研究背景：鴉片類藥物替代維持療法在生命留存（life-saving）上的效果在國際上持續被關注，然而自2006年台灣施行替代療法至今，目前尚無以美沙冬與丁基原啡因為主要維持藥物的替代療法成癮者之死亡流行病學報告。
研究目的：瞭解接受以美沙冬與丁基原啡因作為海洛因成癮替代維持療法（以下簡稱替代療法）病患的死亡率與相關危險因子之探討。比較接受替代療法與未接受者在死亡率上的差異，並進行重要死因別死亡率的比較，以推估台灣推行替代療法後，對海洛因成癮者生命留存(life-saving)的效果。
研究材料與方法：以世代追蹤法（cohort study），追蹤983位接受替代療法的海洛因成癮者，追蹤時間為2006年2月至2012年1月(個案最長追蹤時間為71個月)，另外透過國家藥癮系統資料庫確定300位於追蹤時間內未曾接受替代療法的個案，作為對照組。以存活分析（survival analysis）作為探討成效的推論性統計分析，瞭解接受替代療法個案與未接受者的存活差異，並以Cox regression model 來推論重要變項的相對危險性。接著瞭解影響接受替代療法個案死亡率的重要因子，並比較持續替代療法時期與中斷時期的存活差異。
研究結果：與未接受替代療法個案相較，接受治療的個案年齡顯著較大（37.8±7.7: 36.6±11.7, p <0.05）、教育程度較低(約2/3接受替代療法個案在基本國民教育（國中）以下) 、非法犯罪史比例較高(非法藥物使用前科：91.5%:74.1%,p<0.001;財產犯罪前科：46.5%:26.1%,p<0.001) 、
海洛因使用年數較長(6.9±4.3:5.7±5.2, p<0.001)、曾經出現共用針頭針具之行為比例較高(78.3%:40.8%,p<0.001)、以靜脈注射的方式使用海洛因比例較高 (91.0%:84.5%,p=0.0016)、C型肝炎以及HIV愛滋病毒帶原比例較高(C型肝炎:91.4%:86.4%,p=0.038; 愛滋病毒帶原:18.1%:6.3%,p<0.001)。
經過存活分析並校正重要變項後，Cox Regression Model顯示接受替代療法個案的死亡率為15.5/1000人年(95% 信賴區間:11.8 –19.2），顯著低於未治療個案的23.9/1000人年(95% 信賴區間:15.8 –31.9）(Adjusted Harzard Ratio: 0.47; 95% 信賴區間:0.28 – 0.79）。然而，接受替代療法個案自殺死亡率為3.88/1000人年，顯著高於未治療個案的0.7/1000人年。比較接受替代療法的個案中斷接受治療時期與接受治療時期的死亡相對危險比則達到七倍(All Cause Mortality Relative Risk = 7)。
結論：接受替代維持療法的個案存活率明顯高於未接受者，能繼續替代維持療法時期的死亡率也顯著較低，治療對於存活的保護作用並未受減害政策嘉惠許多特殊族群（如：愛滋病毒帶原者，緩起訴等等）影響，建議日後仍應繼續擴大替代維持療法的可近性。而接受治療個案比起未接受治療者有較高之自殺死亡率，臨床上宜注意此類個案共患憂鬱症的危險性，並適時進行自殺防治的評估。

Background: Recent years have seen increased concern being given to the life-saving effect of Opioid Substitution Treatment (OST) on heroin abusing population and OST have been implemented in Taiwan since 2006, evidence-base research is helpful for the future direction of OST strategies.
Objective: To investigate the mortality among heroin users and related risk factors. The current study also aims to examine reductions in mortality related to OST.
Material and Methods: A cohort of heroin users (N=1283) who had been evaluated were recruited from 2006-2008. These subjects were followed through December 31, 2011(longest following period: 71 months). We divided the cohort to receiving OST or not (OST group, N=983 and non-OST group, N=300) through the National MMT system. Record linkage performed to identify the death of these patients was managed by computerized files of Death Certification System. Crude mortality rate was calculated according to age, sex, receiving OST or not, period in-or out-of-treatment and medication type. Survival analysis was conducted to compare between heroin users receiving OST or not. The mortality risk among the heroin users after seeking OST was also examined using Cox regression model.
Results: Compared with non-OST group, the characteristics OST group were: older age (37.8±7.7:36.6±11.7, p <0.05), lower educational level (two-thirds below junior high school), longer length of heroin use (6.9±4.3:5.7±5.2, p<0.001), higher proportion of criminal records( illegal drugs offense：91.5%:74.1%,p<0.001;Property offense：46.5%:26.1%, p<0.001.), ever needle/syringe sharing (78.3%:40.8%,p<0.001), IDUs (Injection drug users) (91.0%:84.5%,p=0.0016), HCV-seropositive (91.4%:86.4%,p=0.038) and HIV-seropositive (18.1%:6.3%,p<0.001).The result of survival analysis showed that the all-cause mortality rate per 1000 person-year among OST group (15.5/1000 py) was lower than non-OST group (23.9/1000 py).After adjustment for significant covariates using the Cox regression model, all-cause mortality rate among OST group still had better survival outcome(Adjusted Harzard Ratio: 0.47; 95% CI: 0.28 – 0.79).However, the mortality rate directly related to suicide among OST group was significantly higher than non-OST group, (3.88/1000 py: 0.7/1000 py, p < 0.05). The survival analysis among OST group showed that the all-cause mortality relative risk between out-of-OST and in-OST period was 7.
Conclusions: The all-cause mortality rate among OST group is significantly lower than non-OST group. Among OST group, the survival outcome among in-OST period is better than out-of-OST period. The life-saving effect of enrollment and continued participation in OST still exists under the circumstances that harm reduction strategies in Taiwan is more attractive for HIV carrier and ex-prisoner. However, mortality from suicide among OST group is higher than non-OST. In addition to increasing the availability and access of OST program, suicide prevention program should be given high priority in order to prevent mortality among this high risk population.

中文文獻
行政院衛生署疾病管制局(2005)。毒品病患愛毒品病患愛滋減害試辦計畫。取自 www2.cdc.gov.tw/public/Attachment/93618471071.doc
行政院衛生署疾病管制局(2012)。101年7月替代治療執行情形。取自
http://www2.cdc.gov.tw/ct.asp?xItem=22061&ctNode=1885&mp=1
王甯祺(2006): 愛滋病在台灣的新危機：靜脈毒癮與C型肝炎。感染控制雜誌。16卷1期
吳怡君(2008)。海洛因防制政策-減害成效。台灣競爭力論壇。2008.07.16。取自http://www.tcf.tw/?p=1038。
楊秋月、蕭淑貞（1999）：藥物濫用個案家屬照顧需求及其相關因素之探討。護理研究，6(4)，304-313。
英文文獻
Aitken, C., Kerger, M. & Crofts, N. (2000). Drivers who use illicit drugs: behaviour and perceived risks. Drugs: education, prevention and policy, 7(1), 39-50.
Amato, L., Davoli, M., Perucci, C. A., Ferri, M., Faggiano, F., & Mattick, R. P. (2005). An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J Subst Abuse Treat, 28(4), 321-329.
American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders (4th ed. Text Revision). Washington, DC: American Psychiatric Association.
Auriacombe, M., Fatseas, M., Dubernet, J., Daulouede, J. P., & Tignol, J. (2004). French field experience with buprenorphine. Am J Addict, 13 Suppl 1, S17-28.
Auriacombe, M., Franques, P., & Tignol, J. (2001). Deaths attributable to methadone vs buprenorphine in France. JAMA, 285(1), 45.
Ballesteros, M. F., Budnitz, D. S., Sanford, C. P., Gilchrist, J., Agyekum, G. A., & Butts, J. (2003). Increase in deaths due to methadone in North Carolina. JAMA, 290(1), 40.
Bargagli, A. M., Sperati, A., Davoli, M., Forastiere, F., & Perucci, C. A. (2001). Mortality among problem drug users in Rome: an 18-year follow-up study, 1980-97. Addiction, 96(10), 1455-1463.
Bartu, A., Freeman, N. C., Gawthorne, G. S., Codde, J. P., & Holman, C. D. (2004). Mortality in a cohort of opiate and amphetamine users in Perth, Western Australia. Addiction, 99(1), 53-60.
Brooner, R. K., King, V. L., Kidorf, M., Schmidt, C. W., Jr., & Bigelow, G. E. (1997). Psychiatric and substance use comorbidity among treatment-seeking opioid abusers. Arch Gen Psychiatry, 54(1), 71-80.
Brugal, M. T., Domingo-Salvany, A., Puig, R., Barrio, G., Garcia de Olalla, P., & de la Fuente, L. (2005). Evaluating the impact of methadone maintenance programmes on mortality due to overdose and aids in a cohort of heroin users in Spain. Addiction, 100(7), 981-989.
Buster, M. C., van Brussel, G. H., & van den Brink, W. (2002). An increase in overdose mortality during the first 2 weeks after entering or re-entering methadone treatment in Amsterdam. Addiction, 97(8), 993-1001.
Caplehorn, J. R., Dalton, M. S., Haldar, F., Petrenas, A. M., & Nisbet, J. G. (1996). Methadone maintenance and addicts' risk of fatal heroin overdose. Subst Use Misuse, 31(2), 177-196.
Caplehorn, J. R. (1998). Deaths in the first two weeks of maintenance treatment in NSW in 1994: identifying cases of iatrogenic methadone toxicity. Drug Alcohol Rev, 17(1), 9-17.
Caplehorn, J. R., & Drummer, O. H. (1999). Mortality associated with New South Wales methadone programs in 1994: lives lost and saved. Med J Aust, 170(3), 104-109.
Carlin, Tony (2005) An exploration of prisoners' and prison staff's perceptions of the methadone maintenance programme in Mountjoy Male Prison, Dublin, Republic of Ireland. Drugs: Education, Prevention and Policy, 12 (5). pp. 405-416.
Charlton, J. R., Hartley, R. M., Silver, R., & Holland, W. W. (1983). Geographical variation in mortality from conditions amenable to medical intervention in England and Wales. Lancet, 1(8326 Pt 1), 691-696.
Chen, C. C., Kuo, C. J., & Tsai, S. Y. (2001). Causes of death of patients with substance dependence: a record-linkage study in a psychiatric hospital in Taiwan. Addiction, 96(5), 729-736.
Chen, C. C., Tsai, S. Y., Su, L. W., Yang, T. W., Tsai, C. J., & Hwu, H. G. (1999). Psychiatric co-morbidity among male heroin addicts: differences between hospital and incarcerated subjects in Taiwan. Addiction, 94(6), 825-832.
Chen, V. C., Lin, T. Y., Lee, C. T., Lai, T. J., Chen, H., Ferri, C. P., et al. (2010). Suicide attempts prior to starting methadone maintenance treatment in Taiwan. Drug Alcohol Depend, 109(1-3), 139-143.
Darke, S., & Hall, W. (2003). Heroin overdose: research and evidence-based intervention. J Urban Health, 80(2), 189-200.
Darke, S., Kaye, S., & Duflou, J. (2006). Systemic disease among cases of fatal opioid toxicity. Addiction, 101(9), 1299-1305.
Darke, S., Kaye, S., & Ross, J. (2001). Geographical injecting locations among injecting drug users in Sydney, Australia. Addiction, 96(2), 241-246.
Darke, S., Kelly, E., & Ross, J. (2004). Drug driving among injecting drug users in Sydney, Australia: prevalence, risk factors and risk perceptions. Addiction, 99(2), 175-185.
Davoli, M., Perucci, C. A., Forastiere, F., Doyle, P., Rapiti, E., Zaccarelli, M., et al. (1993). Risk factors for overdose mortality: a case-control study within a cohort of intravenous drug users. Int J Epidemiol, 22(2), 273-277.
Davoli, M., Perucci, C. A., Rapiti, E., Bargagli, A. M., D'Ippoliti, D., Forastiere, F., et al. (1997). A persistent rise in mortality among injection drug users in Rome, 1980 through 1992. Am J Public Health, 87(5), 851-853.
Degenhardt L, Hall W, Lynskey M, Warner-Smith M.(2004). Chapter 13. Illicit drug use. In: Ezzati M, Lopez AD, Rodgers A, Murray R, editors. Comparative Quantification of Health Risks: Global and Regional Burden of Disease Attributable to Selected Major Risk Factors. 2nd edition ed. Geneva: World Health Organization, 1109-1176.
Degenhardt, L., Bucello, C., Mathers, B., Briegleb, C., Ali, H., Hickman, M., et al. (2011). Mortality among regular or dependent users of heroin and other opioids: a systematic review and meta-analysis of cohort studies. Addiction, 106(1), 32-51.
Donny, E. C., Brasser, S. M., Bigelow, G. E., Stitzer, M. L., & Walsh, S. L. (2005). Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteers. Addiction, 100(10), 1496-1509.
Friedman, L. N., Williams, M. T., Singh, T. P., & Frieden, T. R. (1996). Tuberculosis, AIDS, and death among substance abusers on welfare in New York City. N Engl J Med, 334(13), 828-833.
Fugelstad, A., Annell, A., Rajs, J., & Agren, G. (1997). Mortality and causes and manner of death among drug addicts in Stockholm during the period 1981-1992. Acta Psychiatr Scand, 96(3), 169-175.
Fugelstad, A., Stenbacka, M., Leifman, A., Nylander, M., & Thiblin, I. (2007). Methadone maintenance treatment: the balance between life-saving treatment and fatal poisonings. Addiction, 102(3), 406-412.
Gibson, A., Randall, D., & Degenhardt, L. (2011). The increasing mortality burden of liver disease among opioid-dependent people: cohort study. Addiction, 106(12), 2186-2192.
Goldstein, A. & Herrera, J. (1995) Heroin addiction and methadone treatment in
Albuquerque: a 22-year follow-up. Drug and Alcohol Dependence, 40,
139-150.
Gossop, M., Stewart, D., Treacy, S., & Marsden, J. (2002). A prospective study of mortality among drug misusers during a 4-year period after seeking treatment. Addiction, 97(1), 39-47.
Gronbladh, L., Ohlund, L. S., & Gunne, L. M. (1990). Mortality in heroin addiction: impact of methadone treatment. Acta Psychiatr Scand, 82(3), 223-227.
Hall, W., Lynskey, M., & Degenhardt, L. (2000). Trends in opiate-related deaths in the United Kingdom and Australia, 1985-1995. Drug Alcohol Depend, 57(3), 247-254.
Hardman J., Limbird L., Goodman Gilman A. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill, Inc.; 2001.
Harris, E. C., & Barraclough, B. (1998). Excess mortality of mental disorder. Br J Psychiatry, 173, 11-53.
Heinemann A, Andresen H, Raschke P. Methadone-associated mortality among opiate users in Hamburg/Germany 1990-2001 (in German). Suchtmed. 2005;7:27-32.
Hickman, M., Madden, P., Henry, J., Baker, A., Wallace, C., Wakefield, J., et al. (2003). Trends in drug overdose deaths in England and Wales 1993-98: methadone does not kill more people than heroin. Addiction, 98(4), 419-425.
Hser, Y. I., Anglin, D., & Powers, K. (1993). A 24-year follow-up of California narcotics addicts. Arch Gen Psychiatry, 50(7), 577-584.
Huang, Y. F., Kuo, H. S., Lew-Ting, C. Y., Tian, F., Yang, C. H., Tsai, T. I., et al. (2011). Mortality among a cohort of drug users after their release from prison: an evaluation of the effectiveness of a harm reduction program in Taiwan. Addiction, 106(8), 1437-1445.
Hulse, G. K., English, D. R., Milne, E., & Holman, C. D. (1999). The quantification of mortality resulting from the regular use of illicit opiates. Addiction, 94(2), 221-229.
Kessler, R. C., McGonagle, K. A., Zhao, S., Nelson, C. B., Hughes, M., Eshleman, S., et al. (1994). Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry, 51(1), 8-19.
Kintz, P. (2002). A new series of 13 buprenorphine-related deaths. Clin Biochem, 35(7), 513-516.
Kreek MJ (1991): Using Methadone Effectively: Achieving Goals by Application of Laboratory, Clinical, and Evaluation Research and by Development of Innovative Programs. In Improving Drug Abuse Treatment, edited by R. W. Pickens, C.G.
Langendam, M. W., van Brussel, G. H., Coutinho, R. A., & van Ameijden, E. J. (2001). The impact of harm-reduction-based methadone treatment on mortality among heroin users. Am J Public Health, 91(5), 774-780.
Leukefeld, & C.R. Schuster. NIDA Research Monograph No. 106. Rockville, MD: U.S. Department of Health and Human Services.
Li, L., Levine, B., & Smialek, J. E. (2000). Fatal methadone poisoning in children: Maryland 1992-1996. Subst Use Misuse, 35(9), 1141-1148.
Lin, J. J., Chang, S. S., & Lu, T. H. (2010). The leading methods of suicide in Taiwan, 2002-2008. BMC Public Health, 10, 480.
Ling, W., Wesson, D. R., Charuvastra, C., & Klett, C. J. (1996). A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch Gen Psychiatry, 53(5), 401-407.
Lu, T. H., Huang, Y. T., & Chiang, T. L. (2011). Using the diamond model to prioritize 30 causes of death by considering both the level of and inequality in mortality. Health Policy, 103(1), 63-72.
Marsch, L. A. (1998). The efficacy of methadone maintenance interventions in reducing illicit opiate use, HIV risk behavior and criminality: a meta-analysis. Addiction, 93(4), 515-532.
Marx, A., Schick, M. T., & Minder, C. E. (1994). Drug-related mortality in Switzerland from 1987 to 1989 in comparison to other countries. Int J Addict, 29(7), 837-860.
Masson, C. L., Barnett, P. G., Sees, K. L., Delucchi, K. L., Rosen, A., Wong, W., et al. (2004). Cost and cost-effectiveness of standard methadone maintenance treatment compared to enriched 180-day methadone detoxification. Addiction, 99(6), 718-726.
Maxwell, J. C., Pullum, T. W., & Tannert, K. (2005). Deaths of clients in methadone treatment in Texas: 1994-2002. Drug Alcohol Depend, 78(1), 73-81.
Michels, II, Stover, H., & Gerlach, R. (2007). Substitution treatment for opioid addicts in Germany. Harm Reduct J, 4, 5.
Mills, K. L., Lynskey, M., Teesson, M., Ross, J., & Darke, S. (2005). Post-traumatic stress disorder among people with heroin dependence in the Australian treatment outcome study (ATOS): prevalence and correlates. Drug Alcohol Depend, 77(3), 243-249.
Neeleman, J., & Farrell, M. (1997). Fatal methadone and heroin overdoses: time trends in England and Wales. J Epidemiol Community Health, 51(4), 435-437.
NIDA (National institute on drug abuse). (2002, November 4). InfoFacts: Drug Abuse and AIDS. from http://www.nida.nih.gov/PDF/Infofacts/DrugsAIDS04.pdf

NIDA:NIH Scientific Report Provides Judges with Public Health Solution to Crime. July，2006
Pirnay, S., Borron, S. W., Giudicelli, C. P., Tourneau, J., Baud, F. J., & Ricordel, I. (2004). A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths. Addiction, 99(8), 978-988.
Quaglio, G., Talamini, G., Lechi, A., Venturini, L., Lugoboni, F., & Mezzelani, P. (2001). Study of 2708 heroin-related deaths in north-eastern Italy 1985-98 to establish the main causes of death. Addiction, 96(8), 1127-1137.
Randall, D., Degenhardt, L., Vajdic, C. M., Burns, L., Hall, W. D., Law, M., et al. (2011). Increasing cancer mortality among opioid-dependent persons in Australia: a new public health challenge for a disadvantaged population. Aust N Z J Public Health, 35(3), 220-225.
Research Report Series: Therapeutic Community. National Institution of Drug Abuse August 2002
Rounsaville, B. J., Weissman, M. M., Kleber, H., & Wilber, C. (1982). Heterogeneity of psychiatric diagnosis in treated opiate addicts. Arch Gen Psychiatry, 39(2), 161-168.
Rutstein, D. D., Berenberg, W., Chalmers, T. C., Child, C. G., 3rd, Fishman, A. P., & Perrin, E. B. (1976). Measuring the quality of medical care. A clinical method. N Engl J Med, 294(11), 582-588.
Schifano, F., Corkery, J., Gilvarry, E., Deluca, P., Oyefeso, A., & Ghodse, A. H. (2005). Buprenorphine mortality, seizures and prescription data in the UK, 1980-2002. Hum Psychopharmacol, 20(5), 343-348.
Sees, K. L., Delucchi, K. L., Masson, C., Rosen, A., Clark, H. W., Robillard, H., et al. (2000). Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial. JAMA, 283(10), 1303-1310.
Soyka, M., Apelt, S. M., Lieb, M., & Wittchen, H. U. (2006). One-year mortality rates of patients receiving methadone and buprenorphine maintenance therapy: a nationally representative cohort study in 2694 patients. J Clin Psychopharmacol, 26(6), 657-660.
Soyka, M., Penning, R., & Wittchen, U. (2006). Fatal poisoning in methadone and buprenorphine treated patients -- are there differences? Pharmacopsychiatry, 39(3), 85-87.
Teesson, M., Ross, J., Darke, S., Lynskey, M., Ali, R., Ritter, A., et al. (2006). One year outcomes for heroin dependence: findings from the Australian Treatment Outcome Study (ATOS). Drug Alcohol Depend, 83(2), 174-180.
Termorshuizen, F., Krol, A., Prins, M., & van Ameijden, E. J. (2005). Long-term outcome of chronic drug use: the Amsterdam Cohort Study among Drug Users. Am J Epidemiol, 161(3), 271-279.
U.S. Food and Drug Administration. Subutex (buprenorphine hydrochloride) and Suboxone tablets (buprenorphine hydrochloride and naloxone hydrochloride) Approved to Treat Opiate Dependence. FDA Talk Paper 2002, October 8.
UNAID (1999). Joint United Nations Programme on HIV/AIDS. Drug use and HIV/AIDS [document no. UNAIDS 99.1E]. United Nations General Assembly, Special Session on Drugs. Geneva: UNAIDS Best Practice Collection Key Material, March:1–12.
United Nations Office for Drug Control (2005) World illicit drug report 2005. New York: United Nations Publications.
Van Ameijden, E. J., Langendam, M. W., & Coutinho, R. A. (1999). Dose-effect relationship between overdose mortality and prescribed methadone dosage in low-threshold maintenance programs. Addict Behav, 24(4), 559-563.
Vingoe, L., Welch, S., Farrell, M., Strang, J.(1994). Heroin overdose among a treatment sample of injecting drug misusers: accident or suicidal behaviour. J Subst Use,4(2),88-91.
Walker, D. J., Zacny, J. P., Galva, K. E., & Lichtor, J. L. (2001). Subjective, psychomotor, and physiological effects of cumulative doses of mixed-action opioids in healthy volunteers. Psychopharmacology (Berl), 155(4), 362-371.
WHO, World Health Organization Geneva, HIV/AIDS in Asia and the Pacific Region 2003.
Wittchen, H. U., Apelt, S. M., Buhringer, G., Gastpar, M., Backmund, M., Golz, J., et al. (2005). Buprenorphine and methadone in the treatment of opioid dependence: methods and design of the COBRA study. Int J Methods Psychiatr Res, 14(1), 14-28.
World Health Organization (WHO). United Nations Offices on Drug and Crime, UNAID. Substitution maintenance therapy in the management of opoid dependence and HIV/AIDS prevention. WHO/UNODC/UNAIDS position paper 2004, France.
Zador, D., & Sunjic, S. (2000). Deaths in methadone maintenance treatment in New South Wales, Australia 1990-1995. Addiction, 95(1), 77-84.
Zador, D. A., & Sunjic, S. D. (2002). Methadone-related deaths and mortality rate during induction into methadone maintenance, New South Wales, 1996. Drug Alcohol Rev, 21(2), 131-136.