慢性失眠及 安眠藥物的使用

1. 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

2. 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。

3. 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。

4. 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？

5. Insomnia Has Several Definitions Difficulty falling asleep Difficulty staying asleep Next-day consequences Given adequate opportunity to sleep + Early morning awakenings Non-refreshing sleep NHLBI. Am Fam Physician. 1999;59 (abstract).

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

7. The Majority of Insomniacs is Chronically Ill % Isomniacs with Persistence of Complaints in Two-Years Follow-Up in Primary Care Surveys Mean 68% % % % % % Mild insomnia Severe insomnia Insomnia (DSM-III-R) Elderly, difficulty falling asleep Elderly, disturbed sleep continuity Ganguli et al. 1996; Hohagen et al. 1993; Katz and McHorney 1998

8. Chronic Insomnia: Epidemiology Prevalence Natural History • 30% of general population complains of sleep disruption • 10% has daytime functional impairment • Few studies describe the course and duration of insomnia Incidence Risk Factors • Higher prevalence of insomnia in: • Women (especially postmenopausal) • Divorced, separated, widowed adults • Psychiatric and physical illnesses • Very little is known about chronic insomnia’s incidence • Only a few studies have examined incidence Other risk factors include cigarette smoking, alcohol, coffee consumption, and numerous prescription drugs NIH Statement. Sleep. 2005;28:1049-1057.

9. Some evidence suggests a relationship between chronic insomnia and impaired memory, cognitive functioning, and depressed mood Chronic Insomnia Chronic Insomnia: Consequences Consequences Quality of Life • Associated with high health care utilization • Direct and Indirect Costs: estimated in the tens of billions of dollars annually • Reduces quality of life • Hinders social functioning • Related to impaired work performance Public Health Burden Comorbidities • Seldom appears without one or more other disorders • Common comorbidities: depression, generalized anxiety, substance abuse, attention deficit, and a variety of physical problems • Difficult to evaluate because literature is not developed • Focus is on populations rather than people NIH Statement. Sleep. 2005;28:1049-1057.

10. Comorbid Psychiatric Disorders With Insomnia * † † * * * Percentage *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.

11. Medical Conditions Associated With Insomnia ‡ * ‡ † ‡ † ‡ ‡ † * Adjusted Odds Ratio *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.

12. Impact of Sleep Difficulties on Daily Functioning Rating Ability as Poor (%) Greater Impaired Function Doghramji PP. J Clin Psychiatry. 2001;62(suppl 10):18-26.

13. Impact of Insomnia on Physical and Emotional Health and Social Functioning SF-36 Subscales* * P<0.0001 Greater Interference *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.

14. 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.

15. Therapeutic Goals in Treating Insomnia Next-Day Functioning Sleep Onset Sleep Maintenance • Time to fall asleep • Number of awakenings • Duration of awakenings • Alertness • Functioning • Vitality Sleep Duration • Total sleep time

16. Assessment of Insomnia • Initial Screening • Nature of complaint • Daytime consequences • Frequency • Duration Additional History for Persistent Insomnia • Precipitating events • Exacerbating factors • Sleep-wake schedule • Other nocturnal symptoms • Associated behaviors • Cognitions • Previous treatments • Psychiatric disorders • Substance abuse • Concomitant medications • Medical/neurological illness • Other sleep disorders Adapted from Winkleman JW. Available at: http://www.medscape.com/viewprogram/3807

17. Chronic Insomnia: Treatment Considerations Cognitive Behavioral Therapy (CBT) • Benzodiazepine Receptor Agonist • Benzodiazepines • Non-Benzodiazepines Alternative Meds: Melatonin and Herbal Remedies TREATMENT OTC Antidepressants* Atypical Antipsychotics* *Not FDA approved for treatment of insomniaNIH Statement. Sleep. 2005;28:1049-1057.

18. 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?

19. 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

20. 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 efficacy 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 was 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 latency, 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.

21. Insomnia: Challenges for PhysiciansInitiating 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.

22. 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, and 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.

23. 台灣鎮靜安眠類藥品使用盛行率以及相關後遺症之研究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。

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

25. The prescribing pattern among different specialities from 2001-2004 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

26. The prescribing frequency among different BZDs from 2001-2004 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

27. The prescribing amount among different BZDs from 2001-2004 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

28. 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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