緩釋性納曲酮：良好但並非是萬能
資料來源：www.thelancet.com Vol 391 January 27, 2018；財團法人數台灣紅絲帶基金會編譯
與其他成癮不同，鴉片類藥物使用障礙有幾種高度有效的治療藥物可用，特別是美沙酮、丁基原啡因和納曲酮。美沙酮在許多環境中是較難以取得或被接受，因此提供者和患者經常面臨丁基原啡因 – 納囉克松舌下錠（BUP-NX）和緩釋型納曲酮注射劑（XR-NTX）之間的選擇。當緩釋型納曲酮注射劑上市以來，許多提供者和研究人員預期其和口服納曲酮有相似的問題，較難開始啟動治療、順從性差，以及和促動劑藥物相比其有更高復發和藥物過量可能性之顧慮。直到最近，都還沒有直接比較並可以指導這種治療選擇之試驗。而現在同時比較BUP-NX和XR-NTX兩種藥物的兩個試驗已經完成，一個在挪威和一個在美國。挪威非劣效性隨機臨床研究顯示，兩種藥物在個案的存留於治療中以及有效性上相似。在刺胳針醫學雜誌上，約書亞·李（Joshua D Lee）及其同事報導了美國的一項多中心隨機開放式研究，針對在戒毒單位住院的病人（年齡大於或等於18歲）被隨機分配接受每月XR-NTX（n = 283）肌肉注射或每日在典型的社區門診中心服用舌下BUP-NX（n = 287）24週。本研究係針對XR-NTX在現實環境中採用時有關其可行性以及在治療上的安全性和有效性等幾個突出問題。為了平衡兩種治療的成功潛力，在不同階段的戒毒過程中隨機分配採用之藥物。研究的主要發現是，在有意願治療的群體中使用XR-NTX的人其復發率高於使用BUP-NX者（185 [65％] vs 163 [57％];風險比[HR] 1.36,95％ CI1.10-1.68）。然而，這個結果主要是由於XR-NTX有較少人被徵召加入以及在徵召失敗間所導致的高複發情形。因此，一旦成功開始治療，兩種藥物的有效性和安全性相似：474名參與治療的受試者中，XR-NTX組的鴉片類藥物復發事件發生率為52％，BUP-NX組為56％（優勢比0.87,95％CI0.60-1.25; P = 0.44），隨時間的演進其復發相對危險性上亦無顯著差異（HR 0.92,95％CI0.71-1.18; p = 0.49）。這些結果有兩個主要的涵義，首先，這些發現增加了支持XR-NTX其有效性和安全性的科學佐證文獻。成功的徵召使用後兩種藥物的相似表現與挪威研究的結果一致。這些結果是目前針對這兩種藥物直接比較唯一已發表的試驗，兩項研究都表明XR-NTX是一種促動劑治療中有效的替代性藥物，且應該被認定為在鴉片類藥物使用障礙的有效治療中亦是選擇之一。其次，由於XR-NTX在徵召使用上實質性的障礙將繼續面臨挑戰，因徵召失敗可能會導致復發和藥物過量，這一點尤其重要。事實上，在美國這項研究中，大多數XR-NTX徵召失敗確實導致復發［79名中有70名（89％）］，證實了這個問題的範疇。由於鴉片類藥物過量的高風險和美國藥物過量死亡率之持續上升，這種治療的失敗更令人擔憂。在這項研究中，兩組之死亡數相當（XR-NTX兩例，BUP-NX三例）。整體藥物過量（致命和非致命）差異在各組之間沒有差異，但值得注意的是XR-NTX的數量是18，而BUP-NX是10。考量到這項研究沒有能力去檢測藥物過量的差異，故後續應該繼續評估無法完成鴉片類藥物戒毒過程和無法有效徵召到使用XR-NTX，可能會增加藥物過量的風險。這項研究可能會被批評為僅侷限於徵召戒毒單位的急性住院病人，雖然這限制了研究結果外推的一般性，但是它反映了一種臨床常見的情況，適合這種比較藥物有效性試驗的目的，這些結果亦為治療提供了重要指導。在XR-NTX與BUP-NX之間進行選擇其常見的情況是非常複雜的，涉及許多因素，如患者喜好、治療史、目前生理上對鴉片類藥物依賴的程度，以及戒毒治療之取得等。對於處於鴉片類依賴狀態的患者，必須認真考慮企圖徵召使用XR-NTX其失敗和後續之復發的較高機會，除非在徵召使用前他們已處於足夠長的時間以完全從鴉片類藥物中撤出。對於許多這些患者來說，BUP-NX可能是更安全的初始策略，因為有更好的機會可更快速且成功的採用。以 XR-NTX用於不同的門診戒斷和採用的程序正在調查中，但是過程仍然具有挑戰性，需要進一步的測試。但是，對於完全已撤離鴉片類藥物的患者，現在可以認為XR-NTX相較於BUP-NX是一種具有相當的安全性和有效性的良好治療選擇。儘管XR-NTX存在徵召使用之問題，但許多患者選擇BUP-NX治療的原因有很多種，即使在門診病人中也是如此– – 優先避免使用促動劑、家庭或同伴的影響、刑事司法系統的要求或以前促動劑治療失敗。不幸的是，這種選擇就像在某些國家和其他場域一樣，有時會因為促動劑治療取得的限制而被強迫提供給患者。由於兩種藥物都是有效的，而且不清楚哪一種藥對於每個病人更好，所以決策者應該努力使兩種治療選擇均可採用，避免優先強制使用某一種藥物。另一個相關的問題是，美國的許多治療方案不提供任何鴉片類藥物治療，有時甚至不鼓勵使用藥物並將其視為劣質的治療模式。這種廣泛的誤解需要解決，亦需要針對鴉片類藥物使用障礙者之各級治療服務系統中藥物之取得進行改善。最後，這些結果帶來了幾個重要的研究需求上的關注。首先，繼續努力改進XR-NTX的徵召使用過程將有助於提高這種治療的安全性和可用性。另外，作者在此一研究和其他研究中對遺傳和其他治療調節因子的鑑定，將透過治療匹配的改進來進一步指導藥物之選擇。最後，未來的研究也應該著重找出個案流失的原因，並提高治療中的留存率，除了在其他治療處置方法外，還是要考慮使用藥物治療此一模式。
Extended-release naltrexone: good but not a panacea
資料來源：www.thelancet.com Vol 391 January 27, 2018
Unlike other addictions, opioid-use disorder has severalhighly effective medication treatments available, inparticular methadone, buprenorphine, and naltrexone.Methadone is the least accessible or acceptable of thesein many settings, so providers and patients are oftenfaced with a choice between buprenorphine-naloxone(BUP-NX) and extended-release naltrexone injection(XR-NTX).
Since XR-NTX became available, many providersand researchers expected it to have similar problemsto oral naltrexone—difficulty starting the treatment,poor adherence, and concerns about the possibility ofhigher relapse and overdose compared with agonistmedication. Until recently, no direct comparison trialwas available to guide this treatment selection.
Two concurrent trials comparing BUP-NX withXR-NTX have now been completed, one in Norway andone in the USA. The Norwegian randomised clinicalnon-inferiority studyshowed similar retention andeffectiveness of both agents. In The Lancet, Joshua D Leeand colleagues report on the US study, a multicentre,open-label, randomised trial. Patients (aged 18 yearsand older) at inpatient detoxification units wererandomly assigned to receive monthly XR-NTX (n=283)intramuscular injections or daily sublingual BUP-NX(n=287) for 24 weeks in typical community outpatientsettings. The study addresses several outstandingquestions about use of XR-NTX in real-world settingsregarding feasibility of induction, and the safety andeffectiveness of the treatment.To balance the successpotential for the two treatments, randomization and inductions occurred at different stages in thedetoxification process.
The main outcome of the study was higher relapsefor XR-NTX than with BUP-NX in the intention-to-treatpopulation (185 [65%] vs 163 [57%]; hazard ratio[HR] 1.36, 95% CI 1.10–1.68). However, this outcomewas primarily due to fewer XR-NTX inductions andhigh relapse among induction failures. Therefore, oncetreatment was successfully initiated, both medicationswere similar ineffectiveness and safety: among the474 participants inducted to treatment, the proportionof opioid-relapse events was 52% for the XR-NTX groupand 56% for the BUP-NX group (odds ratio 0.87, 95% CI0.60–1.25; p=0.44), with no difference in the relativehazard of relapse over time (HR 0.92, 95% CI 0.71–1.18;p=0.49).
There are two main implications of these results.First, these findings add to growing scientific literaturesupporting the effectiveness and safety of XR-NTX.The similar performance of the two medications aftersuccessful induction is consistent with the results of theNorwegian study.7 These are the only published directcomparison trials of these two drugs, and both studiesshow that XR-NTX is a valid alternative to agonisttherapy that should be considered among effectivetreatment options for opioid use disorder.
Second, the substantial induction hurdles forXR-NTX continue to present challenges, whichare especially important because induction failuremight lead to relapse and overdose. In fact, inthis US study most XR-NTX induction failures didrelapse (70 [89%] of 79), confirming the scope ofthis problem. Such treatment failures are even moreworrisome because of the high risk of overdosewith opioids and the continuing rise in overdosedeaths in the USA. In this study, deaths wereequivalent in the two groups (two for XR-NTX andthree for BUP-NX). Differences in total overdoses(fatal and non-fatal) did not differ between groups,but the numbers were noteworthy—18 for XR-NTXversus ten for BUP-NX. Considering that the studywas not powered to detect overdose differences,there should be continued evaluation of how failureto complete opioid detoxification and induction ontoXR-NTX might increase overdose risk.
The study might be criticised for restricting inductionsto acute inpatient detoxification units only. Althoughthis does limit generalisability, it reflects a commonclinical scenario, which fits with the aims of thiscomparative effectiveness trial.
These results offer important guidance for treatment.The common situation of choosing between XR-NTXand BUP-NX is highly complex, involving numerousfactors such as patient preference, treatment history,current level of physiological opioid dependence, andaccess to detoxification treatment, among others. Withpatients who are in an opioid-dependent state, the higherchance of induction failure and subsequent relapse withXR-NTX induction attempts must be carefully considered,unless they will be in a controlled setting long enoughto withdraw completely from opioids before induction.BUP-NX might be a safer initial strategy for many of thesepatients because of the better chance of a quick successfulinduction. Different outpatient withdrawal and inductionprocedures for XR-NTX are being investigated, but theprocess remains challenging and in need of further testingHowever, for patients fully withdrawn from opioids,XR-NTX can now be considered a good treatment optionwith equivalent safety and effectiveness to BUP-NX.
Despite the induction problems with XR-NTX, manypatients choose this treatment over BUP-NX for a varietyof reasons, even in an outpatient setting—preferenceto avoid agonists, influence from family or peers,requirements from the criminal justice system, or previousfailure of agonist therapy. Unfortunately, this choice issometimes forced on patients because of limits on accessto agonist therapy, as is the case in certain countries andother settings.5,13 Since both medications are effective,and it is not clear which one will be better for each patient,policy makers should work to make both treatmentoptions available and avoid preferentially mandating onemedication over the other. A related problem is that manytreatment programmes in the USA do not offer any opioidmedication treatment or sometimes even discouragemedication as an inferior mode of treatment. Thiswidespread misconception needs to be addressed andaccess to medication for opioid use disorder at all levels ofthe treatment delivery system needs to be improved.
Finally, these results bring attention to severalimportant research needs. First, continuing efforts toimprove the induction process for XR-NTX will helpenhance the safety and availability of this treatment.Additionally, identification of the genetic and othertreatment moderators by the authors in this and otherstudies will further guide medication selection throughimproved treatment matching. Last, future researchshould also work to identify the causes of dropout andimprove retention, with medication in addition to othermethods of treatment.