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出门在外也不愁健康杂谈（43）
第四十三章&&
西塞尔内科24版412章“睡眠疾病”原文粘贴及部分翻译。
&&&&&&&&&&&
附一：失眠的药物治疗
&&&&&&&&&&&
附二：Sleep and Stroke Risk
&&&&&&&&&&&
附三：&& 2014 柳叶刀年终回顾之睡眠篇
&&&&&&&&&&&&&&&&&&&&&&&
DISORDERS OF SLEEP（睡眠病）
&&&&&一&&&&
DEFINITION（定义）
&&& Wake-sleep
complaints are second only to complaints of pain as the
that patients seek medical attention. Undiagnosed and untreated
wake-sleep
complaints extract an enormous toll at the personal level in terms
and at the societal level in socioeconomic consequences. Knowledge
sleep and its disorders has expanded rapidly over the past half
particularly with the discovery that sleep is far more than the
absence of wakefulness. Sleep is an active brain process that
includes two
divergent states: non&rapid eye movement (NREM) and rapid eye
(REM) sleep. A complex array of neurotransmitters,
neuropeptides,
and circulating humoral sleep-promoting factors interact with
multiple areas
of the central nervous system to determine wakefulness, REM sleep,
NREM sleep.
译文：患者寻求医生的理由，失眠症仅次于痛疼。按个人的痛苦和在社会经济方面对社会的影响，未诊断和未治疗的失眠症占很大的份量。睡眠知识和睡眠病知识在过去半个世纪以来，已发展很快。特别是发现更多见的是被动的唤醒。睡眠是脑活动的过程，包括二个不同的时期：非快速眼球运动睡眠和快速眼球运动睡眠。神经传递激素，神经肽，和循环体液促睡眠因子和皮层中枢系统互相作用决定是非快速眼球运动睡眠还是快速眼球运动睡眠。
二&& PATHOBIOLOGY（病理学）
Wakefulness is controlled by the reticular activating system of the
brain stem, which projects to the thalamus and cortex. Inhibition
projections, which is modulated by neurons in the pons and
midbrain, results
in sleep. REM sleep, during which most dreaming occurs, is
generated within
the tegmentum of the pons with modulation from the norepinephrine-
serotonin-containing neurons of the locus caeruleus and the dorsal
nucleus. Electrical events generated in the pontine reticular
formation (i.e.,
ponto-geniculo-occipital [PGO] waves) are propagated through the
oculomotor
and visual system during REM sleep simultaneously with REMs.
waves are suppressed by norepinephrine, and the serotonin neuronal
suppress PGO waves and REM; cholinergic neurons are stimulatory.
input can induce an action potential in neurons below their usual
threshold.
Such PGO-facilitated activity in the visual system may play a role
random imagery of dreaming.
译文：苏醒是由脑干喙部的网状激活系统调控的，脑干是与丘脑和大脑皮层相联系的。由桥脑和中脑的神经原调控的这类联系抑制，结果引起睡眠。多数梦境发生时，快速眼球运动是在桥脑被盖部由去甲肾上腺素和含五羟色胺的天兰色神经核和背脊核起动引起的。在桥脑网状结构（桥脑外膝体枕部波，PGO）中发生电势是通过眼球运动和在快速眼球运动睡眠中视觉系统传播的。去甲肾上腺素可抑制PGO波。五羟色胺神经原系统抑制PGO波和快速眼球运动。胆碱能神经原是受激动。PGO插入在神经原中产生一般阈值以下的主动电势。因此，在视觉系统中促PGO活性在梦幻中起了作用。
&&&&&&&&&&
Hypocretins (orexins) are sleep modulatory neuropeptides made in
lateral hypothalamus with projections to the locus caeruleus and
raphe, as well as to the thalamus, where they modulate the release
of excitatory
(glutamate) and inhibitory (γ-aminobutyric acid)
neurotransmitters.
Disruption of this system induces narcolepsy in animals, and
hypocretin
neurotransmission is deficient in most narcoleptic patients
译文：食欲肽是在丘脑下部侧面投射至天兰核和背脊核，也投射至丘脑形成的调节睡眠的神经肽。哪里神经肽调节兴奋（谷氨酸盐）和抑制（γ-氨基丁酸）的神经传递介质。这个系统的裂解在动物中引起发作性睡病，食欲素神经传递物质在多娄发作性睡眠病患者中是不足的。
Stage of Sleep（睡眠期）
Sleep stages in humans are defined electroencephalographically and
behaviorally
(Table 412-1). Sleep includes NREM and REM sleep. NREM sleep
can be divided into four stages.
In stage I NREM sleep, patients are drowsyand may maintain some
environmental awareness. The electroencephalogram (EEG) loses its
alpha rhythm (8 to 13 Hz) and develops theta (3 to
7 Hz) vertex potentials (i.e., negative deflections
recorded from the
midline) occur, especially in response to sensory stimuli. Slow
lateral eye
movements take place, and spontaneous motor activity, as monitored
electromyography (EMG), is diminished. Stage I represents about 5%
normal sleep time.
译文：人类的睡眠期由脑电图和人的行为表现来确定的。睡眠包括非快速眼球运劫睡眠（NREM
）和快速眼球运劫睡眠（REM）。&非快速眼球运劫睡眠又分成四个时期。&
1期非快速眼球运劫睡眠&，患者昏昏欲睡但仍对环境保持某种程度的警觉。脑电图上没有它的阿尔法节律(8
to 13 Hz)，发生B-活性(3 to7 Hz)，锥形电势（即是从中线记录到负性偏移）发生。
特别是对感觉剌激的反应中，慢侧眼球运动发生。和当肌电图监测时自发的运动减少，1期睡眠占5%的正常睡眠时间。&&&
&Stage II NREM sleep is characterized by sleep
spindles (12 to 14 Hz),
vertex sharp waves, and K complexes (i.e., biphasic, high-voltage
slow waves
often followed by sleep spindles). Slow lateral eye movements may
EMG activity is further reduced. Stage II NREM sleep represents 50
of sleep and increases with age.
Stages III and IV NREM sleep are characterized by slow or delta
(&4 Hz) and are therefore called delta sleep or deep sleep. If
20 to 50% of the
EEG is delta activity, the patient is in stage III if delta
activity is 50%
or greater, the sleep event is called stage IV. Deep sleep
constitutes 10 to 20%
of sleep time (less with advancing age). EMG activity is
diminished. Eye
movements are not seen, and ventilation is regular.
&&&&&&11期非快速眼球运劫睡眠特征是纺锤(12
Hz)锥形波和K复合形波（即双期，高电势慢波学接着睡眠纺锤波）。慢侧眼运动可以持续，肌电图上活动进一步减少，随着年龄增加，11期非快速眼球运劫睡眠占睡眠的50
60%。&&&&&
&111期和1V期非快速眼球运劫睡眠特征是慢的或B-波(&4
Hz)，因此称为B-睡眠或深睡眠。假如脑电图上20 to 50%是B活性波，患者是111期非快速眼球运劫睡眠
.假如B活性波占50%以上，睡眠称1V期非快速眼球运劫睡眠。深睡眠占睡眠时间的10 to
20%（随年龄减少）。肌电图活动减少，没有眼球运动可见。呼吸通气有节律。
In REM sleep, the EEG resembles that of waking, with low-voltage,
frequencies. Abrupt REMs and irregular ventilation and heart rate
present. Penile tumescence occurs, and muscle tone is depressed
because of
suppression of activity in all somatic muscles except the
diaphragm. REM
sleep occupies 20 to 25% of sleep time. Dreaming occurs during
all stages of
NREM sleep and during REM sleep.
There is some evidence that procedural (i.e., motor learning such
typing) and declarative (i.e., episodic learning such as recalling
events) memory consolidation occurs during REM sleep. REM sleep
increases after task training. After episodic learning, memory
consolidation
is accomplished during slow wave sleep by rapid reactivation of the
hippocampal
neurons previously activated by the place or event to be
remembered.
Alternatively, it has been hypothesized that dream sleep functions
random stimulator of the cortex to remove weak memories and thus
only stronger memories to be retained.
译文：在快速眼球运劫睡眠，脑电图类似于清醒时，有电势低，频率混合。突然的快速眼球运劫睡眠和不规则的呼吸节律和心律是存在的。阴茎勃起发生。因为，除了膈肌外，全身的骨骼肌活性抑制，肌张力抑制。快速眼球运劫睡眠占睡眠时间的20
to 25%，在所有的快速眼球运劫睡眠和非快速眼球运劫睡眠时期都可以做梦。
在快速眼球运劫睡眠有回忆（如学习打字动作）和追踪记忆（回忆事件发生地点）可以发生。经训练后，快速眼球运劫睡眠时间可增加。经历某事件后，因记忆某事件发生的地点和经过在慢波睡眠时期，原先激活的海马回神经原可引起快速的回放。有一种理论认为，“做梦”，是大脑皮层去掉弱记忆的剌激，允许保留了强的记忆。&
CLINICAL MANIFESTATIONS（临床表现）
Most sleep complaints fall into four categories: hypersomnia
(excessive
daytime sleepiness), insomnia (trouble falling or staying asleep),
rhythm (biologic clock) disorders, and parasomnias (complex
arising during the sleep period).
Hypersomnia is typically manifested as the tendency to fall asleep
in inappropriate
or undesirable settings such as at work, while talking with
or while driving. Sleepiness from any cause can result in impaired
attention, with adverse, occasionally disastrous socioeconomic
consequences
in the classroom, in the workplace, or on the highways. The most
cause of hypersomnia is volitional sleep deprivation for social or
reasons. Volitional sleep deprivation can usually be diagnosed by
the history
or sleep diary. Nonvolitional sleep deprivation&related sleepiness
always due to an underlying sleep disorder, most commonly either
obstructive
sleep apnea or narcolepsy (Table 412-2).
译文：大多数睡眠障碍分四类：嗜睡（白天过度的睡眠），失眠症（入睡困难），生理睡眠规律(生物钟）紊乱，和深眠状态（在睡眠时发生的复杂的行为）。嗜睡典型表现是在不适当时候或不适当的地方,如工作时，当与别人谈话时或驾驶时，顷向入睡。任一原因产生的嗜睡的结果损害了人的注意力，在讲台上，在工作的地方，或在高速路上产生不利的影响，偶尔发生灾难性社会经济后果。嗜睡的最常见的原因是因社会和经济理由，强制性减少了睡眠的时间。强制性睡眠不足由病史和睡眠记录可诊断。非强制性的睡觉不足总是由于睡眠病所致。最常见的是睡眠时阻碍呼吸的暂停综合征或发作性睡病。
&&&&&&&&&&
DIAGNOSIS（诊断）
Subjective（主观的）
Sleep Diaries and Sleepiness Scales
&& Sleep diaries kept for a
period of 2 or 3 weeks may reveal valuable information
about a patient’s subjective perception of wakefulness and sleep.
One useful
scale is the Epworth Sleepiness Scale (Table 412-3), which is
frequently used
as a screening tool for identifying excessive daytime sleepiness
and generally
correlates with other measures of sleep propensity. A score higher
suggests a high probability of a sleep problem. This scale may
be limited by
its lack of sensitivity in that there may be a striking discrepancy
self-perceived sleepiness and the physiologic sleepiness that can
be documented
by formal sleep studies
译文：睡眠记录和瞌睡。
对患者主观的睡和醒的感觉，2至3周的睡眠纪录可提供有价值的信息。一份有用的记录是英国 Epworth
睡眠纪录表，其对诊断过度睡眠是常用的检查工具，通常和其他的睡眠检查方法结果相符。这种记分法缺乏敏感性。在自我感觉睡眠与正规的睡眠研究证明的生理性睡眠间有明显的矛盾。
2&& Objective（客观的）
（1）& Polysomnography（多睡眠描记法）
Polysomnography (Chapter 100) determines states of sleep and
wakefulness
by recording eye movements, submental EMG activity, and the EEG. If
sleepdisordered
breathing is suspected, additional monitoring such as
oral/nasal
airflow, chest/abdominal movement, hemoglobin oxygen saturation,
transcutaneous or end-tidal CO2 is used. A full EEG helps evaluate
of arousal, REM sleep behavior disorder, and nocturnal
译文：通过记录眼球运动，下颏肌电图活动和脑电图检查，多睡眠措记法测定睡眠和觉醒的情况，假如患睡眠病，呼吸运动可疑，其它的监测如口或鼻气流，胸腹运动，血红蛋白氧饱和度及经皮或潮气末端的二氧化碳测量都可以使用。完整的脑电图有助于评估睡眠障碍，快速眼球运动睡眠行为病和夜间阵发发作。&&&&&&&&
（2）&& Multiple Sleep Latency
Test(多个睡眠潜伏试验）&&&
The multiple sleep latency test, which assesses the tendency to
fall asleep
during normal waking hours, consists of five 20-minute nap
opportunities at
2-hour intervals. An all-night polysomnograph is generally
performed the
night before to determine the quality and quantity of the preceding
sleep. Normal, fully rested adults do not usually fall asleep in
less than 10 minutes and uncommonly display REM sleep during
daytime naps. Patients
with narcolepsy typically fall asleep in 5 minutes or less and
often display
REM sleep during at least two of the daytime naps. This test is not
performed in patients with obstructive sleep apnea because an
explanation
for the hypersomnia should have been identified by the preceding
polysomnograph.
译文：多个睡眠潜伏试验，可评估在正常清醒时，顷向入睡，包括二小间隔五次二十分钟的瞌睡，在测定前夜睡眠数量和质量前，一整夜的多个睡眠潜伏试验要进行。正常情况下，充分休息成人在少于十分钟一般不入睡。和在白天瞌睡者很少表现快速眼球运动睡眠。发作性睡眠患者在不足五分钟就可入睡，在白天瞌睡至少二次，常显示出快速眼球运动睡眠。在阻塞性睡眠呼吸暂停患者中，这种实验一般不进行，因为，由先前整夜多睡眠测试睡眠过度已经确定了。
&&&&&&&&&&&
（3）& Actigraphy（活动变化记录仪）
Analysis of sleep diaries may be insufficient to verify a tentative
diagnosis in
patients with reported insomnia or suspected abnormalities in the
wake-sleep
cycle. In such cases, definitive objective data may be obtained by
actigraphy
in which a small, wrist-mounted device records activity plotted
time—usually over a period of 1 to 3 weeks. There is direct
correlation
between the rest/activity recorded by the actigraph and the
wake-sleep
pattern as determined by
polysomnography.&&&&
&译文：在主诉失眠或怀疑睡眠障碍的患者中，睡眠日志分析不足以作出临时的诊断。由一个小型，手腕式的装置实时记录超过1至3周时间的活动，这种客观资料可以得到。通过活动记录，休息与活动间记录是直接正相关系，由多睡眠描记图可测定睡眠的模式。
&&&&&&&&&&
六&&& SPECIFIC
SLEEP DISORDERS（特别的睡眠病）
&&&&&&&1&&&
&Obstructive Sleep Apnea（阻塞性睡眠呼吸暂停症）
&&& Obstructive
sleep apnea (Chapter 100), which is the most common medical
disorder causing hypersomnia, affects more than 2% of adult women
of adult men. It is seen primarily in overweight people who are
loud snorers,
but it may also occur in children and thin individuals.
Obstructive sleep apnea is characterized by collapse of the upper
during sleep. This upper airway collapse may be associated with a
fall in the
blood oxygen level and results in repetitive arousal (up to 100 per
sleep) to re-establish upper airway airflow. These brief arousals
are not perceived
by the individual but result in excessive daytime sleepiness.
Obstructive
sleep apnea is described in detail in Chapter 100.
&&&&&&&&&2&&&
Narcolepsy（发作性睡病）
（1）& EPIDEMIOLOGY AND PATHOBIOLOGY（流行病学和病理学）
&&& Narcolepsy
affects 1 in 2000 individuals. It has a clear genetic
component,
with more than 90% of affected individuals carrying the
HLA-DR2/DQ1
(under current nomenclature, HLA-DR15 and HLA-DQ6) gene, which
found in less than 30% of the general population. Despite a genetic
component,
the risk in a first-degree relative is only 1 to 2%, but this risk
represents
a 10- to 40-fold increase over that in the general population.
Thus, the genetic
component is neither necessary nor sufficient to cause
narcolepsy.
Hypocretin-1 is an excitatory neuropeptide found in a very
circumscribed
group of neurons confined to the hypothalamic region. Patients
narcolepsy have lost hypocretin cells, possibly by an
immune-mediated
phenomenon.
&&&&&&&&&&&
（2）& CLINICAL MANIFESTATIONS（临床表现）
&Narcolepsy is characterized by the tendency to
fall asleep inappropriately
during the daytime, particularly during sedentary or nonstimulating
activities,
despite having obtained an adequate amount of sleep the
night. Other symptoms of narcolepsy include (1) cataplexy (sudden
spells of muscle weakness), often triggered by emotionally laden
(2) hypnagogic (occurring at sleep onset) or hypnopompic (occurring
sleep offset) (3) sleep paralysis (awakening to
find the entire
body paralyzed—with the exception of being able to breathe and move
eyes); (4) and (5) disrupted nighttime
Patients with narcolepsy do not sleep more per 24 hours than
nonnarcoleptics
instead, they are unable to maintain the normal
boundaries
of wakefulness, NREM sleep, and REM sleep. The automatic
(driving past the desired freeway exit, putting clothing into the
refrigerator)
represents an admixture of wakefulness and NREM sleep, with
wakefulness to perform complex behavior but not enough for
awareness of the behavior. Sleep paralysis and cataplexy represent
the simultaneous
occurrence of REM sleep&related muscle paralysis and
wakefulness.
If the paralysis intrudes into wakefulness, the result is
if it persists
into wakefulness from a period of REM sleep, sleep paralysis
results. The
waking hallucinations represent the release of sleep-related
dreaming into
wakefulness, and the disrupted nighttime sleep is a manifestation
“state boundary dyscontrol” aspect of narcolepsy. Sleep paralysis
and hypnagogic/
hypnopompic hallucinations, but not cataplexy, are often
experienced
by people who do not have narcolepsy—particularly in the setting of
deprivation.
&&&&&&&&&&&&&&
（3）& DIAGNOSIS（诊断）
Sleep laboratory evaluation of patients with narcolepsy includes
polysomnography
and the multiple sleep latency test. Results of the all-night
polysomnograph
will usually be unremarkable. The multiple sleep latency test
demonstrate objective hypersomnolence, and REM sleep may be
during the daytime naps.
Levels of hypocretin-1 are undetectable in the cerebrospinal fluid
of most patients with narcolepsy who experience cataplexy and are
0602 positive. Absent CSF hypocretin-1 levels are not found in
conditions that could be confused clinically with narcolepsy, thus
suggesting
that CSF hypocretin determinations could be of value in the
diagnosis of
narcolepsy in difficult cases.
&&&&&&&&&&&&&
（4）& TREATMENT（治疗）
&&& Stimulant
medications such as methylphenidate (e.g., 10 to 60 mg/day),
methamphetamine (e.g., 20 to 60 mg/day), dextroamphetamine (e.g., 5
60 mg/day), and modafinil (e.g., 100 to 400 mg/day) are generally
and well tolerated. Sodium oxybate (20 to 40 mg/kg per night in
doses), alone or combined with modafinil, can reduce sleep
disruption significantly.
However, responses to these medications are variable among
individuals,
and clinical judgment is needed to titrate to an effective dose.
Dependency,
tolerance, or abuse of stimulant medications is uncommon in
patients with
narcolepsy, and there is no indication for “drug holidays.”
Cataplexy is often
controlled by tricyclic antidepressants (e.g., imipramine, 25 to 50
bedtime), selective serotonin re-uptake inhibitors (e.g.,
fluoxetine, 10 to
20 mg/day), or selective norepinephrine re-uptake inhibitors (e.g.,
venlafaxine,
25 to 37.5 mg/day). γ-Hydroxybutyrate (20 to 40 mg/kg per night in
doses) has been used in difficult cases.&
&&&&&&&&&&&&
Insomnia（失眠症）
Insomnia (Table 412-4) is defined not simply by total sleep time
but rather
by difficulty in initiation and maintenance of sleep, poor quality
and a insufficient duration of sleep, such that functioning in the
awake state
is impaired.
&&&&&&&&&译文：失眠症不是简单地由睡眠总时间来定的，相反是开始入睡和维持睡眠很难。睡眠质量很差和睡眠难以持久。醒着时有不适感。
&&&&&&&&&&&&&
（1）&& EPIDEMIOLOGY（流行病学）
Insomnia, the most prevalent sleep complaint, affects up to 10 to
20% of the
adult population and is second only to the complaint of pain as a
seek medical attention.
译文：最常见关于睡眠的主诉是失眠症，在成人中有10
至20%患失眠症，作为看医生的理由，主诉失眠是仅次于痛疼的症状。&&&&&&&&&&&&&&
&&&&&&&&&&&&
（2） &PATHOBIOLOGY（病理学）
There is growing evidence that some insomniacs may be in a constant
of hyperarousal because many are actually less sleepy during the
normal subjects are as measured by objective daytime nap studies,
also have increased 24-hour metabolic activity.Many people with
insomnia have identifiable psychiatric or psychological problems,
and untreated insomnia is a risk factor for the future
developmentof psychiatric problems such as depression (Chapter 404)
or substance abuse
(Chapter 33). Importantly, the relationship between insomnia and
psychiatric
conditions is bidirectional: depression may cause insomnia, and
may cause depression.
译文：在兴奋状态的人群中，失眠症患者数呈增长的趋势，因为他们在白天比正常人实际上缺少睡眠。即使包括白天瞌睡时间。有些患者二十四小时代谢活动率增加。许多患者确有心理学和精神学的问题，未经治疗的失眠症是对未来发生&心理学问题如抑郁症或虐待症的风险因素。重要的是，失眠症与精神状况之间的关系是双向的：抑郁症可以引起失眠症，失眠症也可以引起抑郁症。&&&&&&&&&&&&&&&
&&&&&&&&&&&&&
CLINICAL&&&
MANIFESTATIONS（临床表现）
Patients with insomnia complain of an inability to sleep long
enough or well
enough to awaken feeling rested or restored despite having an
amount of time to devote to sleep. Sleep deprivation as a result of
inadequate
time to devote to sleep is not insomnia. Many patients complain
nonrestorative sleep. Daytime consequences include feeling tired
or fatigued
or having trouble concentrating. True excessive daytime sleepiness
(inappropriate
or uncontrollable sleep episodes during the day) is extremely rare
insomniacs.
译文：失眠症患者主诉不能长时间的睡眠，或尽管有足够时间的睡眠，醒来感觉恢复的並不舒适
。睡眠时间不足引起的睡眠剥夺不是失眠症。许多患者主诉睡眠后无恢复健康感。白天感觉困倦或疲劳或精神不能集中。在失眠症患者中真正在白天明显的睡意（在白天不适当的或不能控制的睡眠）是少见的。&&&&&&&&&&&&&&&&&
&&&&&&&&&&&&
& （4）& DIAGNOSIS（诊断）
Insomnia is a clinical diagnosis. Sleep diaries and actigraphy may
helpful in difficult cases. Formal sleep studies are rarely
indicated unless
there is reason to suspect a coexisting sleep disorder such as
obstructive
sleep apnea
译文：失眠症是临床诊断。在诊断困难的病例，睡眠记录和活动记录是非常有帮助的。正规的睡眠研究是少的，除非有理由怀疑有共存睡眠症患者，如阻塞性睡眠呼吸暂停症。
&&&&&&&&&&
（5）& TREATMENT（治疗）&
&Behavioral therapy for insomnia (Table 412-5) can
be quite effective
but may be very time-consuming. 1 Over-the-counter sleep aids are
of little,
if any benefit.
&&& Although
medications used to treat depression are often prescribed to
insomnia, there is very little evidence that they are effective in
the treatment
of insomnia not associated with depression. Nevertheless, if
patients with
insomnia are physiologically hyperaroused, a case may be made for
administration of sedative-hypnotic agents. 2 Three classes of
medications are
approved for the treatment of insomnia: the benzodiazepines (e.g.,
temazepam,
15 to 30 triazolam, 1.25 to 2.5
estazolam, 1 to 2 mg at bedtime), the newer, nonbenzodiazepines
(e.g., zolpidem,
5 to 10 zolpidem controlled release, 6.25 to 12.5 mg
zaleplon, 5 to 10 or eszopiclone, 1 to 3 mg
bedtime), and a melatonin agonist (ramelteon, 8 mg at bedtime).
behavioral and pharmacologic treatments are often effective.
Benzodiazepines
may be administered safely and effectively for longer than 3
Tolerance, abuse, and dependency can be associated with chronic
benzodiazepine
administration in patients with well-documented sleep disorders,
the incidence of these complications is relatively low. Melatonin
is normally
secreted by the pineal gland (Chapter 230) in synchronization with
the lightdark
cycle. Its effect on sleep is variable, and its efficacy in
treating insomnia
has been disappointing.
译文：失眠症的行为治疗是相当有效的。介也是非常耗时间的。给处方安眠药很少，有益处的。虽然，用于治疗抑郁症的药品也用于治失眠症，在治疗不伴抑郁症的患者中，抗抑郁症药品有效的证据是不足的。然而，假如失眠患者精神呈高度兴奋，服用安眠镇静药是可以的。治疗失眠症有三类药品是批准使用：苯二氮类药品（唑吡旦，睡前&5
to 10 mg&，唑吡旦控释药，睡前6.25 to 12.5 mg，扎来普隆，睡前5 to 10
mg，或&吡嗪哌酯，睡前1 to 3 mg ）。褪黑激素激动药（ramelteon 睡前8 mg
）。行为治疗和药品治疗联合常有效。苯二氮卓类可安全有效的服用长达三周，耐受性，依赖性，成瘾在确诊睡眠症患者长期服用患者中，但是，这种伴发症是相当少见的。在黑灯环境下同步时Melatonin
正常是由松果体分泌的，在睡眠时它的功能是变化的，在治疗失眠症它的作用还未证明。
&&&&&&&&&&&
4&&&&&Restless
Legs Syndrome（足徐动综合征）
Restless legs syndrome, which is one of the most common causes of
insomnia, is a neurologic sensory/movement disorder that affects 5
of the general population. It is described in detail in Chapter
&&&&&&&&&&&
Disorders of Circadian Rhythm（昼夜节律病）
&&&&&&&&&&&&
（1）& DEFINITION（定义）
Most living creatures follow a relentless and pervasive daily
rhythm of activity
and rest that is ultimately linked to the geophysical light-dark
cycle. Plants,
animals, and even unicellular organisms show daily variations in
activity, locomotion, feeding, and many other functions. The
importance of
the light-dark cycle on the human biologic clock is underscored by
that only a third of totally blind humans will be entrained to the
environment,
a third will have a 24-hour cycle that is out of phase with the
environment,
and the remaining third have a free-running pattern that is longer
译文：大部分生物遵循每天休息和活动交替都有持续的，不断的节律。这与地球物理学上的白天与黑夜交替循环有极大的联系。植物，动物，和甚至是单细胞生物在新陈代谢活动，运动，感觉和许多的功能方面每天都有差异。在人类生物钟白天与黑夜交替循环的重要性由下事实证明的。仅有三分之一的盲人对环境改变有反应，三分之一的没有二十四小时环境变化感觉，余下的三分之一是长于二十四小时的自由模式。
&&&&&&&&&&&&&
（2）& EPIDEMIOLOGY（流行病学）
&&& In the
absence of blindness, the etiology of primary circadian
dysrhythmias
is unknown. There is good evidence that genetic factors contribute
some cases.
译文：在没有失明生物中，原始的昼夜节律紊乱的病因学还不清楚。在某些例子，有证据表明与遗传因素有关。
&&&&&&&&&&&&&&
（3）& PATHOBIOLOGY（病理学）
The function of the biologic clock is to promote wakefulness.
maximal wakefulness occurs during daylight hours. For reasons that
understood, the biologic clocks of people with circadian
dysrhythmias are
inexorably out of synchronization with the environment, thus making
it difficult
or impossible to adjust to demands of the environment.
Exposure to bright light has a potent effect on the biologic clock,
exposure at strategic times during the wake-sleep cycle results in
a change in
the underlying rhythm. For example, evening light exposure may
clock, whereas morning light exposure may advance it.
译文：生物钟的功能是促使换醒，正常情况下，最易换醒是在白天的时候，理由尚不清楚。人类生物钟昼夜规律的紊乱是与环境同步严重的扰乱有关。因此，使人很难或不可能調整好对环境的适应。暴露在强光下对生物钟有明显的影响。昼夜睡眠规律时间变更引起基本节律改变。例如，晚上光线强延迟了睡眠的生物钟。然而在早上光线强可以提前清醒生物钟时间。
&&&&&&&&&&&&&&
（4）& CLINICAL MANIFESTATIONS AND
DIAGNOSIS（临床表现和诊断）
The primary symptom of disorders of circadian rhythm is an
inability to
sleep during the desired sleep time. Once asleep, there is no
abnormality of
sleep per se, only an abnormality of the timing of sleep. The
result is often a
complaint of insomnia if sleep is attempted during the “wake” cycle
clock or a complaint of sleepiness if wakefulness is attempted
during the
clock’s sleep period. Wake-sleep schedule disorders fall into two
categories:
(1) primary malfunction of the biologic clock per se and (2)
malfunction as a result of environmental effects on the underlying
clock. The
primary disorders may be difficult to diagnose because they
typically masquerade
as other sleep, medical, or psychiatric disorders, such as
hypersomnia,
insomnia, substance (sedative-hypnotic or stimulant) abuse,
psychiatric conditions.
译文:昼夜生物钟规律紊乱疾病的主要的症状是在要求睡眠时，不能入睡。一旦睡着了，睡眠本身没有异常。只是睡眠时间有差异。假如睡觉只注意醒的时间，主诉睡得不够，或睡觉只注意睡得时间，主诉醒的时间长，结果常主诉失眠。昼夜生物钟紊乱疾病分为二类：（1）生物钟本身原发性功能紊乱。（2）继发性的功能紊乱，指环境改变对生物钟的影响。原发性疾病诊断很难。因为，其它的睡觉因素，药品或精神疾病如嗜睡症，失眠症，滥用药品（精神催眠药或兴奋药）或精神病情况等都可以假装是该病。
The diagnosis is made by the history. Most people, if asked what
wake-sleep pattern would be if they had 3 weeks of vacation
without any
constraints on their wake-sleep activities (meals, work, school,
family activities),
can provide an accurate estimate of their inherent wake-sleep
Sleep diaries and actigraphy may be helpful in difficult cases. The
disorders (such as jet lag and shift work) are usually immediately
on simple questioning of the patient.
译文：由病史可做出诊断。对大多数的人群，假如他们有三周假期，对睡眠活动又没有任何的强制时，询问他们的睡觉的模式，就能作出他们固有的睡眠模式准确的评估。对诊断困难的病例，睡眠日誌和活动图是有帮助的。在简单询问患者，继发性疾病（如飞行员的时差，和换班工作者）一般可立即诊断。
&&&&&&&&&&&&&&&&&
（5）& TREATMENT（治疗）
The mainstays of treatment of the primary circadian dysrhythmias
are chronotherapy,
phototherapy, and pharmacologic therapy.
译文：原发性昼夜节律紊乱病的支持治疗是生物钟疗法，光疗和药品治疗。
&&&&&&&&&&&&&
Chronotherapy（生物钟疗法）
In chronotherapy, the desirable total sleep time is determined by
sleep logs
during a “free-running” period. The patient then delays or advances
of sleep by a few hours every day and sleeps only the predetermined
of hours until the onset of sleep occurs at the desired time, at
which point the
patient attempts to maintain that time. This method requires
several days of
free time and can be difficult if sleeping quarters cannot be kept
quiet during the several day sleeps required.
译文：生物钟疗法，指在自由活动时期，合理的总睡眠时间由睡觉的记录来定。然而，患者每天延迟或提前发生睡眠或只是提前几个小时睡，直到睡眠发生在合理的时间上。此时，患者注意维持这段时间。假如睡眠的地址，在要求的几天中不能保证是黑暗的和安静，这种方法要实施是困难的。
&&&&&&&&&&&&&
Phototherapy（光疗）
The timing and duration of phototherapy depend on the diagnosis
individual response. The patient sits at a prescribed distance from
a bright light
that furnishes an illuminance of greater than 2500 lux at that
distance. The
effect of light on human rhythms varies with the intensity,
wavelength, timing,
and duration of exposure. This intervention can be performed at
home, withthe timing of light exposure individualized for a given
patient’s complaint.
Light exposure in the morning will advance the clock, whereas
exposure will delay the clock. Once the desired sleep period
time has been
achieved, continued light exposure must be maintained.
译文：光疗的时间和间期取决于诊断和个体反应。在离光源特定的距离，光源强度大于2500 lux
（勒克斯）条件下，患者坐着。对人的睡眠节律光的效果随光的强度，波长，时间和暴露的间期不一而有差异。这种治疗可在家进行。对光疗的时间按患者要求要个体化。在早上光疗将提前生物钟。晚上光疗却延迟生物钟。一旦，合理的睡眠时间达到了，继续光疗要进行。
&&&&&&&&&&&&&
Pharmacologic Therapy（药物治疗）
administration of melatonin, 3 mg 4 to 5 hours before the desired
of sleep onset, may assist in advancing the timing of the biologic
译文：在要求睡眠前4&至 5 小时的时候，服用褪黑激素。可以帮助提前生物钟睡眠的时间。
&&&&&&&&&&&
JET LAG, SHIFT WORK, AND PERSISTENT PRIMARY（飞行时差，换班，连续工作）
&&&&&&&&&&&
（1）& CIRCADIAN DYSRHYTHMIAS（生理节奏，节律障碍）
The best way to manage jet lag is to assume the wake-sleep pattern
destination site immediately. Sedative-hypnotic medication may
reduce the
sleep-onset insomnia associated with jet lag. Jet lag usually
resolves at a rate
of 1 day per time zone change.
译文：处理飞行时差最好的方法是立即评估目的地的换醒睡眠模式。镇静催眠药可以减轻飞行时差的失眠。飞行时差一般发生的速率是每个时区改变一天。
Management of shift w options include
medications and exposure to bright light at night or
sedative-hypnotic medication
and protection of the sleep environment during the day (or both).
biologic clocks of night shift workers virtually never completely
adjust to the
night shift because the drive home in the morning resets the clock
and workers tend to sleep at conventional times during nights
Treatment with medications is justified in patients who have
persistent
symptoms despite chronotherapy and phototherapy. For example,
modafinil,
100 to 200 mg during the night shift, is effective for the
excessive sleepiness
and loss of attention associated with shift work sleep disorder.
has modest benefits 3 but is no better than napping, bright light,
modafinil. 3 The administration of 3 mg of melatonin 4 to 5 hours
before the
desired onset of sleep may be of benefit, especially in individuals
who travel
across five or more time zones, particularly in an eastward
译文：换班的处理是很难的。选择的方法包括在夜间服兴奋药和光线明亮或白天服镇静催眠药和创造睡眠的环境（或二者都用）。夜班工作的生物钟实际上决没有完全调整到晚上状态，因为在每天早上完全重复到生物钟状态和在晚上习惯睡觉的时间工人就要睡觉了。尽管已用生物钟调整和光疗，对有持续的症状患者药品治疗还是恰当的。例如，在夜班工作的人服用莫达非尼100&到
，对克服瞌睡是有效的，减少因瞌睡引起的注意力不足。咖啡因有适当的好处。但是，不比午睡，明亮的光线或服用莫达非尼好。在睡觉前4&至
5小时，服用褪黑激素3 mg 是有益的。特别是向东方向飞行旅游的超过五个以上的时区的人更有利。
&&&&&&&&&&&&&&
（2）&&DELAYED SLEEP
SYNDROME（耽搁睡眠综合征）
&&& In delayed
sleep phase syndrome, the patient falls asleep late and rises
There is a striking inability to fall asleep at an earlier, more
desirable time.
This syndrome may be manifested as either sleep-onset insomnia or
hypersomnia, particularly in the morning. Delayed sleep phase
syndrome is
the most common of the primary circadian dysrhythmias and may, in
be the consequence of societal increases in opportunities for
nighttime activity.
Combinations of chronotherapy, phototherapy, and medications may
effective in “resetting” the clock, as for circadian dysrhythmias.
Unfortunately,
the treatment regimen must be maintained, or the clock will
become delayed.
&&&&&&&&&&&&&&&&&&
（3）&& ADVANCED SLEEP PHASE
SYNDROME（老年人睡眠综合征）
Individuals suffering from advanced sleep phase syndrome fall
asleep early
and awaken earlier than desired. They are unable to remain awake
they fall asleep in the early evening and awaken in
the very early
hours of the morning. This syndrome may be manifested as
hypersomnia,
particularly in the evening, or sleep maintenance insomnia.
Patients complain
of interruption of evening activities by their sleepiness. They may
evening social activities for fear of the intrusive sleepiness. The
undesirable
early morning awakenings in this condition may lead to a
misdiagnosis of
depression. Exposure to bright light in the evening may delay the
clock to a
more acceptable pattern.
译文：老年人睡眠综合征患者睡的早，醒的早。他们不能在合理的时间醒。他们很早就睡，早上很早就醒。这种综合症表现为过度睡眠，特别是在晚上，或睡觉时失眠。患者常陈诉瞌睡干扰了晚上的活动。因怕瞌睡而避免夜间的社会活动。在这种情况下，不恰当的早醒可以错误诊断为抑郁症。在晚上在明亮的光线下可以延缓更能接受的生物钟模式。
&&&&&&&&&&&&&&&&
（4） &OTHER ABNORMALITIES OF CIRCADIAN
RHYTHM（其它睡眠节律异常症）
Other, less common circadian dysrhythmias include a “non&24-hour
pattern” in which the wake-sleep period is longer than 24 hours
sleep begins at a later time each cycle, as well as an “irregular
wake-sleep
pattern” characterized by a completely chaotic and unpredictable
&&&&&&&&&&&&&&&
Parasomnias（反常睡眠症)
Parasomnias are defined as unpleasant or undesirable behavioral or
experiential
phenomena occurring predominately or exclusively during sleep.
attributed to psychiatric disease, it is now clear that parasomnias
manifestation of a wide variety of completely different conditions,
which are diagnosable and treatable. The common parasomnias are
of “dissociated sleep states,” which represent the simultaneous
admixture of
wakefulness with either NREM sleep (disorders of arousal such as
confusional
arousal, sleepwalking, or sleep terrors) or REM sleep (REM
behavior disorder). The parasomnias, like narcolepsy, support the
that wake and sleep are not mutually exclusive states and that
sleep is not
necessarily a global brain phenomenon
Isolated, often bizarre sleep-related events may be experienced by
normal individuals, and most do not warrant further extensive or
evaluation. However, serious attention should be paid to complaints
of sleeprelated
behavior that is potentially violent or injurious. In these cases,
sleep studies using a full EEG montage with continuous audiovisual
monitoring
is indicated to establish a correct diagnosis and treatment
&&&&&&&&&&&&&&&&
DISORDERS OF AROUSAL(觉醒病）
Disorders of arousal tend to arise from NREM sleep and usually
occur in the
first third of the sleep cycle and rarely during naps. They are
childhood and usually decrease in frequency with increasing
Disorders of arousal may be triggered by febrile illness, prior
sleep deprivation,
physical activity, emotional stress, or medications. They are not
by significant underlying psychiatric problems.
Clinical manifestations vary across a broad spectrum ranging from
confusional
arousal to somnambulism (sleepwalking) to sleep terrors. Some
patients perform more specialized behavior, such as sleep-related
eating and
sleep-related sexual activity, without conscious awareness. Such
may have forensic implications.
&&&&&&&&&&&&&&&&
&TREATMENT（治疗）
&Most disorders of arousal, such as simple
sleepwalking or sleep terrors,
require no treatment other than reassurance of their benign nature.
behavior is bothersome or potentially injurious, medical management
benzodiazepines (e.g., clonazepam, 0.5 to 1.0 mg 30 minutes before
or tricyclic antidepressant medications (e.g., imipramine, 25 to 50
minutes before bedtime) or behavioral treatment in the form of
self-taught
relaxation exercises is often effective
&&&&&&&&&&
&7& RAPID EYE MOVEMENT SLEEP
BEHAVIOR DISORDER（快速眼球运动睡眠行为病）
The most common and best-studied REM sleep parasomnia is the REM
behavior disorder.
&&&&&&&&&&&&
（1）&EPIDEMIOLOGY AND PATHOBIOLOGY（流行病学和病理学）
REM sleep behavior disorder predominately affects males (about 90%)
usually begins after the age of 50 years. Acute REM sleep behavior
is often due to undesirable side effects of prescribed medications,
most commonly
antidepressant medications and particularly the selective
re-uptake inhibitors. Chronic REM sleep behavior disorder, which
preceded by a lengthy prodrome of REM sleep behavior disorder, can
idiopathic or associated with neurodegenerative disorders,
particularly the
synucleinopathies (Parkinson’s disease, multiple system atrophy, or
with Lewy bodies), in which it may be the first symptom and precede
manifestations of the underlying process by more than 10 years
416). There is also a higher incidence of REM sleep behavior
in patients with narcolepsy, in whom this tendency may be
aggravated by
the tricyclic antidepressants or selective serotonin re-uptake
inhibitors
prescribed to treat cataplexy.
&&&&&&&&&&&&&&&
（2）& CLINICAL MANIFESTATIONS（临床表现）
In these patients, somatic muscle atonia—one of the defining
features of
REM sleep—is absent, thereby permitting the acting out of dream
mentation,
often with violent or injurious results. The initial complaint is
sleep behavior usually accompanying vivid dreams. Such behavior may
in repeated injury, including ecchymoses, lacerations, and
fractures.
&&&&&&&&&&&&&&&
（3）& &DIAGNOSIS（诊断）
The diagnosis may be suspected by the clinical history, but formal
studies are indicated. Patients with REM sleep behavior disorder
demonstrate increased EMG activity during REM sleep, thus
confirming the
clinical suspicion.
The benzodiazepine clonazepam (0.5 to 2.0 mg 30 minutes before
is a highly effective treatment of REM sleep behavior disorder,
with a sustained
response rate of nearly 90%, although its mechanism of action is
Melatonin, 6 to 12 mg at bedtime, may also be effective.
&& 附一：失眠的药物治疗（网络资料）
失眠患病率依次为醒后不解乏（38％）、夜间频醒（32％）、入睡困难（21％）和早醒不能再睡（21％）。35-40％的失眠病人共患一种以上的精神疾病，以情感障碍、焦虑障碍和物质滥用最常见。
失眠可降低职责履行，降低生产力，降低生活质量，增加旷工旷课率，增加意外事故率，增加健康护理费用，增加抑郁症率（5倍），恶化精神疾病和内科疾病，故需治疗。治疗失眠的目标要现实，如果病人6～7小时睡眠白天就能感觉良好，不一定需要8小时不间断的睡眠。
1 非处方药和保健药
抗组按药几项一过性和小型非安慰剂试验发现，苯海拉明25—50mg改善主观睡眠潜伏期和睡眠质量，但3～4天后发生耐受。如果病人正服心血管药，有认知损害、尿潴留或排尿不畅，应避免用抗组胺药。
褪黑激素给10例志愿者晚8时服褪黑激素5mg，可缩短睡眠潜伏期，延长主观睡眠；就寝前15分钟服褪黑激素，则不缩短睡眠潜伏期，提示不同时间服褪黑激素的效果不同。
难治性失眠。难治性失眠病人服褪黑激素1mg或5mg，非但不改善客观入睡或睡眠持续时间，而且还减少主观睡眠时间，提示褪黑激素治疗难治性失眠无效。目前，美国食品药品管理局未批准褪黑激素用作催眠药。
精神分裂症。几项研究显示，精神分裂症病人的夜间褪黑激素升高较迟钝，褪黑激素有镇静性能，其升高迟钝可解释精神分裂症的睡眠障碍率比常人高，Shami等随机双盲、交叉研究给伴睡眠障碍的精神分裂症病人服褪黑激素2mg，明显改善睡眠。
认知和血管效应。褪黑激素有镇静效应，白天服用可损害操作能力。褪黑激素能激动褪黑激素1型受体，收缩血管；激动褪黑激素2型受体，舒张血管。血压正常者服褪黑激素降低血压，而高血压服硝苯吡啶稳定者服褪黑激素升高血压。
L-色氨酸合成褪黑激素的基质，促进睡眠。美国食品药品管理局2001年2月公布的资料表明，1989年至少有1500例服L-色氨酸者引起嗜酸性粒细胞增多症-肌痛综合征，其中37例死亡，于是限制了在食物中添加L-色氨酸。
缬草酊是一种缬草植物衍生物，美国食品药品管理局将之归为营养物质。缬草酊能激活大鼠皮质神经元的腺苷受体，可能还是1-氨基丁酸（GABA）回收抑制剂，故可增加慢波睡眠。其撤退症状类似苯二氮卓类药物（BZDs）的撤退症状。4个报告表明，缬草酊可引起肝中毒，故禁用于活性肝病。有认为缬草酊是一种细胞色素P450
3A4（CYP 3A4）抑制剂，但有矛盾结果。
1.5 饮酒 饮酒入睡常迅速耐受，下半夜增加夜醒频度，恶化腿不宁综合征和阻塞性睡眠窒息，是治疗长期失眠的不良选择。
抑郁症“充分治疗”后，即使缓解心境症状，还可残留失眠，而失眠是抑郁复发的最强预报指标。镇静性抗抑郁药治疗失眠比抗抑郁的用量低，见表1。
曲唑酮曲唑酮治疗失眠比治疗抑郁更常见。早期研究给9例病人服曲唑酮150mg/夜&3周，比较断药前后，发现曲唑酮不改善睡眠潜伏期或总睡眠时间，但降低觉醒性，增加慢波睡眠（3，4相睡眠），改善主观睡眠质量，提示曲唑酮至少能短期治疗原发性失眠，但50mg的效果不如唑吡坦10mg。
2.2 米氮平
6例重性抑郁症病人用米氮平治疗2周（第1周15mg，第2周30mg），主观改善睡眠发作潜伏期和总睡眠时间。将米氮平固定剂量与逐渐增量比较，发现两组改善睡眠潜伏期和总睡眠时间的效果相似，提示米氮平增量对失眠效果未必更好。
三环抗抑郁药两个小型研究表明，阿米替林改善睡眠连续性的效果不一致，多虑平（25-50mg）增加总睡眠时间，改善主观睡眠质量。看来，失眠共患抑郁症时可选用镇静性抗抑郁药。
2.4 抗抑郁药与苯二氮卓（BZD）受体激动剂
BZD受体激动剂包括BZDs（如阿普唑仑和氯硝西泮）和选择性α1亚单位BZD受体激动剂（如唑吡坦、扎来普隆和艾司佐匹克隆）。镇静性抗抑郁药说明书上未限制其持续使用时间，使人们误以为，镇静性抗抑郁药比BZD受体激动剂更安全。其实，镇静性抗抑郁药比BZD受体激动剂的安全差。只有当伴物质滥用的失眠时，选用镇静性抗抑郁药才更有利，因为BZD受体激动剂强化物质滥用。
3 抗精神病药
典型抗精神病药典型抗精神病药增加总睡眠时间和睡眠功效，缩短睡眠潜伏期和睡眠发作后醒来时间。其中氯丙嗪还延长快眼动潜伏期，增加慢波睡眠。
不典型抗精神病药在抑郁症，氯氮平增加总睡眠时间、睡眠功效和2相睡眠，缩短睡眠潜伏期、慢波睡眠和觉醒时间。在精神分裂症，奥氮平增加总睡眠时间、2相睡眠、慢波睡眠和快眼动睡眠，缩短觉醒和1相睡眠，利培酮增加慢波睡眠；在正常人，奎硫平诱导睡眠，改善睡眠连续性。抗精神病药改善睡眠结构可能对抗精神病本身有利。
治疗镇静不良反应病例研究显示，利他林改善氯氮平的镇静效应。病例报告和开放标签尝试研究发现，莫达芬尼辅助抗精神病药治疗，缩短总睡眠时间，增加唤醒时间，减轻疲劳，改善生活质量，但精神分裂症病人服兴奋剂有复燃或恶化精神病的危险性。
睡行症典型抗精神病药治疗可引起睡行症，特别是当抗精神病药联合碳酸锂时。开始服奥氮平也观察到睡行症，因为奥氮平增加慢波睡眠，故增加唤醒障碍（睡行症是一种唤醒障碍）。
睡眠有关运动障碍包括不宁腿综合征和间歇性肢体运动障碍，这两种障碍均有多巴胺能不足，抗精神病药阻断多巴胺受体，理论上引发这两种障碍，实际上，病人不服典型抗精神病药2周以上，睡眠期间每小时5次以上腿急跳引起唤醒率达13％，而病人服典型抗精神病药时，这种率不过14％，看来典型抗精神病药不明显引发这两种障碍。
一个病例报告发现，奥氮平治疗与不宁腿综合征和间歇性肢体运动障碍有关。第二个病例报告表明，利培酮治疗与不宁腿综合征和间歇性肢体运动障碍有关，在换成另一种不典型抗精神病药后，这两个病例都缓解。最后，奎硫平在健康人群依赖于剂量引起间歇性肢体运动障碍，在双相I型障碍病人引起不宁腿综合征。
睡眠性窒息精神分裂症病人常服不典型抗精神病药，后者常引起肥胖，而肥胖可引起睡眠性窒息，用鼻腔持续正压通气治疗可明显改善这种窒息。
&4 BZD受体激动剂
改善睡眠病人服三唑仑或氟安定，74—84％的报告失眠改善，并因此而再次服药。当精神分裂症用抗精神病药治疗时，其残留失眠可用BZD受体激动剂治疗，但应少用，特别是共患睡眠性窒息、酒精或药物滥用史的病人。
减少慢波睡眠给8例无睡眠障碍志愿者双盲交叉服氟安定15mg，26mg（原文如此）或45mg安慰剂，结果发现，氟安定各种剂量比安慰剂均明显减少慢波睡眠（P均&0.05）。
4.1.3 改善内科症状
Ealsh等对伴失眠的类风湿性关节炎病人研究发现，服三唑仑治疗6夜，比安慰剂明显缩短早晨关节僵硬的持续时间。这可能与三唑仑改善了失眠引起的不适有关。
选择种类入睡困难宜用短效BZD受体激动剂（如咪哒唑仑）或雷美尔通（雷美替胺，ramelteon）；夜间频醒或广泛性焦虑宜用长效BZD受体激动剂（氯硝西泮）；当伴有物质滥用时，可选雷美尔通。
服用剂量开始服低剂量，如效果不满意，几天后渐增量，以达最低有效剂量。如果失眠或白天痛苦太严重，需要立即缓解，开始可用稍大剂量。某些精神疾病病人需用比推荐剂量高的BZD受体激动剂才有效。
4.2.3&服用时间应睡前或睡前几分钟服BZD受体激动剂。如服用距睡前时间过长，可增加不良反应危险性。雷美尔通说明书上说明，可在睡前30分钟内服用。
4.2.4&服用期限对一过性失眠和短期失眠，临床医生喜欢用短效BZD受体激动剂，如唑吡坦或扎来普隆，持续治疗时间为4周之内。一些长期失眠者服BZD受体激动剂有效后，难以断药，如果企图断药，随访2年时再服率很高。故没理由阻止该药长期服用。
4.3&不良反应
依赖多数病人服BZD受体激动剂限于2周之内，即使服用数月或数年，也罕见逐渐增量，逐渐增量说明病情加重或耐受，而耐受才会引起撤退症状，撤退症状是BZD受体激动剂依赖的主要原因。既然罕见逐渐增量，故依赖也罕见。有成瘾倾向、突然中断BZD受体激动剂者易感撤药症状。
反跳反跳性失眠是当突然中断一种BZD受体激动剂时，引起比疗前还要重的失眠，一般仅持续一夜，中、短效BZD受体激动剂撤除时更易发生，长效BZD受体激动剂血药浓度下降缓慢，不发生；中断剂量越高，反跳越重；BZD受体激动剂持续使用时间不一定与反跳有关。用BZD受体激动剂最低有效量就能平抑这种失眠，然后逐渐减量。
4.3.3 顺行性遗忘 药物吸收后识记困难。血药浓度越高，识记越难；离睡眠越近，识记越难。这些因素均可导致服药后回忆困难。
跌倒加拿大一项大型研究证明，单用麻醉药、抗抑郁药和抗抽搐药明确引起跌倒，BZD受体激动剂引起跌倒的危险性报告自相矛盾。Bras—sington等发现，64岁以上的失眠老人服与不服BZD受体激动剂的跌倒率都高，但无失眠的老人服BZD受体激动剂不增加跌倒率，提示失眠是跌倒的危险因素。而BZD受体激动剂不是跌倒的危险因素。
4.3.5 认知和漫游症
BZD受体激动剂减退认知和运动功能，对睡眠期间有责任或义务者，如夜间需照顾幼童的父母，随叫随到的医疗或公安人员，夜间需入厕的老人，应告知其潜在风险。另外，BZD受体激动剂的镇静作用可引起漫游症和自动症意外。
药物比较表2列出了美国食品药品管理局未批准治疗失眠的BZDs，表3列出了美国食品药品管理局批准治疗失眠的药物。其中半衰期长的次日残余效应大（如白天思睡、运动共济差和跌伤），这对老人的危害尤大。
&& 4.3.7 慎用
①BZD受体激动剂恶化阻塞性睡眠窒息，故不用于有阻塞性睡眠窒息者；②多数BZD受体激动剂经肝代谢，故肝病者用量宜低；③BZD受体激动剂和雷美尔通在妊娠妇女的安全性未经证实，故不用于妊娠妇女；④有酒精中毒或药物滥用史者服BZD受体激动剂应仔细监测其依赖形成；⑤社会饮酒者中量饮酒强化了催眠效应，使安全界限变窄。
选择性α1亚单位BZD受体激动剂选择性α1亚单位BZD受体激动剂的共同特点是：半衰期短，次日残余效应弱，撤退反应轻，成瘾危险性小，治疗老人失眠安全有效。在美国，这些药物已成为催眠药的主流。
唑吡坦多导仪研究显示，每夜服唑吡坦达5周持续有效，无耐受迹象。唑吡坦10mg间断服用12周，与安慰剂相比，可改善睡眠潜伏期、觉醒频度、总睡眠时间和睡眠质量，在不服唑吡坦的夜间，也不发生反跳性失眠。
扎来普隆可天天服，也可间断服，间断服无明显反跳。常在上床后再服，持续作用时间仅1～4小时，不增加总睡眠时间。下半夜还有5小时就要起床，也可服用，醒后无残余思睡效应。
艾司佐匹克隆原发性失眠服艾司佐匹克隆（3mg/夜&6个月）比服安慰剂的主观睡眠潜伏期短，醒来次数少、醒来持续时间短，总睡眠时间增加，睡眠质量、白天警醒和健康感改善，其功效维持可达1年。
老年失眠。231例原发性失眠老人（65～85岁）随机分配服艾司佐匹克隆1mg、2mg或安慰剂2周，结果2mg组比安慰剂组的睡眠潜伏期短（50分钟；86分钟，P=0.0034），但1mg组对睡眠潜伏期无明显影响。
更年期妇女失眠。一项研究（N=410）发现，艾司佐匹克隆比安慰剂治疗更年期和绝经早期的失眠有效，对诱导睡眠、维持睡眠、睡眠持续时间、睡眠质量和次日功能均有较大改善。继发性改善抑郁。FAVA等报告，艾司佐匹克隆联合氟西汀比安慰剂联合氟西汀的汉密尔顿抑郁量表评分低，即使除去睡眠项也是如此。可能是艾司佐匹克隆通过改善睡眠而改善焦虑，通过改善焦虑而减轻抑郁严重度。
5 其他催眠药
噻加宾为选择性GABA回收抑制剂。38例健康成人每天限制睡眠5小时内达4天，睡前服噻加宾8mg或安慰剂，结果噻加宾比安慰剂增加慢波睡眠，醒后不损害警醒性精神运动性任务，更好执行威斯康辛卡片分类任务。另有研究发现，噻加宾治疗广泛性焦虑症相关联的失眠有效。
加波沙朵加波沙朵为突触外GABAA受体激动剂，有3种效应：①缩短睡眠潜伏期：26例原发性失眠病人随机分配服加波沙朵5mg、15mg或安慰剂，加波沙朵15mg比安慰剂明显缩短睡眠潜伏期（24分钟；30分钟，P&0.05）；②增加慢波睡眠：原发性失眠病人服加波沙朵15mg比服安慰剂增加慢波睡眠（114分钟；94分钟，P&0.001）；③改善睡眠质量：无睡眠紊乱的63～78岁志愿者连服加波沙朵或安慰剂3夜，加波沙朵比安慰剂的睡眠质量好，睡眠深。
雷美尔通为特异性褪黑激素l型和2型受体激动剂。达峰时间0.5～1.5小时，起效快；半衰期1—2.6小时，活性代谢物半衰期2～5小时，清除快。故雷美尔通适用于入睡困难，给一过性失眠病人服雷美尔通16mg或64mg，能缩短睡眠潜伏期，增加总睡眠时间，两种剂量疗效相当。给原发性失眠病人每夜服雷美尔通4—32mg，中度缩短睡眠潜伏期，但不增加总睡眠时间。美国执行机构唯一不控制的睡眠药物就是雷美尔通。最近，美国食品药品管理局已批准雷美尔通治疗入睡困难。
雷美尔通无滥用潜力，无撤退症状，无反跳性失眠。升高成年妇女的催乳素水平，降低成年男性的睾酮水平。雷美尔通经肝脏细胞色素P450
1A2代谢，轻度肝病就能升高雷美尔通血药浓度，中度以上肝病者应慎用。氟伏沙明抑制细胞色素P450
1A2，戏剧性升高雷美尔通血清浓度，应避免联用。
总之，BZD受体激动剂治疗失眠安全有效，而非处方药和保健药、镇静性抗抑郁药、抗精神病药和其他催眠药治疗失眠尚缺乏系统支持证据。
&&&&&&&&&&&&&&&&&&&&&&&
附二：Sleep and Stroke Risk
Whatever it takes—drinking a glass of warm milk or counting
sheep—here’s another reason you must do what you can to get your
ZZZs. People under the age of 35 with insomnia are eight times more
likely to suffer a stroke, a Taiwanese study has shown.
The researchers analyzed health records for 21,000 people with
insomnia and 64,000 non-insomniac patients in a control group.
Along with finding that people ages 18 to 35 had an increased risk
of stroke compared to non-sufferers, they were also 54 percent more
likely to end up in the hospital as a result of a stroke.
The link between the staying up all night and stroke isn’t
completely clear, but other findings show that insomnia can alter
cardiovascular health through systematic inflammation, impaired
glucose tolerance—a precursor to type-2 diabetes—or increased blood
pressure, which are all possible reasons for this heightened
Still, strokes are most common for people 65 and older. While this
research ups younger people’s risk, keep in mind that the
likelihood that insomnia will cause stroke is still relatively low.
Over the course of four years in the study, only 583 of the
insomniacs, or 2.7 percent, had to be admitted to a hospital for
stroke. That’s still better than the national average of 1 in 14
stroke victims who are under the age of 45. (Take the quiz to see
if you’re at risk for one of the top 5 man killers.)
disturbance has always been a risk factor for stroke, but don’t
jump to conclusions too quickly. “Many people will describe a host
of sleep problems as ‘insomnia.’” says W. Christopher Winter, M.D.,
Health&sleep
expert. Often, patients’ unfamiliarity with what constitutes
insomnia can lead to misinterpretation and unnecessary anxiety,
says Winter. In other words, many people tend to generalize their
inability to sleep by thinking it’s insomnia, when in reality there
are plenty of other sleep-related issues you could be enduring,
like sleep apnea, which has more pressing health dangers than
stroke risk.
It doesn't mean you can't try killing two birds with one stone,
though. It’s known that regular exercise can lower your blood
pressure and reduce your risk of stroke at an older age. However,
research also suggests that exercise is effective in treating
chronic insomnia, working as a mechanism that helps reduce anxiety
and raise serotonin levels. A moderate level of exercise in the
early afternoon might be just what you need to help tuck you in at
night. (Need more help? Try these 6 better sleep
strategies.)&&&&&&
附三：&& 2014 柳叶刀年终回顾之睡眠篇
睡眠对记忆巩固、白天警觉性、情绪处理、代谢及免疫功能至关重要。过去 12
个月发布的一些研究，揭示了婴儿与老年人中，睡眠的新功能，并且发现有助于治疗睡眠障碍的新机制。年终柳叶刀杂志，对其主要结果进行了回顾。
一、REM 期间肌肉抽搐现象的有关研究
在小狗入睡期间，能够出现肌肉抽搐现象，仿佛它们正在积极做梦一般；而在婴儿快速动眼（REM）睡眠期也会出现这种现象。这种抽搐被认为由脑干激发，但在此之前，相关机制尚不明确。而近期一项关于新生大鼠的研究显示，肌肉抽搐参与记忆
- 运动皮层的塑造过程，有助于新生儿大脑的发育。
在清醒状态时，神经系统触发运动，并同时产生运动指令副本（即“伴随放电”），从而将预期变化告知感觉皮层。而 Tiriac
博士及其同事发现，REM
睡眠期间的抽搐现象，不同于清醒时的运动，它们并未连同“伴随放电”，而是由感觉皮层处理，触发初级运动皮层的剧烈活动。
二、睡眠有助于清除β淀粉样蛋白
脑内β淀粉样蛋白 (Aβ)
的累积，被认为是导致阿尔茨海默病的机制之一。逐渐增多的证据提示，Aβ在清醒状态中产生，而在睡眠期间清除。实际上，人类及啮齿动物睡眠期间，脑脊液内
Aβ的浓度，显著降低。
正如预期所示，一项针对健康中年男子的研究显示，清醒状态下，个体脑脊液（CSF）中 Aβ的浓度，显著增加。与睡眠前相比，睡眠后 CSF
内 Aβ1&42 的浓度降低 6%（睡眠时间最长者，Aβ1&42 降低最明显）。
而在睡眠完全剥夺个体中，Aβ1&42 浓度没有降低，因此慢性睡眠障碍的患者，可能导致
Aβ的逐渐累积。这些发现提示，在慢性睡眠剥夺的现代化生活方式中，允许更多的睡眠时间，或许有益。
三、阻塞性睡眠呼吸暂停综合征的治疗进展
阻塞性睡眠呼吸暂停综合征较为常见，能够导致白天嗜睡并增加心血管疾病风险。阻塞性睡眠呼吸暂停综合症患者，睡眠期间，舌头无法受到脑干的有效刺激，而阻碍上呼吸道。手术治疗，持续气道正压通气，或使用牙科器具拉动舌头等方法，有助于保证睡眠期间上呼吸道的开放。不幸的是，这些方式并非总是有效或良好耐受。
电刺激舌下神经方法，是治疗上的主要进展。在吸气开始时，舌下神经被起搏器刺激，而拉向前方。舌下神经刺激，可以使 12
个月后呼吸暂停发作次数从 29 次 / 小时降至 9 次 / 小时，并改善患者血氧浓度，白天嗜睡以及生活质量。
然而，舌下神经刺激，无法取得持续效果，一旦连续 5
晚没有进行刺激，睡眠呼吸暂停症状将会恢复。目前舌下神经刺激是一项昂贵治疗方式，但不可否认，它具有更广泛应用的潜力。
四、帕金森病患者白天过度嗜睡现象的机制研究
帕金森病患者，白天过度嗜睡症状由多重机制诱导，包括药物镇静效果，睡眠质量较差，以及觉醒系统的神经退行性病变。 Videnovic
博士及其同事，研究了没有外部时钟及光照情况下的昼夜节律，结果显示，相比于健康对照组，帕金森病患者夜间褪黑素分泌降低；并且白天嗜睡的患者，褪黑素分泌将进一步降低。
褪黑素减低，或许有助于解释夜间入睡困难及白天警觉性减低问题。临床实践中，频繁通过睡前口服褪黑素，来改善失眠并降低快速动眼睡眠行为障碍。未来应该进一步明确，褪黑素能否改善帕金森病患者，隔日警觉性问题。
五、克莱恩 - 莱文综合症的有关研究
莱文综合症（睡美人综合征），是一种影响青少年的罕见神经系统疾病，以嗜睡、现实感丧失（感觉在梦中，与现实脱节）、意识混乱、冷漠等症状的复发
- 缓解为特征。尽管在发作间期，患者表现正常。
目前，尚不清楚克莱恩 - 莱文综合症的病因，但近期一项纳入 41
名患者的影像学研究，鉴定了现实感丧失的机制。结果显示，症状发作间期，间脑与关联皮层区域呈低灌注状态，而在症状发作时，右颞 -
顶交界处（包括角回），有额外的低灌注现象，并与现实感丧失的强度及发作持续时间相关。
这些结果提示，患者之所以感到不现实，是因为颞交界处没能完全将温度、疼痛、表面皮肤感觉与听觉、视觉信息相整合。这些发现有助于提示现实感丧失的潜在机制，而现实感丧失症状，常见于神经精神类疾病中，可以导致自我感丧失以及灵魂出窍的感觉。
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