研究背景
長期使用benzodiazepines (BZD)的盛行率約在2.0-7.4%之間，雖然BZD用於短期治療的成效已廣被認可，然而長期使用的合理性卻仍存在著爭議；長期使用BZD可能會增加發生交通事故、跌倒和認知功能受損的風險，而最被關注的問題莫過於可能導致病人產生耐受性和依賴性，甚至是出現濫用的情形。因此本研究之目的為探討隨著病人使用BZD的時間增長，其使用劑量的變化與劑量升至較高的使用者比例，並探討BZD長期使用者之臨床特性及處方型態與使用劑量升至較高的關聯性。

研究方法
以全民健康保險研究資料庫之2005年抽樣歸人檔，串聯該100百萬人2004年至2007年間的承保資料作使用；研究對象為自2005年第一筆BZD處方箋開始，未間斷的使用BZD至少720天的長期使用者，其中年齡小於18歲、初始劑量較高、指標日期後720天內有住院紀錄或指標日期前180天內未投保者予以排除；並依照指標日期前90天內是否接受過BZD處方將研究對象進一步分為新使用者和持續使用者，又依年齡分為18-44歲、45-64歲及65歲以上者，分別探討其使用劑量的變化。劑量測量單位為WHO所制定的定義每日劑量(DDD)，將劑量較高定義為大於1.5 DDD；最後以條件式邏輯迴歸分析使用劑量升至較高的相關因子。

研究結果
自2005年起長期使用BZD的成人共有12,700人，盛行率為1.64%；歷經排除條件篩選後，最終研究對象為6,341人，以持續使用者(86.0%)和65歲以上者(47.9%)居多，併用藥品部分以抗憂鬱藥的處方比例為最高，佔18.1%，共病症則以慢性疼痛居首，佔49.7%。
在未間斷地使用BZD共720天的時間中，所有研究對象的使用劑量之中位數大致維持在0.68 DDD左右，而使用劑量之平均值由0.70 DDD升至0.85 DDD，則有逐漸升高的趨勢；這樣的結果亦反應在不同使用者和各年齡層的使用劑量變化中，除了新使用者與18-44歲者的使用劑量之中位數在初期有些許上升的趨勢之外；整體而言，使用劑量隨年齡增加而遞減，而持續使用者的使用劑量高於新使用者。使用劑量升至較高之使用者比例的統計結果，隨使用時間增長有顯著地逐漸增加的趨勢(p<0.0001)，直至末期有超過兩倍的成長。最後以多變項邏輯迴歸分析的結果顯示，在研究對象之臨床特性部分，患有慢性疼痛、失眠及焦慮症者會顯著增加使用劑量升至較高的風險(p<0.01)；而處方型態的部分，任一筆處方之處方劑量較高、主要使用作為安眠藥之BZD、主要使用短效型BZD、併用兩種或三種以上BZD、主要使用之BZD藥品規格為每單位藥品大於1 DDD者，亦會顯著增加劑量升至較高的風險(p<0.05)。

研究結論
對大多數的BZD長期使用者而言，其使用劑量並未隨使用時間增長而有明顯變化，且多維持在一般的治療範圍內；然而，使用劑量之平均值的逐漸爬升則反應出其中可能有使用情形較為極端的使用者存在，且這類使用者的人數可能有逐漸增加或者其使用劑量逐漸升高的趨勢，值得未來研究的注意。
另外，BZD長期使用者中，患有慢性疼痛、失眠及焦慮症者會顯著增加劑量升至較高的風險，而任一筆處方之處方劑量較高、主要使用作為安眠藥之BZD、主要使用短效型BZD、併用兩種或三種以上BZD、主要使用之BZD藥品規格為每單位藥品大於1 DDD者，亦會顯著增加劑量升至較高的風險。

關鍵字
Benzodiazepines、BZD、zolpidem、zopiclone、鎮靜安眠藥、長期使用、劑量變化、健保資料庫

Background
The prevalence of long-term benzodiazepines (BZD) use is around 2.0-7.4%. Although efficacy of BZD has been well-documented for short-term treatment, the legitimacy of long-term use remains controversial, given the increased risk of traffic accidents, non-accidental falls and cognitive function impairments. By far the most widely reported problems of long-term BZD use, however, lie in the development of tolerance, dependence or even abuse. Hence, the aims of this study were to examine changes in dosages and proportion of high dose users over time among long-term BZD users, and to identify factors associated with escalation to a high dose.

Methods
This was a retrospective cohort study using the original claim data from 2004 to 2007 of one million individuals randomly sampled from the 2005 Registry for Beneficiaries of National Health Insurance (NHI). We identified long-term BZD users who continuously used BZD for at least 720 days from the first prescription in 2005. Then patients aged younger than 18, not starting BZD in therapeutic range, ever hospitalized in 720 days after index date or not enrolled in NHI in 180 days before index date were excluded.
The study subjects were further grouped by (1) user status: new users (received no BZD prescription in 90 days before index date) and continuing users (received at least one); (2) age: aged 18-44, aged 45-64 and aged 65 or order. We converted dosage of all prescribed BZDs to Defined Daily Dose (DDD) and defined high dose as over 1.5 DDD. Finally, conditional logistic regression analyses were carried out to evaluate characteristics associated with escalation to a high dose.

Results
A total of 6,341 subjects were included and most were continuing users (86.0%) and users aged 65 or older (47.9%). Antidepressants and chronic pain accounted for the highest proportion of comedications and comobidities, respectively.
Overall, the median daily dosage remained constant at 0.68 DDD over 720 days of continuous use, and the mean daily dosage increased from 0.70 DDD to 0.85 DDD. The dosage trend was similar between user groups and among age groups, respectively except for the median daily dosage of new users and users aged 18-44 increased slightly in early stage but reach stable state later. The median daily dosage of continuing users was higher than new users, and young users were higher than old users. The proportion of high dose users significantly increased over time (p< 0.0001). Patient characteristics significantly associated with escalation to a high dose included displaying comorbid chronic pain, insomnia and anxiety. Prescribing characteristics including having any prescription which was indicated high dose and containing two or more BZD, mainly using hypnotic BZD, short-acting BZD, and high unit dose formulations of BZD (>1 DDD) also significantly increased the risk.

Conclusions
Overall, dosage among most long-term BZD users remained constant and well within the therapeutic range. The rise of the mean daily dose reflected there may be some extreme high dose users with increment in number or dosage over time.
Factors significantly increased the risk of escalation to a high dose included those suffering from comorbid chronic pain, insomnia and anxiety, having any prescription which was indicated high dose and containing two or more BZD, mainly using hypnotic BZD, short-acting BZD, and high unit dose formulations of BZD (>1 DDD).

Keywords
Benzodiazepines, BZD, z drugs, sedatives, hypnotics, long-term use, dosage, dose escalation

1.Soumerai SB, Simoni-Wastila L, Singer C, Mah C, Gao X, Salzman C, et al. Lack of relationship between long-term use of benzodiazepines and escalation to high dosages. Psychiatr Serv. 2003; 54(7): 1006-11.
2.行政院衛生署. 苯二氮平類(Benzodiazepines)藥品用於鎮靜安眠之使用指引. In: 行政院衛生署管制藥品管理局, editor.; 2007.
3.Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor. Basic & Clinical Pharmacology. New York. McGraw-Hill Companies. 2009. Ch.22 Sedative-Hypnotic Drugs. 11 ed.
4.Jaime N. Delgado, William A. Remers著 廖俊凱, 周慈怡譯. Wilson and Gisvold's藥物化學. 合記書局. 台北市. 1995: 476-481.
5.Laurence L. Brunton, Keith L. Parker. Goodman & Gilman's manual of pharmacology and therapeutics. New York. McGraw-Hill Companies. 2006. Ch.16 Hypnotics and Sedatives.
6.Drover DR. Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet. 2004; 43(4): 227-38.
7.Wafford KA. GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence? Curr Opin Pharmacol. 2005; 5(1): 47-52.
8.Bateson AN. Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal. Curr Pharm Des. 2002; 8(1): 5-21.
9.Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry. 2005; 18(3): 249-55.
10.林雅竹. 安眠鎮靜劑之使用評估及失眠患者用藥指導之研究 [碩士論文]: 國立成功大學; 2004.
11.Vogel G. Clinical uses and advantages of low doses of benzodiazepine hypnotics. J Clin Psychiatry. 1992; 53 Suppl: 19-22.
12.D'Hulst C, Atack JR, Kooy RF. The complexity of the GABAA receptor shapes unique pharmacological profiles. Drug discovery today. 2009; 14(17-18): 866-75.
13.Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002; 300(1): 2-8.
14.Whiting PJ. GABA-A receptor subtypes in the brain: a paradigm for CNS drug discovery? Drug Discov Today. 2003; 8(10): 445-50.
15.Sanger DJ. The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents. CNS Drugs. 2004; 18 Suppl 1: 9-15; discussion 41, 3-5.
16.Stevens JC, Pollack MH. Benzodiazepines in clinical practice: consideration of their long-term use and alternative agents. J Clin Psychiatry. 2005; 66 Suppl 2: 21-7.
17.Clinical distinctions between long-acting and short-acting benzodiazepines. J Clin Psychiatry. 1992; 53(Suppl): 4-7; discussion 8-9.
18.Chouinard G, Lefko-Singh K, Teboul E. Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem. Cellular and molecular neurobiology. 1999; 19(4): 533-52.
19.David S. Tatro. Drug interaction facts 2010 :the authority on drug interactions. St. Louis, Missouri. Wolters Kluwer Health. 2010. .
20.Weinling E, McDougall S, Andre F, Bianchetti G, Dubruc C. Pharmacokinetic profile of a new modified release formulation of zolpidem designed to improve sleep maintenance. Fundam Clin Pharmacol. 2006; 20(4): 397-403.
21.Moen MD, Plosker GL. Zolpidem extended-release. CNS Drugs. 2006; 20(5): 419-26; discussion 27-8.
22.Morin AK, Willett K. The role of eszopiclone in the treatment of insomnia. Advances in therapy. 2009; 26(5): 500-18.
23.Nutt DJ, Stahl SM. Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics. Journal of psychopharmacology (Oxford, England). 2010; 24(11): 1601-12.
24.Fernandez C, Martin C, Gimenez F, Farinotti R. Clinical pharmacokinetics of zopiclone. Clin Pharmacokinet. 1995; 29(6): 431-41.
25.MICROMEDEX Healthcare Series 1.0/DrugDex System/Evaluations 2010/12 (accessed at http://newmdx.csis.com.tw/hcs/librarian).
26.Dailymed 2011/1. (accessed at http://dailymed.nlm.nih.gov/dailymed/about.cfm).
27.The electronic Medicines Compendium (eMC) 2011/1. (accessed at http://www.medicines.org.uk/EMC/default.aspx).
28.Kilicarslan T, Haining RL, Rettie AE, Busto U, Tyndale RF, Sellers EM. Flunitrazepam metabolism by cytochrome P450S 2C19 and 3A4. Drug Metab Dispos. 2001; 29(4 Pt 1): 460-5.
29.Tanaka E. Clinically significant pharmacokinetic drug interactions with benzodiazepines. Journal of clinical pharmacy and therapeutics. 1999; 24(5): 347-55.
30.UpToDate 2010/12. (accessed at http://www.uptodate.com/online/content/search.do).
31.Woolcott JC, Richardson KJ, Wiens MO, Patel B, Marin J, Khan KM, et al. Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med. 2009; 169(21): 1952-60.
32.Takkouche B, Montes-Martinez A, Gill SS, Etminan M. Psychotropic medications and the risk of fracture: a meta-analysis. Drug Saf. 2007; 30(2): 171-84.
33.Ishigooka J, Sugiyama T, Suzuki M, Kobayashi K, Takeuchi H, Murasaki M. Survival analytic approach to long-term prescription of benzodiazepine hypnotics. Psychiatry Clin Neurosci. 1998; 52(5): 541-5.
34.吳佳璇. 台灣鎮靜安眠類藥品使用盛行率以及相關後遺症之研究. In: 行政院衛生署管制藥品管理局, editor.; 2007.
35.Zandstra SM, Furer JW, van de Lisdonk EH, van't HM, Bor JH, van Weel C, et al. Different study criteria affect the prevalence of benzodiazepine use. Soc Psychiatry Psychiatr Epidemiol. 2002; 37(3): 139-44.
36.Petitjean S, Ladewig D, Meier CR, Amrein R, Wiesbeck GA. Benzodiazepine prescribing to the Swiss adult population: results from a national survey of community pharmacies. Int Clin Psychopharmacol. 2007; 22(5): 292-8.
37.Cheng JS, Huang WF, Lin KM, Shih YT. Characteristics associated with benzodiazepine usage in elderly outpatients in Taiwan. Int J Geriatr Psychiatry. 2008; 23(6): 618-24.
38.Fang SY, Chen CY, Chang IS, Wu EC, Chang CM, Lin KM. Predictors of the incidence and discontinuation of long-term use of benzodiazepines: a population-based study. Drug Alcohol Depend. 2009; 104(1-2): 140-6.
39.Veronese A, Garatti M, Cipriani A, Barbui C. Benzodiazepine use in the real world of psychiatric practice: low-dose, long-term drug taking and low rates of treatment discontinuation. Eur J Clin Pharmacol. 2007; 63(9): 867-73.
40.Romach MK, Somer GR, Sobell LC. Characteristics of long-term alprazolam users in the community. J Clin Psychopharmacol. 1992; 12(5): 316-21.
41.中央健康保險局/醫事機構/醫事服務/疾病分類代碼及範圍/ 2001年 ICD-9-CM疾病碼一覽表 (Accessed at http://www.nhi.gov.tw/webdata/webdata.asp?menu=3&menu_id=56&webdata_id=1008&WD_ID=75).
42.Kao Yang YH, Kuo CW, Hung HJ, Jia SW. Classification of Pharmaceutical Products Reimbursed by National Health Insurance by the ATC system. The Chinese Pharmaceutical Journal. 2002; 54: 283-90.
43.WHO - ATC/DDD index 2008. (accessed at http://www.whocc.no/atc_ddd_index/).
44.行政院主計處/政府統計/全國統計資料/人口/人口靜態統計/人口數及人口增加率 (accessed at http://www.dgbas.gov.tw/ct.asp?xItem=15408&CtNode=4594).
45.行政院衛生署中央健康保險局業務執行報告. 2010年11月 (accessed at http://www.nhi.gov.tw/webdata/webdata.asp?menu=1&menu_id=4&webdata_id=3287&WD_ID=).
46.Hollingworth SA, Siskind DJ. Anxiolytic, hypnotic and sedative medication use in Australia. Pharmacoepidemiol Drug Saf. 2010; 19(3): 280-8.
47.周碧瑟. 健保資料既有疾病(comorbidity)之驗證─以北部某醫學中心為例 (accessed at http://www.nhi.gov.tw/webdata/webdata.asp?menu=1&menu_id=12&webdata_id=1408&WD_ID=).
48.Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004; 329(7456): 15-9.
49.Becker ML, Kallewaard M, Caspers PW, Visser LE, Leufkens HG, Stricker BH. Hospitalisations and emergency department visits due to drug-drug interactions: a literature review. Pharmacoepidemiol Drug Saf. 2007; 16(6): 641-51.
50.Wang LM, Wong M, Lightwood JM, Cheng CM. Black box warning contraindicated comedications: concordance among three major drug interaction screening programs. Ann Pharmacother. 2010; 44(1): 28-34.
51.Vitry AI. Comparative assessment of four drug interaction compendia. British journal of clinical pharmacology. 2007; 63(6): 709-14.
52.Abarca J, Malone DC, Armstrong EP, Grizzle AJ, Hansten PD, Van Bergen RC, et al. Concordance of severity ratings provided in four drug interaction compendia. Journal of the American Pharmacists Association : JAPhA. 2004; 44(2): 136-41.
53.Vonbach P, Dubied A, Krahenbuhl S, Beer JH. Evaluation of frequently used drug interaction screening programs. Pharm World Sci. 2008; 30(4): 367-74.
54.成大醫院藥劑部/藥物交互作用警訊查詢 (accessed at http://140.116.253.135/newhomepage/index.asp).
55.行政院衛生署藥品交互作用資料庫系統 2010/12. (accessed at http://dif.fda.gov.tw/).
56.David S. Tatro. Drug Interaction Facts 2011: The Authority on Drug Interactions. Saint Louis, Mo. Wolters Kluwer Health/Facts & Comparisons. 2010.
57.UpToDate/Drug interactions/Lexi-Interact™ Online 2010/12. (accessed at http://www.uptodate.com/crlsql/interact/frameset.jsp).
58.Chan A, Tan SH, Wong CM, Yap KY, Ko Y. Clinically significant drug-drug interactions between oral anticancer agents and nonanticancer agents: a Delphi survey of oncology pharmacists. Clin Ther. 2009; 31 Pt 2: 2379-86.
59.蘇俊中、高雅慧、林嘉音. 降血壓藥品對於老年人睡眠之影響 [碩士論文] 國立成功大學臨床藥學研究所; 2009.