慢性失眠及安眠藥物的使用

慢性失眠及安眠藥物的使用

財團法人佛教慈濟綜合醫院精神醫學部佛教慈濟大學精神科

林喬祥醫師

個案描述一 • 28 歲的王先生，唸專科時期開始就有經常睡不好，經常

得要躺超過一個小時才能入睡，遇到有考試壓力或者和朋友之間有些爭執時就更不好睡，就算睡著了，一有聲響很容易就醒過來，又得躺好一陣子才能再入睡。學校畢業後因為家庭經濟因素開始工作，睡眠狀況還是不理想。王先生曾經在一般開業醫師診所處方過安眠藥，效果還不錯。但是他很擔心常用會成癮，總是盡量不用安眠藥，有時一整個星期都沒有一天睡得好。他聽別人說什麼方法可以治失眠，都會去試，但是效果都不好。到後來每天一天黑就覺得要找一點上床準備睡覺，但是又覺得害怕、怕那一天又會睡不好或睡不著…。長期下來，白天不但會常頭暈，而且越來越沒耐性，常常提不起勁來，感覺自己快要垮了，近半年來已經把休假請光，還請了不少病假，最近才由朋友介紹到精神科看門診。

個案描述二• 36 歲的陳女士離婚後因為背負卡債及家庭經濟重

擔，有入睡困難和睡眠中斷的睡眠障礙已有 4 、5 年。剛開始看精神科時，吃 1 、 2 顆安眠鎮靜藥物就可以睡上幾個小時，但是總覺得睡不夠，半夜一醒過來就再吃 2 顆，有時已經塞了 7 、 8顆安眠藥還是睡不好。後來藥不夠時她就到另一家醫院的精神科開藥。雖然有醫師建議她應該要嘗試其他改善睡眠的方法，並且控制使用安眠藥，但是她就是擔心不吃睡不著，雖然她也知道其實吃了也不一定睡得好，有時候就乾脆把安眠藥配著啤酒吃，最近喝酒的量也漸漸多起來。

問題討論 • 問題一：慢性失眠應用藥物治療治療前應

有的評估及處置？

• 問題二：安眠藥到底是持續用好還是盡量不要用？

• 問題三：安眠藥的療效究竟如何？

Insomnia Has Several Definitions

NHLBI. Am Fam Physician. 1999;59 (abstract).

Difficulty falling asleep

Next-day consequences

Difficulty staying asleep

Non-refreshing sleep

Early morning awakenings

+

Giv

en

ad

eq

uate

op

port

un

ity t

o s

leep

Chronic Insomnia: Definition• Chronic insomnia vs. Acute insomnia

– Acute insomnia may occur in anyone at one time or another

– Varied definitions for chronic insomnia

• Durations ranging from 30 days – 6 months

• Chronic insomnia is often associated with a wide range of adverse conditions including:

– Mood disturbances

– Difficulties with concentration and memory

– Some cardiovascular, pulmonary, and gastrointestinal disorders

NIH Statement. Sleep. 2005;28:1049-1057.

Insomnia is the most common sleep complaint across all stages of adulthood, and for millions, the

problem is chronic

Insomnia can be a symptom of other disorders, like depression, or it can be a primary disorder in itself

Insomnia is the most common sleep complaint across all stages of adulthood, and for millions, the

problem is chronic

Insomnia can be a symptom of other disorders, like depression, or it can be a primary disorder in itself

The Majority of Insomniacs is Chronically Ill

59

83

53

7569

0

10

20

30

40

50

60

70

80

90

Mild

insomnia

Severe

insomniaInsomnia (DSM-III-R)

Elderly, difficulty falling asleep

Elderly, disturbed sleep continuity

%

%

%

%%

Mean 68%

% Isomniacs with Persistence of Complaints in Two-Years Follow-Up in Primary Care Surveys

Ganguli et al. 1996; Hohagen et al. 1993; Katz and McHorney 1998

Chronic Insomnia: Epidemiology

PrevalencePrevalence• 30% of general population complains

of sleep disruption

• 10% has daytime functional impairment

Natural HistoryNatural History

• Few studies describe the course and duration of insomnia

IncidenceIncidence

• Very little is known about chronic insomnia’s incidence

• Only a few studies have examined incidence

Risk FactorsRisk Factors Higher prevalence of insomnia in:

• Women (especially postmenopausal)

• Divorced, separated, widowed adults

• Psychiatric and physical illnesses

Other risk factors include cigarette smoking, alcohol, coffee consumption, and numerous prescription drugs


Chronic Insomnia: Consequences

• Some evidence suggests a relationship between chronic insomnia and impaired memory, cognitive functioning, and depressed mood

Chronic InsomniaChronic

Insomnia

ConsequencesConsequences

• Associated with high health care utilization

• Direct and Indirect Costs: estimated in the tens of

billions of dollars annually

Quality of LifeQuality of Life

•Reduces quality of life

•Hinders social functioning

•Related to impaired work performance


ComorbiditiesComorbidities• Seldom appears without

one or more other disorders

• Common comorbidities: depression, generalized

anxiety, substance abuse, attention deficit, and a

variety of physical problems

Public Health Burden

Public Health Burden

• Difficult to evaluate because literature is not

developed

• Focus is on populations rather than people

Comorbid Psychiatric Disorders With Insomnia

23.9%

14.0%

8.6%

7.0%

4.2%

5.1%

0% 5% 10% 15% 20% 25% 30%

Anxiety Disorder

Major Depression

Dysthymia

Alcohol Abuse

Drug Abuse

Other PsychiatricDisorders

*P<.001 compared with those with no sleep complaint.†P<.05 compared with those with no sleep complaint.Ford DE et al. JAMA. 1989;262:1479-1484.

Percentage

*

*

*

*

†

†

1.6 1.61.4

2.2

0.9

1.6

2.5

1.5 1.5

2.7

1.8

1.4

0.0

3.0

CHF COPD Backproblems

Hipimpairment

Peptic ulcer Prostateproblems

Mild Insomnia

Severe Insomnia

Medical Conditions Associated With Insomnia

*P≤.001; †P≤.05. ‡P≤.01.CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease.Katz DA et al. Arch Intern Med. 1998;158:1099-1107.

‡ ‡

*

†

*

‡

†

†

‡

Ad

juste

d O

dd

s R

ati

o

‡

Impact of Sleep Difficulties on Daily Functioning

0

2

4

6

8

10

12

14

CopingAccomplishing

Tasks General MoodPersonal

RelationshipsFamily

Life/ Social Life

No Sleep Difficulties

Occasional Sleep Difficulties

Frequent Sleep Difficulties(n=1027)

Rati

ng

Ab

ilit

y a

s P

oor

(%)

Doghramji PP. J Clin Psychiatry. 2001;62(suppl 10):18-26.

Gre

ate

r Imp

aire

d F

un

ctio

n

Impact of Insomnia on Physical and Emotional Health and Social Functioning

35

55

75

95

Control Insomnia

Body Pain

General Health

Mental Health

Role Emotional

Role Physical

Social Functioning

Vitality

Physical Functioning

*Scale ranges from 0 to 100, with higher scores reflecting greater quality of life. Adapted from Zammit GK et al. Sleep 1999;22(suppl 2):S379-S385.

SF-36 Subscales*

* P<0.0001

Gre

ate

r In

terf

ere

nce

Impact of Insomnia in the Workplace

• Daytime functioning and loss of productivity– Two to three times as many days of poor productivity

and concentration in individuals with insomnia as in good sleepers

• Absenteeism– Severe insomniacs were absent from work twice as

often as good sleepers• Work accidents

– Seven times higher rate of work accidents in insomniacs than in good sleepers

Metlaine A, et al. Industrial Health. 2005;43:11–19.

Therapeutic Goals in Treating Insomnia

Sleep OnsetSleep Onset Sleep MaintenanceSleep Maintenance

Number of awakenings

Duration of awakenings

Number of awakenings

Duration of awakenings

Time to fall asleep Time to fall asleep

Sleep DurationSleep Duration

Total sleep time Total sleep time

Alertness

Functioning

Vitality

Next-Day FunctioningNext-Day Functioning

Initial ScreeningInitial Screening• Nature of complaintNature of complaint• Daytime consequencesDaytime consequences• FrequencyFrequency• DurationDuration

Initial ScreeningInitial Screening• Nature of complaintNature of complaint• Daytime consequencesDaytime consequences• FrequencyFrequency• DurationDuration

• Precipitating events• Exacerbating factors• Sleep-wake schedule• Other nocturnal

symptoms

• Precipitating events• Exacerbating factors• Sleep-wake schedule• Other nocturnal

symptoms

• Associated behaviors• Cognitions• Previous treatments• Psychiatric disorders

• Associated behaviors• Cognitions• Previous treatments• Psychiatric disorders

• Substance abuse• Concomitant

medications• Medical/neurological

illness• Other sleep disorders

• Substance abuse• Concomitant

medications• Medical/neurological

illness• Other sleep disorders

Assessment of Insomnia

Adapted from Winkleman JW. Available at: http://www.medscape.com/viewprogram/3807

Additional History for Persistent InsomniaAdditional History for Persistent InsomniaAdditional History for Persistent InsomniaAdditional History for Persistent Insomnia

Chronic Insomnia: Treatment Considerations

TREATMENTTREATMENT

Cognitive Behavioral

Therapy (CBT)Benzodiazepine

Receptor Agonist• Benzodiazepines

•Non-Benzodiazepines

Antidepressants*

Atypical Antipsychotics*

OTC

Alternative Meds:Melatonin and

Herbal Remedies

*Not FDA approved for treatment of insomniaNIH Statement. Sleep. 2005;28:1049-1057.

Treat Insomnia with Drugs

Before treating insomnia with drugs, consider:• Is the underlying cause being treated

( depression, mania, breathing difficulties, urinary frequency, pain, etc.)?

• Are other drugs being given at appropriate times (i.e. stimulating drugs in the morning, sedating drugs at night)?

• Are the patient’s expectations of sleep realistic ( sleep requirements decrease with age)?

• Have all sleep hygiene approaches (see table below) been tried?

Guidelines for Prescribing Hypnotics

• Use the lowest effective dose• Use intermittent dosing (alternate nights or less) where

possible• Prescribe for short-term use (no more than 4 weeks) in

the majority of cases• Discontinue slowly• Be alert for rebound insomnia/withdrawal symptoms• Advise patients of the interaction with alcohol and other

sedating drugs• Avoid the use of hypnotics in patients with respiratory

disease or severe hepatic impairment and in addiction-prone individuals

Prescribing Guidelines, The Maudsley, 2007

The efficacy and safety of drug treatments for chronic insomnia in adults: a meta-analysis of RCTs

J Gen Intern Med. 2007 Sep;22(9):1335-50. Epub 2007 Jul 10 • BACKGROUND: Hypnotics have a role in the management of acute insomnia; however, the effic

acy and safety of pharmacological interventions in the management of chronic insomnia is unclear.

• OBJECTIVE: The objective of this paper is to conduct a systematic review of the efficacy and safety of drug treatments for chronic insomnia in adults.

• DATA SOURCES: Twenty-one electronic databases were searched, up to July 2006. • STUDY SELECTION: Randomized double-blind, placebo-controlled trials were eligible. Quality w

as assessed using the Jadad scale. Data were pooled using the random effects model. • DATA SYNTHESIS: One hundred and five studies were included in the review. Sleep onset laten

cy, as measured by polysomnography, was significantly decreased for benzodiazepines (BDZ), (weighted mean difference: -10.0 minutes; 95% CI: -16.6, -3.4), non-benzodiazepines (non-BDZ) (-12.8 minutes; 95% CI: -16.9, -8.8) and antidepressants (ADP) (-7.0 minutes; 95% CI: -10.7, -3.3). Sleep onset latency assessed by sleep diaries was also improved (BDZ: -19.6 minutes; 95% CI: -23.9, -15.3; non-BDZ: -17.0 minutes; 95% CI: -20.0, -14.0; ADP: -12.2 minutes; 95% CI: -22.3, -2.2). Indirect comparisons between drug categories suggest BDZ and non-BDZ have a similar effect. All drug groups had a statistically significant higher risk of harm compared to placebo (BDZ: risk difference [RD]: 0.15; non-BDZ RD: 0.07; and ADP RD: 0.09), although the most commonly reported adverse events were minor. Indirect comparisons suggest that non-BDZ are safer than BDZ.

• CONCLUSIONS: Benzodiazepines and non-benzodiazepines are effective treatments in the management of chronic insomnia, although they pose a risk of harm. There is also some evidence that antidepressants are effective and that they pose a risk of harm.

Insomnia: Challenges for Physicians

Initiating Treatment • Insomnia is challenging for clinicians because of the lack of

guidelines for assessment and treatment• General population’s poor understanding of the importance of

insomnia and available treatments• Forty percent of insomniacs self-medicate either with over-the-

counter medications or with alcohol• Only 0.9% of patients in a large managed care group reported

visiting a physician specifically for sleep problems– Yet, 34.2% of these patients reported symptoms of insomnia

• One in 3 patients seeking health care is likely to have insomnia with daytime dysfunction, but is unlikely to seek care for that specific problem

Benca RM. Psychiatr Serv. 2005;56:332–343.Ancoli-Israel S, Roth T. Sleep. 1999;22 (suppl 2):S347-S353.Doghramji PP. J Clin Psychiatry. 2004;65(suppl 16):23-26.

Insomnia: Challenges for Physicians

• In an international study of consequences of insomnia over a 12-month period– Many respondents took no action to alleviate their insomnia symptoms, a

nd this may be due to fear of the implications of treatment, including the possible risks of dependence on medications

– Focus groups of patients describing their insomnia experience reported that they felt that the impact of insomnia on their lives was pervasive and misunderstood by others who were significant to them or treating their sleep complaints

• More research is necessary to determine the long-term effects of insomnia treatments

• Current treatment options do not address the needs of difficult-to-treat patients with chronic insomnia, such as the elderly, and those with comorbid medical and psychiatric conditions.

Benca RM. Psychiatr Serv. 2005;56:332–343.Léger D, Poursain B. Curr Med Res Opin. 2005; 21:1785-1792. Carey TJ et al. Behav Sleep Med. 2005;3:73-86.

台灣鎮靜安眠類藥品使用盛行率以及相關後遺症之研究

• 行政院衛生署管制藥品管理局九十六年度委託科技研究計畫報告 , 民國 97 年 , 吳佳璇、張家銘、張憶壽、林克明、賴虹均、王金龍、蔡芳榆。

• 分析健保歸人檔資料獲得鎮靜安眠類藥品使用年盛行率，使用量，使用方式，以及使用者相關之人口學背景與醫療使用率。

• 預定連續分析數年 (2001~2004) 健保資料，探討變化趨勢。

The prevalence, using amount and characters of BZD users from 2001 to 2004

Year2001 2002 2003 2004

年盛行率 (%)男性女性

18.6414.7922.59

18.7015.0622.40

18.0214.5621.46

18.9415.3122.53

平均年齡 (years)95%CI

47.86(47.65~48.06)

48.75(48.54~48.95)

49.54(49.34~49.74)

50.07(49.87~50.27)

男性 48.38(48.05~48.71)

49.22(48.90~49.55)

50.11(49.78~50.45)

50.50(50.17~50.28)

女性 47.50(47.25~47.75)

48.42(48.17~48.68)

49.16(48.90~49.41)

49.78(49.53~50.03)

每千人日 DDD 27.19 31.05 35.68 40.48

男性 24.03 27.50 31.55 35.09

女性 30.44 34.66 39.77 45.81

台灣鎮靜安眠類藥品使用盛行率以及相關後遺症之研究 , 行政院衛生署管制藥品管理局九十六年度委託科技研究計畫報告 , 民國 97 年

The prescribing pattern among different specialities from 2001-2004

年份處方醫師專科別

2001 2002 2003 2004

DDD(%)

Order(%)

DDD(%)

Order(%)

DDD(%)

Order(%)

DDD(%)

Order(%)

不分科 113341.936.32

3266617.41

118936.575.96

2944215.61

146508.446.43

3055415.91

177267.946.99

3144315.04

家醫科 130386.327.27

1979410.55

143960.617.22

1962410.41

177664.787.79

2143711.16

209575.448.27

2309411.05

內科 612921.5034.18

5735530.56

663942.9333.29

5761330.55

734523.7632.22

5643129.38

806234.2331.81

6126829.30

精神科 555850.7631.00

2826815.06

636615.4531.92

3107316.48

760850.9233.38

3516118.31

850318.2133.55

4071519.47

神經科 184772.7410.31

164858.78

214533.5310.76

175609.31

228175.8210.01

169878.84

230393.459.09

179128.57

耳鼻喉科 39702.622.21

101425.40

39868.612.00

96615.12

40494.341.78

93514.87

42519.621.68

96034.59

總量 1792960.06 187650 1994385.57 188587 2279389.5 192058 2534698.2 209082


The prescribing frequency among different BZDs from 2001-2004

成份年份2001 2002 2003 2004

Orders % Orders % Orders

% Orders %

DIAZEPAM 35233 18.78 31431 16.67 28734 14.96 27329 13.07

LORAZEPAM 29640 15.80 28296 15.00 28071 14.62 28752 13.75

ALPRAZOLAM 20877 11.13 23890 12.67 25562 13.31 28952 13.85

OXAZOLAM 20066 10.69 17901 9.49 16385 8.53 17579 8.41

FLUDIAZEPAM

17631 9.40 17767 9.42 16720 8.71 17501 8.37

ZOLPIDEM HEMITAR

10515 5.60 15894 8.43 22295 11.61 30572 14.62

ESTAZOLAM 9556 5.09 10284 5.45 10333 5.38 11614 5.55

ZOPICLONE 5078 2.71 5293 2.81 4923 2.56 5080 2.43

TOTAL ORDERS

187650 100 188587 100 192058

100 209082 100


The prescribing amount among different BZDs from 2001-2004

成份年份 2001 2002 2003 2004

DDD % DDD % DDD % DDD %

ALPRAZOLAM 277193.30 15.46 325304.25 16.31 369129.30 16.19 399183.60 15.7

FLUNITRAZEPAM

213560.50 11.91 229162.00 11.49 269375.50 11.82 284374.00 11.2

ZOLPIDEM HEMITAR

205076.30 11.44 312553.10 15.67 470962.60 20.66 633665.10 25.0

FLUDIAZEPAM 185661.05 10.36 191894.49 9.62 190751.02 8.37 189635.00 7.4

LORAZEPAM 159.665.52 8.91 168428.18 8.45 180651.96 7.93 195194.88 7.7

ESTAZOLAM 134079.71 7.48 154972.06 7.77 170071.05 7.46 185482.07 7.3

OXAZOLAM 108655.40 6.06 100815.90 5.05 97553.45 4.28 103706.05 4.0

DIAZEPAM 107289.82 5.98 99593.58 4.88 93479.06 4.10 86683.83 3.4

TOTAL DDD 1792960.0 100 1994385.5 100 2279389.5 100 2534698 100


ZOLPIDEM 使用率與使用量增加趨勢值得關注

• ZOLPIDEM 單品項使用率在 2001 至 2004 年間增加幅度明顯，與同屬於 BZD receptor agonists 的 ZOLPICLONE 相對平穩的使用率相較， ZOLPIDEM被廣泛使用，其原因除可能的藥理優越性外，值得進一步探討。

• BZD receptor agonists 是否依賴性與成癮性均優於傳統的 BZD ，雖有報告 * ，仍有待更多資料檢驗。但將近六成醫師認同上列陳述，讓醫師傾向以 BZD receptor agonists 取代長效的 BZD ，成為處理睡眠障礙的藥物首選。

• 因應 BZD receptor agonists （特別是 ZOLPIDEM ）近年大量使用之趨勢，宜有全面性、系統性的評估，以證實其療效並瞭解可能的不良反應，必要時制定相關使用準則，以確保治療效果及用藥安全。

*Jerome H. Jaffe, Roger Bloor, Ilana Crome, Malcolm Carr, Farrukh Alam, Arnol Simmons & Roger E. Meyer (2004). A postmarketing study of relative abuse liability of hypnotic sedative drugs. Addiction, 99, 165–173.

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慢性失眠及 安眠藥物的使用

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慢性失眠及安眠藥物的使用