嗎啡目前被用於治療心肌梗塞引起的胸痛，並被推薦用於此用途，但由於缺乏支持性的臨床研究，其證據等級較低。
此外，美國心臟協會已將非ST段抬高型心肌梗塞（NSTEMI）患者使用嗎啡的建議等級從I級降至IIa級。這項調整是基於CRUSADE（快速風險分層不穩定型心絞痛患者能否透過早期實施美國心臟病學會/美國心臟協會指南來抑制不良預後）註冊研究的結果，該研究表明，
在NSTEMI患者中，使用嗎啡會增加死亡和不良預後的風險。嗎啡也與ST段抬高型心肌梗塞（STEMI）患者行直接經皮冠狀動脈介入治療（PPCI）後再
灌注成功率欠佳和
心肌挽救指數低相關。
然而，在來自FAST-MI（法國急性ST段抬高型和非ST段抬高型心肌梗塞註冊研究）的兩個獨立隊列中，STEMI患者院前使用嗎啡並未增加院內併發症或1年死亡率。由於有這種爭議，需要進一步的研究。
本研究旨在探討嗎啡對接受 PPCI 治療的前壁 STEMI 患者族群臨床結局的影響。
Introduction
Morphine is currently used and recommended for the treatment of chest pain during myocardial infarction, but the level of evidence is low, attributed to the lack of supportive clinical studies.
1,
2,
3,
4Moreover, the American Heart Association has relegated morphine use in patients with non‐ST‐segment elevation myocardial infarction from a Class I to a Class IIa recommendation.
3 This modification was driven by the results from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines) registry showing that, in patients with non‐ST‐segment elevation myocardial infarction, morphine use increased the risk of death and adverse outcome.
5 Morphine has also been associated with suboptimal reperfusion success and a low myocardial salvage index after primary percutaneous coronary intervention (PPCI) in patients presenting with ST‐segment elevation myocardial infarction (STEMI).
6Nevertheless, in 2 independent cohorts from the FAST‐MI (French Registry of Acute ST‐elevation and non‐ST‐elevation Myocardial Infarction) registry, prehospital morphine use in STEMI patients did not increase in‐hospital complications or 1‐year mortality.
7 Because of this controversy, additional investigations are necessary.
The aim of this study was to explore the effect of morphine on clinical outcomes in a population of patients with anterior STEMI referred for PPCI.
結果
Results
The intent‐to‐treat CIRCUS population included 969 patients.
8,
9 Two patients were not included in our analysis because of lack of information on morphine use. Morphine was used before PPCI in 554 (57.3%) patients. Baseline characteristics (Table
1) and periprocedural characteristics (Table
2) were well balanced between groups with and without morphine use. There was a nonsignificant trend toward younger age and a shorter total ischemic time in patients receiving morphine. There was also a trend toward more heart failure and cardiogenic shock in the morphine group: 13.1% versus 10.2% of patients admitted in Killip 2 or 3 and 1.4% versus 0% of patients admitted with cardiogenic in morphine and no‐morphine group, respectively (Table
2).
At 1 year, 236 (24.4%) patients had experienced at least 1 MACE. There was no significant difference in occurrence of MACE between groups: 145 (26.2%) and 91 (22.0%) patients in the groups with and without morphine, respectively (P=0.15; Table
3). Cumulative Kaplan–Meier estimates for the first occurrence of MACE (Figure
1) were not significantly different between groups (P=0.10).
In the Cox model, morphine use was not associated with the incidence of MACE (hazard ratio=1.25; 95% confidence interval [0.96; 1.62]; P=0.10), even after adjustment for age, ischemic time, infarct size (CPK peak), initial and final Thrombolysis in Myocardial Infarction flow, sex, smoking, hypertension, diabetes mellitus, previous myocardial infarction, and Killip class (hazard ratio=1.04; 95% confidence interval [0.75; 1.45]; P=0.82).
Incidence of individual MACE during 1 year was not significantly different between groups (Table
3; Figure
2).
There was no statistically significant difference on MACE occurrence (P=0.56) and on infarct size (P=0.61) between the 4 different treatment subgroups (Table
4). Interaction term, even after adjustment, was not significant and so for each clinical outcome individually (Table S1).
There was no significant difference in rates of all‐cause death at 1 year between groups (32 [5.3%] and 22 [5.8%] deaths in the groups with and without morphine, respectively; P=0.89).
The unadjusted Kaplan–Meier hazard curve for 1‐year all‐cause mortality is presented in Figure
3. No significant difference was observed between the groups with and without morphine (P=0.77).
CPK peak blood concentrations after PPCI were comparable in both groups (4023±118 and 3903±149 IU/L in the groups with and without morphine, respectively; P=0.52; Figure
4).
Rates of adverse left ventricular remodeling were also similar in both groups (205 [37.0%] and 134 [32.4%] patients with adverse remodeling in the groups with and without morphine, respectively; P=0.21).
討論
在一項針對大量急性前壁STEMI患者的研究中，有一半患者在接受PPCI治療前使用了嗎啡，但嗎啡對包括心血管死亡、心臟衰竭、心因性休克、復發性心肌梗塞、不穩定型心絞痛和中風在內的MACE複合主要終點沒有顯著影響。
鮮有其他研究評估急性冠狀動脈綜合症（ACS）患者在接受嗎啡治療以緩解胸痛後的臨床結局。 <sup>
16</sup>與我們的研究結果一致，兩項回顧性研究得出結論，嗎啡/靜脈注射麻醉劑不會對ACS患者的預後產生不良影響。其中一項納入1758例患者（765例ST段抬高型心肌梗塞[STEMI]和993例非ST段抬高型心肌梗塞[NSTEMI]）的研究顯示，使用靜脈注射麻醉劑並未增加30天死亡率。 <sup>
17</sup>第二項研究分析了兩組STEMI患者（分別來自FAST-MI 2010註冊研究的2438例和FAST-MI 2005註冊研究的1726例）<sup>
7 </sup>，結果顯示院前使用嗎啡與院內併發症和1年死亡率的增加無關。
相反，一項基於CRUSADE註冊研究的美國回顧性研究<sup>
5 </sup>（納入57039例非ST段抬高型急性冠狀動脈綜合症患者）報告稱，嗎啡治療會增加死亡率，並質疑其在這些患者中的安全性。由於在人群、研究日期和設計方面的差異，很難將CRUSADE研究與我們的研究進行比較。 CRUSADE研究回顧性地納入了非ST段抬高型急性冠狀動脈綜合症患者，這與ST段抬高型心肌梗塞患者不同。研究於2002年至2003年間開展，當時口服抗血小板藥物僅限於氯吡格雷，而氯吡格雷與嗎啡的藥理交互作用比替格瑞洛和普拉格雷等近期核准的藥物更為顯著<sup>
18,19 </sup>。
因此，目前似乎沒有太多證據顯示嗎啡在 STEMI 患者中會產生不良後果，而對於 NSTEMI 患者，可能需要格外謹慎。
在本研究中，嗎啡的使用似乎與任何顯著的心臟保護作用無關。關於鴉片類藥物的心肌保護作用，過去報告並不一致。一些研究表明，嗎啡在冠狀動脈繞道手術等外科手術中具有心臟保護作用，但這些研究的樣本量較小，且評估的是間接結果。 <sup>20,21</sup> 在接受急診經皮冠狀動脈介入治療（PPCI）的ST段抬高型心肌梗塞（STEMI
）患者中，嗎啡除了具有遠距缺血預適應的基礎作用外，還顯示出心臟保護作用，
<sup> 22</sup>但在接受度期<sup>
23</sup>在缺血再灌注損傷的實驗模型中，嗎啡透過μ和κ心肌阿片受體抑製粒線體通透性轉換孔
24的開放性<sup> 25,26 </sup>，誘導顯著的心臟保護作用<sup>
27</sup> 。嗎啡還能活化再灌注損傷的挽救激酶路徑<sup>24</sup>。在
動物研究中，這些機制與再灌注前或再灌注後立即靜脈或鞘內注射嗎啡可減少梗塞面積相關<sup>28,29,30</sup>。然而
，由於疾病的複雜性和相關合併症，從動物模型到人類的轉化並非易事，而且我們的數據並未顯示嗎啡對缺血再灌注損傷具有任何心臟保護作用。在不久的將來，兩項尚未發表的研究（臨床試驗 NCT01186445 和 NCT01738100）可能會進一步揭示 ACS 期間冠狀動脈內嗎啡的心臟保護作用。
近年來，人們越來越關注嗎啡在急性冠狀動脈綜合症（ACS）患者鎮痛的應用。嗎啡會抑制胃腸道吸收<sup>35</sup>並誘發嘔吐<sup>16</sup>，從而延遲並減弱口服抗血小板藥物在ACS
患者<sup>31,32,33 </sup>和健康人群<sup>18,19,34</sup>中的釋放高峰和療效。
然而，目前尚無
證據顯示這些
影響具有
臨床意義。在本研究中，雖然嗎啡與ST段抬高型心肌梗塞（STEMI）患者的任何不良預後無關，但嗎啡治療組患者發生主要不良心血管事件（MACE）的趨勢略有增加，但差異無統計學意義。特別是，在經皮冠狀動脈介入治療（PPCI）前使用嗎啡似乎會增加復發性心肌梗塞和心臟衰竭的發生率，儘管這些結果未達到統計學意義（P值分別為0.08和0.28；表
3）。
無論在急性冠狀動脈綜合症（ACS）中使用嗎啡可能對預後產生何種影響，緩解疼痛對於減輕患者不適和避免誘發心律不整的焦慮至關重要。在本研究中，42.7% 的患者未接受任何鎮痛治療，這意味著疼痛可能未被充分控制。這種情況是不可接受的，緩解疼痛應是所有醫療照護的首要任務。由於缺乏符合倫理的安慰劑對照隨機研究，因此難以就嗎啡在此適應症中的安全性得出明確結論。目前尚無嗎啡在此適應症中的替代鎮痛藥物，唯一正在評估的新方法是等摩爾氧氣/氧化亞氮混合物（MEOPA）聯合對乙醯氨基酚，該方案正在正在進行的 SCADOLII（急性冠脈綜合徵鎮痛中 MEOPA + 對乙醯氨基酚與嗎啡治療的比較）試驗中進行研究。正如最近一項綜述所總結的那樣，在缺乏明確不良反應證據的情況下，
應在 STEMI 中使用嗎啡，無需限制。
Discussion
In a large cohort of patients with acute anterior STEMI, morphine was used in half of patients before PPCI and had no significant effect on the composite primary outcome including cardiovascular death, heart failure, cardiogenic shock, recurrent myocardial infarction, unstable angina, and stroke.
Few other studies have evaluated the clinical outcomes of patients who received morphine to alleviate chest pain during an ACS.
16 In line with our results, 2 retrospective studies concluded that morphine/intravenous narcotics did not adversely affect the outcomes in patients with ACS. In 1 study including 1758 patients (765 STEMI and 993 non‐ST‐segment elevation myocardial infarction), the rate of 30‐day death was not increased with the use of intravenous narcotics.
17 In the second study, the analysis of 2 cohorts of STEMI patients (2438 patients from the FAST‐MI 2010 registry and 1726 from the FAST‐MI 2005)
7 suggested that prehospital morphine use was not associated with increased in‐hospital complications and 1‐year mortality.
On the contrary, an American retrospective study based on the CRUSADE registry,
5 which included 57 039 patients who presented with non‐ST‐segment elevation ACS, reported an increase in mortality and challenged the safety of morphine use in these patients. It is difficult to compare the CRUSADE study with ours because of differences in population, study dates, and design. The CRUSADE study retrospectively enrolled non‐ST‐segment elevation ACS patients, who are different from STEMI patients. It was conducted between 2002 and 2003, at a time when oral antiplatelet agent use was limited to clopidogrel, which has more pharmacological interactions with morphine than more recently approved agents such as ticagrelor and prasugrel.
18,
19Thus, it seems that there is currently limited evidence for adverse outcomes associated with morphine use in STEMI patients, whereas additional caution may be necessary in NSTEMI patients.
In our study, morphine use did not appear to be associated with any significant cardioprotective effect. Myocardial protection with opioid use has been inconsistently reported. Several studies suggest a cardioprotective effect especially with morphine in the surgical context of coronary artery bypass graft, but these studies were conducted in small surgical patient populations and assessed indirect outcomes.
20,
21 In STEMI patients undergoing PPCI, a cardioprotective effect could be demonstrated for morphine in addition to the basal effect of remote ischemic conditioning,
22 but no additional myocardial protection was observed with fentanyl in patients undergoing elective PPCI.
23In experimental models of ischemia reperfusion injury, morphine inhibits the mitochondrial permeability transition pore
24 opening through μ and κ myocardial opioid receptors,
25,
26 and induced a significant cardioprotective effect.
27 Morphine also stimulates the reperfusion injury salvage kinase pathway.
24 In animal studies, these mechanisms have been associated with a reduction of infarct size following intravenous or intrathecal morphine use before or immediately after reperfusion.
28,
29,
30 However, the translation from animal models to humans is not straightforward owing to disease complexity and associated comorbidities, and our data do not suggest any cardioprotective effect of morphine on ischemia‐reperfusion injury. In the near future, 2 noncurrently published studies (Clinical Trials NCT01186445 and NCT01738100) may provide additional understanding of the cardioprotective effects of intracoronary morphine during ACS.
In recent years, there has been a growing concern about the use of morphine for pain relief in patients with ACS. Morphine delays and attenuates the release peak and efficacy of oral antiplatelet agents in ACS
31,
32,
33 and healthy
18,
19,
34 patients, by inhibiting gastrointestinal absorption
35 and inducing to vomiting.
16 However, there is no evidence for the clinical relevance of these effects. In our study, although morphine was not associated with any adverse outcome in STEMI patients, there was a nonsignificant trend toward an increase in individual MACE in patients treated with morphine. In particular, recurrent myocardial infarction and heart failure seemed to be more frequent when morphine was used before PPCI, although these results did not reach statistical significance (P=0.08 and 0.28, respectively; Table
3).
Regardless of the potential outcome modifications associated with morphine use during ACS, pain release is essential to decrease patients' discomfort and to avoid proarrhythmic anxiety. In our study, 42.7% patients did not receive any analgesia, meaning that pain was probably undertreated. This is not acceptable, and pain release should be a priority of any medical care. Without ethical possibility of a placebo‐controlled, randomized study, it is difficult to conclude definitively about morphine safety in this indication. There is no analgesic alternatives to morphine in this indication, and the only new approach currently evaluated is equimolar oxygen/nitrous oxide mixture (MEOPA) associated with paracetamol, under investigation in the ongoing SCADOLII (Comparison of MEOPA + Paracetamol Versus Morphine Treatment in Acute Coronary Syndrome Analgesia) trial. In the absence of clear evidence of adverse effects, morphine should be used without restraint in STEMI as was concluded in a recent review.
16
