鴉片類物質成癮造成全球嚴重的健康負荷，台灣為因應此疾患所衍生的愛滋疫情而引進美沙冬作為成癮的替代維持療法（opioid agonist treatment, 簡寫為OAT）已逾十年。然而評估OAT的政策成效長期以來面臨以下問題：首先，雖然藥癮者具有高死亡風險，然而國際上尚未能計量此治療法是否為較佳選擇？能否使藥癮者活得更久或是可挽回多少預期壽命損失。其次，生活品質作為海洛因成癮者健康狀態的重要指標，但是台灣在這方面的相關研究仍顯不足，也缺乏成癮者長期追蹤的生活品質數據。最後，台灣缺乏能呈現鴉片類成癮疾患健康危害的本土數據，且國際上也未能以考量終生的觀點，來驗證此類患者接受OAT的成效。因此本論文首先計量接受OAT組與未接受OAT組的終生預期壽命（life expectancy, 簡寫為LE）和預期壽命損失年數（expected years of life loss, 簡寫為EYLL）的差異，估計OAT比未接受此療法者較少7.8年壽命損失。其次，我們驗證汙名烙印對成癮個案生活品質的負面影響，並呈現情緒障礙為其主要中介作用；也就是說污名化使藥癮者發生情緒障礙，才導致較差之生活品質。最後，透過調整終生存活函數與相應的生活品質平均效用值，並考量兩組的生活品質合併年齡和性別的分布差異後，證實OAT使海洛因成癮者少損失9.7健康人年(quality-adjusted life year, 簡寫為QALY)。
在2006年OAT實行之初，我們共招募了1283名海洛因成癮者（台灣世代）並串聯國家死亡登記檔追蹤至2012年。之後使用Kaplan-Meier法估計存活函數，並進一步利用半母數的存活外推法來推估終生預期壽命。研究世代的EYLL計算，是將研究世代的預期壽命與來自一般族群中選出相匹配年齡與性別的參考世代的預期壽命相減。與一般族群相比，OAT和非OAT組的標準化死亡比（standardized mortality ratio, 簡寫為SMR）分別高了7.5和10.2倍，表示我們的研究世代可能具有高的代表性。相比之下，OAT組和非OAT組的自殺死亡SMR分別高了16.2及3.1倍。在考慮前導期偏差與年齡、性別之後，OAT估計可挽救7.8年的預期壽命損失（EYLL）。
接著，本論文運用終生存活外推法來比較美國與台灣世代接受治療的鴉片類成癮病患的EYLL。美國研究世代來自2006至2009年期間參與治療的1267名鴉片類成癮者；台灣研究世代則是來自於2006年OAT推動初期接受治療的個案共983名，並追蹤兩個世代的存活至2014年。以兩個世代的存活函數外推70年以估計終生預期壽命（LE）。兩個國家的研究世代，分別與各自國家生命表相匹配性別年齡的參考世代的預期壽命相減，分別得到7.7年及16.4年的預期壽命損失(EYLL)。然而，這兩組之間存在顯著的自殺死亡率差異，台灣研究世代的死亡個案中有四分之一死於自殺，而美國研究世代僅為1%。因海洛因使用相伴隨的共病及汙名烙印，常導致這些個案的情緒障礙(憂鬱)，最後造成自殺的結果。此跨國研究呈現台灣鴉片類成癮者的高自殺死亡率與低比例的情緒障礙就醫率，值得台灣重視此族群的污名烙印議題。因此，我們試圖了解汙名烙印(透過簡短版汙名烙印量表(SSS-S)評估)以及情緒障礙(透過華人健康量表(CHQ-12)評估)對生活品質(透過台灣簡明版世界衛生組織生活品質問卷(WHOQOL-BREF)評估)的影響，並以268名海洛因成癮者做為研究族群，探討情緒障礙與汙名烙印之間的潛在中介作用。
透過一系列的迴歸分析(包括Baron and Kenny procedure與Sobel test)以確定SSS-S和CHQ-12是否能預測WHOQOL-BREF的結果。CHQ-12可以預測生活品質四個範疇的結果以及WHOQOL-BREF的全部項目，除了“是否依賴醫療輔助”此項目之外。然而，在校正CHQ-12分數後，SSS-S仍然可以預測生活品質中的社會範疇四個題目的其中三個。情緒障礙完全中介汙名烙印與生活品質的生理、心理、環境三個範疇的關係，並部分中介汙名烙印與社會範疇之間的關係（Sobel test p = 0.02）。情緒障礙似乎是降低汙名烙印對生活品質負面影響的核心因素。
最後，我們計量OAT可以挽救海洛因成癮者的生活品質調整健康餘命(quality-adjusted life expectancy, 簡寫為QALE)(單位為生活品質調整存活人年(quality-adjusted life year, 簡寫為QALY))。利用前述的台灣世代共8年(2006-2014)的存活函數，運用創新的滾動式終生存活外推法在研究世代與一般族群中模擬出相匹配性別年齡的參考世代以估計其存活函數。在2015至2017年間，我們詳細定義這兩組的健康狀態，共招募符合條件的349名個案進行EQ-5D效用值測量，其中生活品質的一般族群對照資料則是來自2009年全國健康訪談調查。生活品質調整健康餘命(QALE)的計算是來自終生生活品質函數及存活函數的乘積來估計。而研究世代與相對應的參考世代間的生活品質調整健康餘命(QALE)的差異即為生活品質調整健康餘命損失(loss of QALE)。在EQ-5D的各個範疇中，OAT組明顯優於非OAT組，在控制其他變項後，此效用值差為0.23。OAT個案的QALE和loss of QALE分別為17.8和18.2健康人年(QALY)；非OAT組的QALE和loss of QALE則為9.2和27.9健康人年(QALY)。考量兩組的生活品質合併年齡和性別的分布差異後，OAT可挽救海洛因成癮者9.7個健康人年(QALY)。

本論文之可能政策蘊涵供參考：
本論文根據台灣本土實證研究所獲得的結論，正好呼應2019年3月由美國國家科學、工程和醫學院的專家委員會(Committee of The National Academies of Sciences(NASEM), Engineering, and Medicine)出版的「Medications for Opioid Use Disorder Save Lives」中所載七項專家共識，簡譯如下：
【NASEM專家共識】
1. 鴉片類成癮疾患是可被治療的慢性大腦疾病。
2. FDA核准用來治療鴉片類成癮的藥物是有效且可挽救生命。
3. 長期接受治療者，有更好的治療成效。
4. 缺乏行為介入計畫的可行性或有效性，不足以成為停止使用鴉片類成癮藥物的理由。
5. 大部分病患皆可因接受此治療而改善；但目前許多個案並未能接受到治療，且不同族群間可獲得治療的機會並不平等。
6. 目前證實此類治療在所有場域皆為有效；當某些醫療或司法場合中不提供此類治療，等於否定FDA核准的適當治療。
7. 處理此類疾患的公共衛生危機的關鍵作為，在於如何克服面對鴉片類成癮治療的障礙（在台灣包括：污名烙印）。

因此，本論文建議藥癮宜更多納入有實證根據的社會倡議，具體建議如下：
本研究驗證海洛因成癮者接受替代維持療法（OAT）除了可多活7.8年外，也可顯著改善生活品質，透過生活品質的進步可增加成癮者兩個健康人年（QALY）的價值，亦即整體可改善9.7個健康人年。OAT實是台灣近年來藥癮最重要的公共衛生政策。然而，由於接受治療個案具有高自殺死亡率，此族群應納入國家級自殺防治計畫的高風險個案，並呼籲精神科臨床人員與自殺關訪員持續追蹤關懷；宜另外提供方案引導其關注自身身心健康，並協助改善其主動就醫的行為。由於長期接受治療具有的益處，建議未來可先參考愛滋病治療的模式，將長期規律且穩定接受治療者的費用納入全民健保給付。
另外，本論文也發現台灣簡明版世界衛生組織生活品質問卷(WHOQOL-BREF)，可作為成癮者健康的評估工具；而海洛因成癮者嚴重的污名問題，除了造成就醫的障礙外，也進一步造成成癮者情緒障礙並影響生活品質。精神疾病的去污名化運動宜納入成癮疾患；成癮也是一種腦部疾病，而接受治療是該病最好的對策。建議政府宜儘快將替代維持療法納入健保，將可促進此類患者其他精神共病的治療，減少其自殺與精神狀態不穩所造成之社會問題。最後，建議本論文的新創研究法，可嘗試應用於未來不同成癮疾患（如酒精與甲基安非他命）的治療成效評估。

Opioid use disorder contributes to a heavy burden of disease globally, including excessive early mortality and poor quality of life. The Taiwan Center for Disease Control (CDC) permitted MET as an agonist treatment for heroin users in response to human immunodeficiency virus (HIV) epidemic since 2006 and the effectiveness of opioid agonist treatment (OAT) should be comprehensively evaluated. This dissertation first estimated the life expectancy (LE) and expected years of life lost (EYLL) in a cohort of heroin users stratified by OAT for comparison. A total of 1283 heroin users recruited in the beginning of OAT implementation (2006) were linked to the National Mortality Registry until 2012 with stratification by OAT. Kaplan-Meier estimation for survival was performed, and it was extrapolated to lifetime to obtain the LE using a semi-parametric method. We further estimated the EYLL for both cohorts by subtracting their life expectancies from the age-, sex-, and calendar year-matched referents simulated from vital statistics. Cause-specific standardized mortality ratios (SMRs) for the OAT and non-OAT groups showed 7.5 and 10.2 compared with the general population, indicating good representativeness for our sample. In contrast, SMR of suicide mortality elevated 16.2- and 3.1-fold in OAT and non-OAT group, respectively. Moreover, OAT saves 7.8 EYLL more than non-OAT after accounting for lead time bias.
Then I applied the novel extrapolation method to compare the treated opioid users between U.S. and Taiwan. Survival data came from two cohorts followed until 2014: The U.S. data are based on a randomized trial of 1,267 opioid-dependent participants enrolled between 2006 and 2009; the Taiwan data are from the OAT group (N=983) that began in 2006, when OAT was implemented in Taiwan. The EYLLs, estimated by subtracting their life expectancies from the age- and gender-matched referents simulated from the vital statistics of their respective country, were 7.7 and 16.4 years for the U.S. and Taiwan/OAT cohort, respectively. However, a striking difference in suicide mortality existed between these two groups, with a suicide mortality rate of 25 percent for the Taiwan cohort versus 1 percent for the U.S. cohort. The combination of comorbidities and the stigma associated with heroin use could lead to psychological distress (depression) and, eventually suicide. The high rate of suicide morality along with the low rates of psychiatric medication among opioid users in Taiwan raises the concern of stigma issue. Thereafter, we attempted to determine the effects of stigma (assessed by the Self-Stigma Scale-Short (SSS-S)) and psychological distress (assessed by the Chinese Health Questionnaire-12 (CHQ-12)) on QOL (as assessed by the brief version of the World Health Organization Quality of Life instrument (WHOQOL-BREF)) and to explore possible mediation effects between psychological distress and stigma in a consecutive sample of 268 heroin users. The CHQ-12 score was predictive of the scores for the four domains and almost all facets of the WHOQOL-BREF except the item, “Dependence on medical aids.” Nonetheless, the SSS-S score predicted three of the four facets of the social QOL after adjustment of the CHQ-12 score. Psychological distress completely mediated the association between self-stigma and the physical, psychological, and environmental domains, and partially mediated association between self-stigma and social QOL (two-tailed Sobel test: p=0.02 for each domain).
Finally, we quantified the quality-adjusted life years (QALY) saved by OAT versus non-OAT from the loss of quality-adjusted life expectancy (QALE) in heroin users. A total of 1283 heroin users stratified by OAT were linked to the National Mortality Registry for 8 years (2006-2014) to obtain survival functions, which were extrapolated to lifetime by applying a rolling extrapolation algorithm of logit transformed survival ratio between the sub-cohorts and age-, sex-, and calendar year-matched referents simulated from vital statistics of Taiwan. On those with a valid state of OAT or non-OAT plus newly recruited consecutive patients, we performed measurement of EQ-5D on 349 participants during 2015-2017 for utility values, while QOL of referents were abstracted from the 2009 National Health Interview Survey. The QALE was calculated by summing the product of the mean QOL function and survival function throughout life. The QALE difference between the cohort and corresponding referents was the loss-of-QALE. QOL of the OAT group was significantly better than that of the non-OAT group in every domain of the EQ-5D, which was quantified to be 0.23 in utility value after controlling for other potential confounding variables. The estimated QALE and loss-of-QALE were 17.8 and 18.2 QALY for OAT subjects, respectively, while those of the non-OAT group were 9.2 and 27.9 QALY. Receiving OAT could save 9.7 QALYs for heroin users compared with non-OAT after accounting for QOL differences along time.

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