Nobrium)
36-200
a
10
Nitrazepam (Mogadon)
15-38
h
10
Nordazepam (Nordaz, Calmday)
36-200
a
10
4-15
a
20
[36-200]
a
10-20
25-100
h
20
8-22
h
20
2
h
0.5
Zaleplon (Sonata)
2
h
20
Zolpidem (Ambien, Stilnoct)
2
h
20
5-6
h
15
6 (9 in elderly)
h
3
Benzodiazepines5
Oxazepam (Serax, Serenid,
Serepax)
Prazepam (Centrax)
Quazepam (Doral)
Temazepam (Restoril, Normison,
Euhypnos)
Triazolam (Halcion)
Non-benzodiazepines with
similar effects4,5
Zopiclone (Zimovane, Imovane)
Eszopiclone (Lunesta)
anxiolytics (a), hypnotics (h) or anticonvulsants (e).
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Benzodiazepines-Indications
•
•
•
•
•
•
Generalized Anxiety Disorder
Panic Disorder (alprazolam)
Insomnia
Schizophrenia
Muscular spasms (diazepam)
Depression
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• Seizure Disorders, epilepsy
(clonazepam , diazepam)
• Delirium
• Alcohol Withdrawal
• Conscious Sedation
insomnia (flurazepam long
acting, temazepam
intermediate, triazolam
short)
Benzodiazepines-Anxiolytics
•
•
•
•
•
•
•
•
chlordiazepoxide (Librium®)
diazepam (Valium®)
clonazepam (Klonopin®)
clorazepate (Tranxene®)
lorazepam (Ativan®)
oxazepam (Serax®)
alprazolam (Xanax®)
Triazolam
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Adverse Effects
• CNS: drowsy, lightheaded, concentration,
MVA (motor vehicle accident)
• Amnesia
• Paradoxical effects
• Resp depression
• Abuse
• Don’t use in pregnant women
ADVERSE EFFECTS OF
BENZODIAZEPINES
•
•
•
•
•
•
•
Oversedation
Drug interactions
Memory impairment
Paradoxical stimulant effects
Depression, emotional blunting.
Adverse effects in the elderly
Adverse effects in pregnancy
ADVERSE EFFECTS OF
BENZODIAZEPINES
•
•
•
•
•
•
Tolerance.
Dependence
Therapeutic dose dependence
Prescribed high dose dependence
Recreational benzodiazepine abuse
Socioeconomic costs of long-term
benzodiazepine use.
Oversedation
• a dose-related extension of the sedative/hypnotic effects
• drowsiness, poor concentration, incoordination, muscle
weakness, dizziness and mental confusion
• more marked in the elderly and may contribute to falls
and fractures
• a significant association between the use of
benzodiazepines and the risk of serious traffic accidents
• should be warned of the risks of driving and of operating
machinery.
Drug interactions
• additive effects with other drugs with
sedative actions
– other hypnotics,
– some antidepressants
– major tranquillisers or neuroleptics
– anticonvulsants
– sedative antihistamines
– alcohol
• may add to the risk of fatality
Memory impairment
• Acquisition of new information is deficient
– lack of concentration and attention
• a specific deficit in "episodic" memory
– the remembering of recent events, the circumstances
in which they occurred, and their sequence in time.
– other memory functions (memory for words, ability to
remember a telephone number for a few seconds,
and recall of long-term memories) are not impaired
• may be responsible for uncharacteristic
behaviors such as shop-lifting.
Paradoxical stimulant effects
• anxiety, insomnia, nightmares, hallucinations at the
onset of sleep, irritability, hyperactive or aggressive
behavior, and exacerbation of seizures in epileptics.
• Attacks of rage and violent behavior, including assault
(and even homicide),
• Less dramatic increases in irritability and
argumentativeness are much more common and are
frequently remarked upon by patients or by their families
• most frequent in anxious and aggressive individuals,
children, and the elderly
• "baby-battering", wife-beating and "grandma-bashing"
Depression, emotional blunting
• Long-term benzodiazepine users are often
depressed
• Benzodiazepines may both cause and
aggravate depression, possibly by reducing the
brain's output of neurotransmitters such as
serotonin and norepinephrine.
• Sometimes the drugs seem to precipitate
suicidal tendencies in mixed anxiety and
depression patients
Depression, emotional blunting
• In 1988 the Committee on Safety of Medicines in
the UK : "benzodiazepines should not be used
alone to treat depression or anxiety associated
with depression. Suicide may be precipitated in
such patients".
• "Emotional anaesthesia", the inability to feel
pleasure or pain
• Chronic benzodiazepine use can be a cause of
domestic disharmony and even marriage breakup.
Adverse effects in the elderly
• more sensitive
• confusion, night wandering, amnesia, ataxia (loss of
balance), hangover effects and "pseudodementia"
• dosage should be half that recommended for adults
• should be short-term (2 weeks) only
• without active metabolites (e.g. oxazepam [Serax],
temazepam [Restoril]) are tolerated better than those
with slowly eliminated metabolites (e.g. chlordiazepoxide
[Librium], nitrazepam [Mogadon]).
Adverse effects in pregnancy
• cross the placenta
• can cause neonatal complications
• "floppy infant syndrome" of lax muscles, oversedation,
and failure to suckle.
• Withdrawal symptoms may develop after about two
weeks with hyperexcitability, high-pitched crying and
feeding difficulties.
• little risk of causing major congenital malformations
• chronic maternal use may impair fetal intrauterine growth
and retard brain development
• such children in later life may be prone to attention
deficit disorder, hyperactivity, learning difficulties, and a
spectrum of autistic disorders
Tolerance
• Tolerance to the hypnotic effects develops rapidly and
sleep recordings have shown that sleep patterns,
including deep sleep (slow wave sleep) and dreaming
(which are initially suppressed by benzodiazepines),
return to pre-treatment levels after a few weeks of
regular benzodiazepine use.
• Tolerance to the anxiolytic effects develops more slowly
• long-term benzodiazepine use may even aggravate
anxiety disorders
Tolerance
• Tolerance to the anticonvulsant effects of
benzodiazepines makes them generally unsuitable for
long-term control of epilepsy
• complete tolerance to the effects on memory and
cognition does not seem to occur; these functions
remain impaired in chronic users, recovering slowly,
though sometimes incompletely, after withdrawal.
• The development of tolerance is one of the reasons
people become dependent on benzodiazepines,
Dependence
• Benzodiazepines are potentially addictive
drugs: psychological and physical
dependence can develop within a few
weeks or months of regular or repeated
use
Therapeutic dose dependence
• They have taken benzodiazepines in prescribed
"therapeutic" (usually low) doses for months or years
• They have gradually become to "need" benzodiazepines
to carry out normal, day-to-day activities
• They have continued to take benzodiazepines although
the original indication for prescription has disappeared
• They have difficulty in stopping the drug, or reducing
dosage, because of withdrawal symptoms
• If on short-acting benzodiazepines they develop anxiety
symptoms between doses, or get craving for the next
dose.
Therapeutic dose dependence
• They contact their doctor regularly to obtain repeat
prescriptions
• They become anxious if the next prescription is not readily
available; they may carry their tablets around with them
and may take an extra dose before an anticipated
stressful event or a night in a strange bed.
• They may have increased the dosage since the original
prescription.
• They may have anxiety symptoms, panics, agoraphobia,
insomnia, depression and increasing physical symptoms
despite continuing to take benzodiazepines.
Therapeutic dose dependence
• the US nearly 11 per cent of a large population surveyed
in 1990 reported some benzodiazepine use the previous
year.
• About 2 per cent of the adult population of the US (around
4 million people) appear to have used prescribed
benzodiazepine hypnotics or tranquillisers regularly for 5
to 10 years or more.
• Similar figures apply in the UK, over most of Europe and
in some Asian countries
• many studies have shown that 50-100 per cent of longterm users have difficulty in stopping benzodiazepines
because of withdrawal symptoms
Prescribed high dose
dependence
• A minority of patients who start on prescribed
benzodiazepines begin to "require" larger and larger
doses.
• At first they may persuade their doctors to escalate the
size of prescriptions, but on reaching the prescriber's
limits, may contact several doctors or hospital
departments to obtain further supplies which they selfprescribe.
Prescribed high dose
dependence
• Sometimes this group combines benzodiazepine misuse
with excessive alcohol consumption.
• Patients in this group tend to be highly anxious, depressed
and may have personality difficulties.
• They may have a history of other sedative or alcohol
misuse.
• They do not typically use illicit drugs but may obtain
"street" benzodiazepines if other sources fail.
Recreational benzodiazepine
abuse
• A large proportion (30-90 per cent) of polydrug abusers
world-wide also use benzodiazepines
• Benzodiazepines are used in this context to increase the
"kick" obtained from illicit drugs, particularly opiates, and to
alleviate the withdrawal symptoms of other drugs of abuse
(opiates, barbiturates, cocaine, amphetamines and
alcohol).
Recreational benzodiazepine
abuse
• The present population of recreational users may be
relatively small, perhaps one tenth of that of long-term
prescribed therapeutic dose users, but probably amounts
to some hundreds of thousands in the US and Western
Europe, and appears to be increasing.
Socioeconomic costs of longterm benzodiazepine use
• Increased risk of accidents - traffic, home, work.
• Increased risk of fatality from overdose if combined with
other drugs.
• Increased risk of attempted suicide, especially in
depression.
• Increased risk of aggressive behaviour and assault.
• Increased risk of shoplifting and other antisocial acts.
• Contributions to marital/domestic disharmony and
breakdown due to emotional and cognitive impairment.
Socioeconomic costs of longterm benzodiazepine use
• Contributions to job loss, unemployment, loss of work
through illness.
• Cost of hospital investigations/consultations/admissions.
• Adverse effects in pregnancy and in the new-born.
• Dependence and abuse potential (therapeutic and
recreational).
• Costs of drug prescriptions.
• Costs of litigation.
Effects of Benzodiazepines on Sleep
• Benzodiazepines in general
–
–
–
–
hasten sleep onset,
decrease nocturnal awakenings,
increase total sleeping time and
often impart a sense of deep, refreshing sleep.
• However, they alter the normal sleep pattern:
– Stage 2 (light sleep) is prolonged and mainly accounts for the
increased sleeping time,
– while the duration of slow wave sleep (SWS) and rapid eye
movement sleep (REMS) may be considerably reduced.
– The onset of the first REMS episode is delayed and dreaming is
diminished
Effects of Benzodiazepines on Sleep
• The suppression of REMS may initially be helpful in
decreasing nightmares, but may also be an important
factor in determining rebound insomnia in drug
withdrawal
• The increase in total sleeping time appears to be greatest
in patients who complain of insomnia and in those with
short baseline sleep duration
Guidelines for the Rational
Use of Benzodiazepines
When and What to Use
General Indications for Drug
Treatment of Insomnia
• An international conference (National Institute of Mental
Health Consensus Conference) on drugs and insomnia
made reasonable general recommendations for
appropriate use of hypnotic drugs, based on the cause
and duration of insomnia
• For transient insomnia caused by disruption of circadian
rhythms such as in overnight travel, rapid transit over
time zones, alteration of shift work or temporary
admission to hospital, an hypnotic drug with a short or
moderate duration of action and few residual effects
would be appropriate to use on 1 or 2 occasions.
General Indications for Drug
Treatment of Insomnia
• For short term insomnia resulting from temporary
environmental stress, hypnotics may occasionally be
indicated, but should be prescribed in low dosages for 1
or 2 weeks only, or intermittently.
• Chronic insomnia, which is usually secondary to other
conditions (physical, psychiatric or psychological),
presents a much greater problem. In selected cases an
hypnotic may be helpful, but it should be used in minimal
effective dosage, intermittently, or in short courses.
Type of insomnia
Dosage and administration
General cases
Transient insomnia (e.g.
disruption of circadian rhythm)
2017/4/5
1-2 nights only. Minimal dosage
(usually not more than
diazepam 2-5mg or equivalent)
53
Type of insomnia
Dosage and administration
Short term insomnia (e.g.
temporary environmental
stress)
Not for more than 2 weeks.
Intermittent if possible (1 night
in 2 or 3 nights). Minimal
effective dosage (start with
small dose; increase if needed,
usually not more than diazepam
10mg or equivalent.
Chronic insomnia (e.g.
secondary to physical,
psychological or psychiatric
causes)
Treat primary cause first.
Intermittent treatment if
possible. Not more than 2 weeks
(course may be repeated after
an interval). Minimal effective
dosage (as above).
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Type of insomnia
Dosage and administration
Special cases
Elderly patients[a]
Use half adult doses
Children
Generally contraindicated, but
single dose may be effective.
Pregnancy and lactation
Avoid regular use in pregnancy,
occasional use safe during
lactation.
Disease states
Avoid in chronic respiratory
disease. May occasionally be
indicated in other disease states is
if insomnia distressing.
Benzodiazepine dependent
patients[a]
Gradual withdrawal possible and
may improve sleep but
withdrawal should not be forced.
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Hypnotics for insomnia
CSM, Curr Problems Pharmacovigilance January 1988, No. 21
SPCs for zopiclone, zolpidem, zaleplon accessed from emc.medicines.org.uk, July 2008
•
Benzodiazepines should be used only if insomnia is severe, disabling or
subjecting the patient to extreme distress
– Use lowest dose, for maximum of 4 weeks
– Use intermittently, if possible
– Taper off gradually
•
Zopiclone, Zolpidem
– Short–term treatment of insomnia…in situations where the insomnia is
debilitating or is causing severe distress for the patient
– Long–term continuous use is not recommended
– Treatment duration: a single course of treatment should not continue
for longer than 4 weeks including any tapering off
•
Zaleplon
– Treatment duration: a single course of treatment should not continue
for longer than 2 weeks.
Benzo-like
• Unrelated to Benzo chemical structure, but
upregulate GABA in a similar manner
• Schedule IV drugs
– Zolpidem (Ambien)
• Middle of the night confusion
– Zaleplon (Sonata)
• Better for falling asleep, not staying asleep
Zolpidem (Ambien)
 imidazopyridine derivative.
acts on benzodiazepine receptors (BZ 1) &
facilitate GABA mediated neuronal inhibition.
 Its action is antagonized by flumazenil.
 rapidly absorbed from GIT and metabolized to
inactive metabolites via liver CYT P450.
 Short duration of action ( 2- 4 h).
 Only hypnotic effect
 Its efficacy is similar to benzodiazepines.
 Minor effect on sleep pattern, but high
doses suppress REM.
 Respiratory depression occur at high doses in
combination with other CNS depressant as
ethanol.
 has no muscle relaxant effect.
 has no anticonvulsant effect.
 Minimal psychomotor dysfunction
 Minimal tolerance & dependence.
 Minimal rebound insomnia.
 Uses
1. a hypnotic drug for short term treatment
of insomnia
2. Dose should be reduced in hepatic or
old patients.
Adverse Effects
– GIT upset
– Drowsiness
– Dizziness
Drug interactions
– Rifampicin (decreases half life)
– Cimetidine (increases half life)
Zaleplon
 Binds to BZs receptors and facilitate
GABA actions.
Zaleplon





Rapid absorption
rapid onset of action
Short duration of action (1 hr)
Metabolized by liver microsomal enzymes
metabolism is inhibited by cimetidine.




Only hypnotic effect
decreases sleep latency
Little effect on sleep pattern
Potentiates action of other CNS depressants
(alcohol).
 Dose reduction as before.
 Used as hypnotic drug
 Advantages
Less impairment of pyschomotor performance than
BZs or zolpidem.
NICE guidance: newer hypnotics (Z-drugs)
NICE TA 77, April 2004
• 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
costs are recommended
• Patients who have not responded to one of these hypnotic drugs
should not be prescribed any of the others.
• zaleplon、zolpidem及zopiclone成分藥品（98/1/1
、98/5/1）
• 1. 使用安眠藥物，病歷應詳載病人發生睡眠障礙
的情形，並作適當的評估和診斷，探討可能的原
因，並提供衛教建立良好睡眠習慣。
• 2. 非精神科醫師若需開立本類藥品，每日不宜超
過一顆，連續治療期間不宜超過6個月。若因病情
需長期使用，病歷應載明原因，必要時轉精神科
專科醫師評估其繼續使用的適當性。
• 3. 精神科專科醫師應針對必須連續使用本藥的個
案，提出合理的精神科診斷，並在病歷上詳細記
錄。
• zaleplon、zolpidem及zopiclone成分藥品（98/1/1
、98/5/1）
• 4. 依一般使用指引不建議各種安眠藥併用，應依
睡眠障礙型態處方安眠藥，若需不同半衰期之藥
物併用應有明確之睡眠障礙型態描述紀錄，且應
在合理劑量範圍內。
• 5. 對於首次就診尚未建立穩定醫病關係之病患，
限處方7日內安眠藥管制藥品。
• 6. zaleplon成分藥品限65歲以下使用。用於治療
難以入睡之失眠病人，僅適用於嚴重，病人功能
障礙或遭受極度壓力之失眠症患者。（98/1/1）
• 文獻顯示具有嚴謹實驗設計，旨在探討安眠用藥
之療效及安全性之臨床試驗，執行期間多未超過
五週，因此目前並無任何安眠藥物核准可用連續
使用超過數週。
• 以使用最普遍且歷史悠久的Benzodiazepine類安
眠藥為例，依照國內外所訂定的標準，皆建議此
類安眠藥不宜長期使用，且應以四至六週為限。
• 至於新一代Non-benzodiazepine 類安眠藥如
Zolpidem，初步研究雖指出當使用達六個月，仍
能有效維持其安眠療效，且未產生耐藥性或嚴重
副作用，但此仍缺乏更為嚴謹之研究來確認
• 各類安眠藥的長期使用，目前均缺乏安全性及療效之實證
研究依據。因此須同時符合以下條件，否則安眠藥的長期
使用是不被鼓勵的：
• 1.失眠症狀在用藥後依然持續；
• 2. 其他非藥物療法已確實執行但仍無法奏效；
• 3. 安眠藥用於病人的療效及安全性定期受到醫師適當的評
估；
• 4. 教育服藥病人充分認知「長期使用安眠藥之療效及安全
性，目前均
• 缺乏足夠的實證依據」之事實；
• 5. 處方者有和病人討論藥物以外治療失眠之可能。即使病
人已接受安眠藥處方，但每次門診時，醫師或相關醫療人
員仍須提醒病人維持良好的睡眠衛生習慣。
Insomnia
NICE TA 77, April 2004; CKS (Prodigy), July 2006; DTB 2004
• Insomnia: difficulty initiating sleep and/or difficulty maintaining sleep
• Prevalence: estimates vary from 10% - 48%
– Higher in women, with increasing age and in those with concurrent
physical or mental health conditions
• Primary insomnia:
– Unknown origin or arising from sleep environment, irregular sleep
routine, or negative conditioning to sleep
• Secondary insomnia:
– Underlying psychological or physical condition, prescribed/OTC
medicines, caffeine or substance misuse
• Important to avoid unrealistic sleep expectations
• For all people with insomnia, offer advice on good sleep hygiene
and stimulus control
– Also consider exercise, relaxation therapies, etc.
Non-drug approaches
CKS (Prodigy), July 2006
• Sleep hygiene:
– Avoid caffeine and nicotine 6 hours before bed time
– Avoid alcohol around bedtime (alcohol may encourage sleep onset but tends
to fragment sleep)
– Avoid heavy meals before sleep (although a light meal may be helpful)
– Avoid exercise within 4 hours of bedtime (although exercise earlier in the day
is beneficial)
– Minimise noise, light and excessive heat during the sleep period.
• Stimulus control measures:
– Only go to bed when sleepy
– Only use the bed for sleeping and sex
– Leave the bedroom if not asleep within 15–20 minutes and go back to bed
only when feeling sleepy again
– Get up at a fixed time in the morning, regardless of the amount of sleep
achieved the previous night
– Avoid sleep during the day.
What would happen to 13 people who take
sleeping tablets for more than a week?
Glass J, et al. BMJ 2005;331:1169

The hypnotic makes no difference
to what happens to these 12
people. Their sleep improves, or
doesn’t improve, just as if they had
taken placebo.
This person finds his/her
sleep improves, who would
not have done had he or she
taken the placebo.

The hypnotic makes no difference
to what happens to these 11
people. They have adverse events,
or don’t have adverse events, just
as if they had taken placebo.
These 2 people have an
adverse event, who would
not have done had they
taken the placebo.
Road traffic accidents and benzodiazepines
Bandolier 1998;57:5 (Hemmelgarn B, et al. JAMA 1997;278:27-31)
Risks of RTA in Quebec
1990-93
Short half-life benzos:
RR 0.96 (95%CI 0.88 to
1.05) NS
Long half-life benzos:
RR 1.28 (95%CI 1.12 to
1.45), higher risk in first
week
Hip fractures and benzodiazepines
Wagner AK, et al. Arch Intern Med 2004;164:1567–72
• Incident RR of hip fracture with BZD vs. no BZD use based on
US claims data (194,071 person years of data, 1988-90):
–
–
–
–
–
–
–
–
Any BZD exposure: 1.24 (95%CI 1.06 to 1.44)
Long half-life BZD only: 1.13 (0.82 to 1.55) NS
Short half-life high potency: 1.27 (1.01 to 1.59)
Short half-life low potency: 1.22 (0.89 to 1.67) NS
>1 BZD type: 1.53 (0.92 to 2.53) NS
New BZD <16 days: 2.05 (1.28 to 3.28)
New BZD 16–30 days: 1.88 (1.15 to 3.07)
Continued BZD: 1.18 (1.03 to 1.35)
• Authors conclude: incidence of hip fracture appears to be
associated with benzodiazepine use.
Note: Different doses were not considered.
Other issues
• Some GPs have misperceptions about the safety and efficacy of Zdrugs compared to benzodiazepines
Siriwardena AN, et al. Br J Gen Pract 2006;56:964–7
• Older people are not always being given appropriate safety
warnings about taking these drugs
Iliffe S, et al. Aging Ment Health 2004;8:242–8
• It is difficult to withdraw from hypnotic drugs
– A letter from the GP can be effective in helping some to stop
Cormack MA, et al. Br J Gen Pract 1994;44:5-8
– CBT can be helpful
Morgan K, et al. HTA 2004:8 (8)
– See CKS guidance for further information
• Published criteria for clinical audit are available
Shaw E, Baker R. Journal Clin Governance 2001;9:45-50, NICE TA 77, April 2004
Summary of key messages
• Non-drug treatments should be considered and used
routinely in all patients
• 1988 CSM advice re benzodiazepines still stands and is
also applicable to Z-drugs
• NICE guidance confirms that Z-drugs offer little or no
advantage over benzodiazepines
• However overall prescribing of benzodiazepines and Zdrugs is not decreasing
• Long-term use of hypnotics is ‘off-label’ and is contrary to
all available evidence and guidance
• Think about auditing benzodiazepine and Z-drug use and
changing practice
• Resources exist for managing withdrawal
• No evidence that new melatonin receptor agonists offer
advantages over existing hypnotics.
Thank You!
May God
Bless You !
2017/4/5
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2005大阪櫻花
Barbiturates
• Bind to GABA-chloride receptor
– Directly activate receptor
– Enhance GABA’s natural action
– No ceiling on effect
• Highly addictive
• Therapeutic uses for
– Seizure
– Anesthesia induction
• Common: Phenobarbital
Other Sedative-Hypnotics
• Antidepressants
– Amitriptyline (Elavil)
– Trazadone
• 1st generation antihistamine
– Diphenhydramine (Benadryl, Nytol, Sominex)
– Doxylamine (Unisom)
– Hydroxyzine (Atarax)
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Trends in prescribing of hypnotics
in general practice in England
NHSBSA, September 2009
3,000,000
2,500,000
Items
2,000,000
1,500,000
1,000,000
500,000
Jun-09
Others
Mar-09
Dec-08
Melatonin
Sep-08
Jun-08
Lormetazepam
Mar-08
Dec-07
Sep-07
Zolpidem
Jun-07
Mar-07
Dec-06
Nitrazepam
Sep-06
Jun-06
Zopiclone
Mar-06
Dec-05
© Copyright NHSBSA 2008
Sep-05
Temazepam
Jun-05
Mar-05
Dec-04
Sep-04
Jun-04
0
Quarter to