阿片類藥物使用障礙的藥物：鍵接照護上的鴻溝

資料來源：刺胳針醫學期刊，www.thelancet.com Vol 391. January 27, 2018；財團法人台灣紅絲帶基金會編譯

在過去的二十年裡，美國一直處在阿片類藥物危機的陣痛中，其特點是死亡人數不斷上升；在2016年，阿片類藥物擔負了該國估計有64,000件致命的藥物使用過量案例之大部分責任。問題始於20世紀90年代，過量地開具阿片類鎮痛藥劑處方，讓疼痛的患者暴露在成癮風險下和製造大量過剩的止痛藥被轉移到廣大社區並被濫用。

此外，美國阿片類藥物成癮者數量的飛快成長，導致愛滋病毒和C型肝炎在這群濫用這些藥物並採注射方式施打者之間的傳播，並由於懷孕母親的阿片類藥物使用，更導致出生即對阿片類藥物依賴嬰兒數量的增加（新生兒戒斷症侯群）。

阿片類藥物危機一直是一個不斷變化的目標；儘管它始於阿片類處方藥物的濫用，而這種情形並打開了海洛因使用量增加的大門。十年以前，在美國大多數濫用阿片類藥物的人都以處方藥物開始，但現在海洛因相較於最普遍的阿片類處方藥物如羥考酮和氫可酮( oxycodone and hydrocodone，註：羥考酮和氫可酮都是麻醉鎮痛藥，用於緩解中度至重度癌症相關或急性疼痛。研究表明，它們的緩解疼痛的特性沒有差異。氫可酮在美國以外地區並不廣泛使用，因此在國際上使用有限。與氫可酮相比，羥考酮似乎具有更高的濫用可能性 )，已成為濫用阿片類藥物的起始藥物。甚至還有更有效的合成阿片類藥物如芬太尼( fetanyl ) 的大量湧入—通常用於攙雜或替代海洛因，因為它在生產上更便宜和更容易於進口—除對使用者增加了風險並使阿片類藥物過量死亡增加之趨勢持續下去，美國政府當局和醫學界正針對著解決這個問題上採用了多種方法。 2016年3月，美國疾病預防和控制中心（CDC）已針對慢性非癌症疼痛修正其阿片類藥物之處方指南，在疼痛管理上建議其他替代的方法，和當需要使用阿片類藥物的時侯，限制其劑量和持續使用的時間。執法和外交部門正在進行努力，以阻止合成阿片類藥物的流入，其中大多數係源自於中國的實驗室。並在拯救過量使用阿片類藥物者之生命上，大多數美國的州已針對警察、緊急醫療人員和阿片類藥物使用者本身採取措施，以增加阿片類藥物的拮抗劑納洛酮( naloxone ) 之可用性。這個安全和容易使用的藥物如果及時給藥，則可以迅速反轉一個受阿片類藥物過量影響的人並恢復其呼吸。而當社區已針對阿片類藥物使用者、他們的家人或潛在的旁觀者分發了納洛酮後，已看到過量死亡人數的減少。納洛酮現在雖然已有易於給藥的鼻腔噴劑可供使用，但針對涉及芬太尼或其他潛在的合成阿片類藥物之服用過量時，有時仍需要有多種之給藥方式。研究人員正在努力開發更有效的和更持久的阿片類拮抗劑以對抗芬太尼之威脅。

成癮治療在減少死亡和傳染病傳播方面上同等重要，雖然在美國歷史上這種治療很難取得，大多數的保險都沒有涵蓋，並且品質上是多變的。過去十年來的醫療改革工作已開始針對物質使用障礙者增加以證據為基礎的治療機會，以及將該等治療整合至更大的醫療保健系統中。藥物治療是阿片類藥物使用障礙的黃金準則，目前經美國食品藥品管理局（FDA）批准的有三種藥物，所有這些藥物都針對μ–阿片受體。美沙酮和丁基原啡因( methadone and buprenorphine )有激動劑作用，解決了渴望和戒斷症狀卻不會產生欣快感，用於長期之維持治療。相反的，納曲酮 ( naltrexone ) 則為受體的拮抗劑，可防止非法阿片類藥物產生影響。

在美國，藥物治療需要與某種形式的諮詢或行為治療相結合，稱之為藥物輔助治療（MAT），但那些可經由MAT而受益者與接受MAT之治療者之間仍然存在巨大差距，這種差距反映了除了是對阿片類藥物使用障礙者缺乏治療能力外，另外更是一種源自於相信這些藥物只是將某一種成癮由另一種成癮予以替代，且根深蒂固的羞恥感進而去反對去使用藥物。這種信念，延續自早期恢復模式中強調完全地戒除所有的藥物，反映了對這些藥物在藥理學和治療上效果的誤解。當阿片類藥物的使用者使用美沙酮或丁基原啡因治療時，適當劑量使用時並不會產生欣快感或觸發條件反應產生渴求。這些藥物可減少戒斷症狀、改善情緒，並在恢復生理平衡上提供協助– 允許患者當他或她們努力朝向復原時，腦部也能夠癒合。

美沙酮，是阿片類藥物使用障礙上第一種被開發的藥物，它比其他的藥物便宜，是全球阿片類藥物使用障礙最常開具的處方藥物。但是在美國，美沙酮與常規醫療保健系統分開，必須在專門的機構中使用，呈現出取得上之障礙。美沙酮停止施藥時需要小心逐漸地減少藥量，以避免發生突然終止有關之嚴重戒斷症狀。丁基原啡因，已在2002年於美國被批准用於阿片類藥物使用障礙，可以在辦公室開具處方使用，且通常與納洛酮(naloxone ) 合併為一個配方( BUP-NX ) ，提供對抗濫用上的一些保護；它藥物過量的風險也低於美沙酮。當施用和整個治療期間需要經常定期且規律地回診。當患者對阿片類藥物具有高的耐受性而採用丁基原啡因治療時可能會有戒斷之症狀。總的來說，研究顯示，美沙酮和丁基原啡因在中到高劑量使用時對減少阿片類藥物之使用同樣有效。證據也顯示使用藥物治療和單獨的採用戒毒方式相比，在治療的留存率和減少阿片類藥物使用上有更大的效果；且藥物治療和單純採用心理社會治療相比，在減少藥物過量死亡上亦有更大的效果。

納曲酮，採拮抗劑治療的方式，通常被認為是耐受性不佳，這主要反映了使用口服納曲酮治療的阿片類藥物使用者其藥物的順從性差。為了改善藥物順從性，延長釋放的納曲酮製劑，這需要每月注射之（XR-NTX），於2010年由美國食品藥物管理局( FDA )開發並批准用於阿片類藥物使用障礙。納曲酮可以由美國的任何醫療提供者開具處方施用，但不會引起欣快效應、身體依賴、戒斷症狀，或呼吸抑制，因此沒有轉移或過量的風險。然而，納曲酮對所有的阿片類藥物使用障礙者，已經呈現其滲透率最低。一個原因是納曲酮的引用時要求患者完全戒毒以防止沉澱性戒斷（所謂的「排毒障礙」），這可能需要幾天逐漸地去減少阿片激動劑藥物的殘留。但是，人們普遍認為拮抗劑比激動劑治療效果差，儘管沒有有效性的比較數據可以去證實這一觀點，但仍然是一個障礙。Joshua D Lee及其同事在「剌胳針」上報導一項由美國國家藥物濫用研究所資助的試驗X：BOT之結果，以及在挪威所進行的一項試驗均顯示BUP-NX和XR-NTX在增加存留於治療和預防復發方面上同樣有效。患者普遍的信念，認為更嚴重的阿片類藥物使用障礙者需要激動劑治療，而美國的研究結果卻並不支持此種看法。

正在進行的遺傳和臨床特徵影響治療反應之研究，最終將支持個人化之治療選擇。但現在，選擇藥物應該考慮患者的需要、合併症和醫療照護的取得。儘管目前有三種可用藥物的功效，它們並非對所有患者都有效，而且每個藥物都有缺點。因此，美國國立衛生研究院正著手與製藥公司建立合作夥伴關係，加快阿片類藥物使用障礙者新藥物的研發和改善現有藥物的配方。每月兩次緩釋型丁基原啡因的製劑正在接受FDA的審查，未來的研究將會確認它們是否有助於改善治療之存留和治療之結果。需要朝向研究如何優化XR-NTX的啟用，因為這是拮抗劑治療最主要的一個障礙；以及朝向如何減少個案流失比率，因所有藥物流失率仍然很高；在Lee和他的同事結束其6個月之試驗時，這一個數字為50％。此外，研究人員仍然需要為嚴重程度不同之阿片類藥物使用障礙者建立適當的治療時間，並在如何結合藥物治療和社會心理介入措施中找出最有效的策略。同步的，執行面之研究亦正在測試新的模型，如何透過一般醫療保健系統（如，急診部門、初級醫療保健、感染症門診）以及刑事司法單位等，讓阿片類藥物使用障礙之藥物提升其獲取之機會。

阿片類藥物過量使用之流行，是近幾十年來美國最嚴重的公共衛生危機之一，針對阿片類藥物使用障礙的有效治療可以有助於去解決它，但結構和態度上的障礙限制其治療之取得。這些障礙是當藥物成癮仍被視為失德而非是醫療狀態的問題，最好經由法律體系而非是透過治療予以解決時代所遺留下來的。這些障礙必須克服，扭轉美國死亡人數不斷升級的局面。而其他阿片類藥物濫用正在上升的國家，更應該吸取美國經驗的教訓，並確保有效的治療方法是廣泛可用。

Medications for opioid use disorder: bridging the gap in care

For the past two decades, the USA has been in the throes of an opioid crisis marked by a rising number of deaths; in 2016, opioids were responsible for most of the nation’s estimated 64 000 fatal drug overdoses.1 The problem began with overprescribing of opioid analgesics in the 1990s, which exposed pain patients to the risks of addiction and produced large surpluses of pain pills that were diverted for misuse by the larger community.

Additionally, the escalating numbers of opioid addicted Americans led to increased HIV and hepatitis C transmission among people who misuse these drugs by injecting them and increased numbers of infants born dependent on opioids as a result of the mother’s opioid use (neonatal abstinence syndrome).

The opioid crisis has been a moving target; while it began with the misuse of prescription opioids, this then opened the door to an increase in heroin use. A decade ago, most people who misused opioids in the USA had initiated with prescription drugs, but now heroin is reported as the opioid of initiation more often than the most commonly prescribed opioids, oxycodone and hydrocodone. There has also been an influx of new, more potent synthetic opioids such as fentanyl—often used to adulterate or replace heroin because it is cheaper to produce and easier to import—that has increased the danger for users and perpetuated the trend towards increasing opioid overdose deaths. US Government authorities and the medical community are addressing the problem in a range of ways. In March, 2016, the US Centers for Disease Control and Prevention (CDC) revised its guidelines for opioid prescribing for chronic non-cancer pain, recommending alternative approaches in pain management and limitations on the dosing and duration of opioids when they are called for. Law enforcement and diplomatic efforts are being made to stem the influx of synthetic opioids, which mostly originate in Chinese laboratories. And to save the lives of people who overdose on opioids, most US states have taken steps to increase the availability of the opioid antagonist naloxone to police, emergency medical personnel, and opioid users themselves. This safe and easily used medication can quickly reverse the effects of an opioid overdose and restore breathing if it is administered in time; and communities that have distributed naloxone to opioid users, their families, or potential bystanders have seen reductions in overdose deaths. Naloxone is now available in an easy-to-administer nasal spray, although multiple administrations are sometimes necessary when overdoses involve fentanyl or other potent synthetics. Researchers are working to develop more potent and longer-lasting opioid antagonists to counter the fentanyl threat.

Addiction treatment is equally important in reducing deaths and infectious disease transmission, although historically in the USA such treatment has been hard to access, is not covered by most insurances, and is of variable quality. Health-care reform efforts during the past decade have begun to increase access to evidence-based treatment for substance use disorders and to integrate that treatment into the larger health-care system. Medications are the gold standard of treatment for opioid use disorder. There are currently three medications approved by the US Food and Drug Administration (FDA), all of which target the μ-opioid receptor. Methadone and buprenorphine have agonist effects, addressing craving and withdrawal symptoms without producing euphoria and are used for long-term maintenance therapy. By

contrast, naltrexone is an antagonist at the receptor and prevents illicit opioids from having an effect.

    In the USA, medications are required to be given in conjunction with some form of counselling or behavioural therapy, called medication-assisted treatment (MAT), but there remains a vast gap between those who would benefit from MAT and those who receive it. This gap reflects both lack of treatment capacity and an entrenched stigma against use of medications for opioid use disorder arising from the belief that these medications simply substitute one addiction for another. This belief, a holdover from early models of recovery that emphasised complete abstinence from all medications, reflects a misunderstanding of the pharmacological and therapeutic effects of these drugs. When an opioid user

is treated with methadone or buprenorphine, the doses used do not produce euphoria or trigger the conditioned responses that generate craving. These medications reduce withdrawal symptoms, improve mood, and help restore physiological balance—allowing the patient’s brain to heal while he or she works towards recovery.

    Methadone, the first medication developed for opioid use disorder, is less expensive than the other medications and is the most frequently prescribed medication for opioid use disorder globally. However,

in the USA methadone must be administered at specialty facilities separate from the regular healthcare

system, presenting access barriers. Methadone discontinuation requires careful tapering to avoid the

severe withdrawal associated with abrupt termination. Buprenorphine, which was approved for opioid use disorder in the USA in 2002, can be prescribed in officebased practices and is now usually given in a formulation with naloxone (BUP-NX) that provides some protection against misuse; it also has a lower risk for overdose than methadone. Clinic visits are required frequently during induction and regularly throughout treatment. Patients with high opioid tolerance might experience withdrawal symptoms when treated with buprenorphine. Overall, research suggests that methadone and buprenorphine are equally effective at reducing opioid use when used at medium-to-high doses. The evidence also shows greater treatment retention and reduced opioid use with medications compared with detoxification alone, and reduced overdose deaths with medications compared with psychosocial treatments alone.

    Naltrexone, the antagonist treatment, is generally thought to be poorly tolerated, which mostly reflects the poor compliance reported among people with opioid use disorder treated with oral naltrexone. To improve compliance, an extended-release naltrexone formulation, which requires a monthly injection (XR-NTX), was developed and approved by the FDA for opioid use disorder in 2010. Naltrexone can be prescribed and administered by any provider in the USA and does not cause euphoric effects, physical dependence, withdrawal, or respiratory depression and therefore poses no risk of diversion or overdose. However, naltrexone has achieved the least penetration of all medications for opioid use disorder. One reason is that naltrexone induction requires that patients be fully detoxified to prevent the precipitation of withdrawal (so-called “detox hurdle”), which can require several days of tapering off opioid agonist medications. However, the widespread belief that antagonists are less effective than agonist treatments, despite the lack of comparative effectiveness data to substantiate this view, remains a barrier. The US X:BOT trial, funded by the National Institute on Drug Abuse and reported by Joshua D Lee and colleagues in The Lancet, and a trial done in Norway suggest that BUP-NX and XR-NTX are similarly effective at increasing treatment retention and preventing relapse. Results of the US trial do not support the widespread belief that patients with more severe opioid use disorder require agonist therapy.

    Ongoing research on the genetic and clinical features that influence treatment response will ultimately support personalised treatment selection. But for now, choice of medications should consider the patient’s needs, comorbidities, and access to care. Despite the efficacy of the three currently available medications, they are not effective for all patients and each has drawbacks. Thus, the US National Institutes of Health is embarking on partnerships with the pharmaceutical industry to accelerate the development of new medications for opioid use disorder and improved formulations of the existing ones. Two monthly extended-release formulations of buprenorphine are under review by the FDA, and future research will determine if they help improve treatment retention and outcomes. Research is needed on how to optimally initiate XR-NTX, since this is a major hurdle with antagonist treatment, and on how to reduce dropout rates, which remain high for all medications—about 50% by the end of the 6-month trial by Lee and colleagues. Furthermore, researchers still need to establish appropriate treatment duration for people with different severity of opioid use disorder and to identify the most effective strategies for combined medication and psychosocial interventions. In parallel, implementation research is testing new models for increasing access to medications for opioid use disorder through the general health-care system (ie, emergency departments, primary care, infectious disease clinics) and criminal justice settings.

    The opioid overdose epidemic is one of the worst American public health crises in recent decades, yet

structural and attitudinal barriers have limited the reach of effective treatments for opioid use disorder that could help address it. These barriers are holdovers from an era when drug addiction was still seen as a moral failing best addressed by the legal system, not a medical condition best addressed through treatment. These barriers must be overcome to reverse the escalating numbers of deaths in the USA. Other countries where opioid misuse is on the rise should learn lessons from the US experience and ensure that effective treatments are widely available.

www.thelancet.com Vol 391 January 27, 2018