In Defense of Morphine (Part 1)

Every time I hope this debate is going to die out, or that science will swing back toward rationality, another study gets published and throws a wrench in things. I’ll type this very carefully:

There is no convincing evidence that morphine causes harm to patients experiencing ST-elevation myocardial infarctions (STEMIs).

As long as there isn’t a contraindication (e.g. hypotension or an allergy), it is fine to give morphine to your patient with a STEMI. MONA is not dead*, FAN is not the solution**, and I see no reason to give our patients with acute cardiac ischemia ketamine***. I think fentanyl is a better choice in most situations, but it’s not because morphine is a “bad drug” or “causes harm”; I just prefer fentanyl’s pharmacodynamic profile. Please, give morphine if the situation dictates or it’s what you prefer.

Why am I worked up? The journal Thrombosis and Haemostasis published a study earlier this week:

Just reading the title pushes me into a prothrombotic state... Though its authors express some appropriate reservations in the Discussion, we all know why they performed this study, what they expected it to show, and how it will be cited for years to come. It demonstrates an association between morphine and worse outcomes in patients with ST-elevation acute myocardial infarction (STEMI). I don’t know why everyone has been ganging up on poor old morphine for acute coronary syndrome (ACS)—maybe because it’s been beloved by so many for so long—but while I may not be able to empathize with the hardships of being popular, I sympathize with the hate it’s been receiving and hope to offer some exculpation.

How did we get here? Let’s start with a little back-story. For decades, morphine has been a staple for treating ACS. It was initially thought to reduce myocardial oxygen demand, dilate coronary arteries, and even exert direct myocardial protective effects through μ-opioid receptor agonism—all of which theoretically bene!t the ischemic heart. I’ll walk through all the data on this someday (I’ve got three different articles that have been stalled in the “draft” phase for a couple of years), but it suffices to say those benefits, if present, are di#cult to detect and almost certainly won’t prevent death or severe morbidity. As a result, we don’t need to administer morphine to every patient with ACS. Heck, I’ve seen it given to asymptomatic patients just because the provider thought they had to as part of the MONA package; that’s overkill. But if we’re not giving morphine to protect the heart, why are we pushing it?

We administer morphine to relieve pain. Even ignoring the argument that reducing pain theoretically reduces catecholamines and stress on the heart, the simple reason to give morphine to our patients with a STEMI is to make them feel better. Many of our patients experiencing acute myocardial infarctions are in moderate to severe pain—some even state they feel like they are going to die. We give morphine to relieve that pain and anxiety because it is the humane thing to do.

A bump in the road Morphine had a good run for the better part of a century. Even after all that time, its cardio-protective properties were still unproven and under investigation, but it didn’t seem to hurt ACS patients either. Until 2005:

I loathe this study. More accurately, I can’t stand how often it is misinterpreted. I get furious when I tally up all the time I’ve wasted explaining why this data does not show morphine causing harm. Diving in... The CRUSADE registry was active from July 2001 to December 2006 as a way of following the in- and post-hospital treatment and outcomes of patients with non-ST-elevation myocardial infarctions (NSTEMIs), and later, STEMIs. Its goals were to examine current practices and outcomes across a huge swath of patients and improve adherence to ACC/AHA guidelines. Unsurprisingly, it was funded by multiple pharmaceutical companies who, I suspect, wanted data to push providers into prescribing more of their medications. At least they didn’t name it something overtly inflammatory like "Get With The Guidelines"...

Anyway, over fifty publications have used the data from the CRUSADE registry, but the above study keeps popping up on my Facebook and Twitter feeds. It retrospectively examined observational data from 17,003 patients who presented with, “ischemic symptoms at rest within 24 hours prior to presentation and high-risk features including ST-segment depression ≥0.5 mm, transient ST-segment elevation 0.5-1.0 mm (lasting for <10 min), and/or positive cardiac markers (elevated troponin I or T and/or creatine-kinase [CK]-MB > upper limit of normal [ULN] for the local laboratory assay).” In simpler terms, they looked at patients with moderate-to-high-risk unstable angina (UA) or NSTEMI. The outcomes examined were, “in-hospital death, recurrent myocardial infarction, congestive heart failure, and cardiogenic shock”—the typical grab-bag of “major adverse cardiac events” (MACE) common to cardiology studies. They looked at both individual outcomes and a composite endpoint, but I don’t see where they picked a primary endpoint.

On their first pass, the investigators looked at the outcomes of patients treated with morphine compared to those who had no morphine administration recorded. Then they adjusted for just about every variable in the registry:

It’s an admirable list of co-variates, but it misses the point. The Achilles’ heel of this study is that patients who received morphine represent a higher-risk group than those who didn’t, for reasons directly affecting why they were administered morphine. None of the variables listed above account for refractory angina, and except for that physician I mentioned who liked to give everyone with a positive troponin 2 mg, it’s not like morphine is randomly administered.

This is a classic example of confounding.

So, not only is this study unable to prove causality since it is retrospective, any associations it identifies linking morphine to poor outcomes are inevitably, and irreparably, biased because sicker patients were more likely to receive the medication.

Look at it this way: It’s unlikely that numeric pain values correspond well to the amount of at-risk myocardium in the patient with ACS [3]. Most of us have seen patients with 10/10 pain from mild unstable angina or, alternately, 1/10 epigastric discomfort experiencing a giant anterior/septal/lateral/apical STEMI. But what does portend a worse outcome in the patient with proven ACS is ongoing pain that’s refractory to medical therapy. It doesn’t much matter if a patient’s ischemic pain is a 1/10 or a 10/10—if it doesn’t resolve with medical therapy, the artery is not open and the myocardium is still ischemic or infarcting. It’s why refractory chest pain in a patient with UA/NSTEMI is a Class I, LOE A indication for immediate revascularization according to the AHA/ACC.

NSTEMI/UA patients rarely receive this recommended management, however. Here’s how it often plays out:

A patient comes in with chest pain and new ST-depression, T-waves inversions, or non-specific ECG changes (even intermittent ST-elevation). He or she gets diagnosed with UA or NSTEMI (depending on the troponin) and admitted to nitro paste and anti-platelet/antithrombotic therapy. On the $oor the pain recurs or was never totally abolished, to begin with, so the patient receives morphine PRN to control the symptoms. The next day, their troponin is through the roof, an echo shows a large area of akinesis, and/or their ECG shows large Q-waves—all because they infarcted through the night and morphine was used to mask the symptoms. The patient eventually goes for angiography and, depending on the findings, revascularization. The infarction is irreversible, but since it’s UA/NSTEMI and not a missed STEMI, no one really cares about the delay (except for the patient, but he or she doesn’t know any better).

I could probably put together a case series of those sorts of encounters, but I doubt I’d get permission to publish a bunch of avoidable bad outcomes... This management is common, and I’m con!dent it was even more prevalent when this data was gathered in the early 2000s.

That is why I almost never recommend giving opioids to a patient with UA/NSTEMI. It masks the problem without fixing anything. This isn’t an issue for recognized STEMIs because they typically receive revascularization regardless of their symptoms, but the pain really is the “5th vital sign” for UA/NSTEMI patients because it can affect critical time-dependent treatment decisions.

Getting back to the article... In this sort of retrospective study, refractory ischemia is intimately entwined with morphine administration. The two cannot be separated and all you can see is a signal for harm associating morphine with worse outcomes. The morphine did not cause those worse outcomes, and even if it did contribute, you cannot measure the e"ect through the bias.

The authors from the CRUSADE article were well aware of this issue and attempted to account for it:

Unfortunately, I don’t see how that fixes things. I cannot explain why a patient would receive morphine but not IV nitro, or vice versa (though patients receiving neither are a lower risk). The reasons are probably too numerous, scattered, or patient-specific to account for here. Looking at the variables measured in the registry, we run into the same issues we’ve encountered before. I don’t see how they can be used to create useful propensity scores. It doesn’t matter if you balance out the groups based on age, chronic health problems, vital signs, or the dozen other factors listed earlier—the real factor that determines who gets IV nitro or morphine was not measured and cannot be included.

No matter how much you try, you cannot make the patients in the morphine group equivalent to the patients in the no-morphine group using a retrospective, observational data. In spite of that, the article soldiers on. As described in the Discussion:

But that’s the point! Patients whose pain was controlled with nitro didn’t need morphine because their ischemia responded to medical therapy—of course, they’ll do better. If they needed morphine on top of nitro, or morphine was used to mask the pain in lieu of nitro, they did worse. That issue invalidates the whole study, but the authors gloss over it and dedicate one sentence in their entire paper to the problem. Still, I cannot fault their final statement. A prospective, randomized, clinical trial is exactly what we need to determine whether morphine causes harm in ACS.

* [Morphine, Oxygen, Nitro, Aspirin] Well there are a lot of stipulations about giving oxygen only if hypoxemic, nitro not really changing outcomes, and morphine maybe not being the preferred agent, but you get my drift.

** [Fentanyl, Aspirin, Nitro] It isn’t a solution only because there isn’t a problem. FAN is a fine alternative for most patients, just not a necessary replacement.

*** Just... why? It’s fine to discuss, and I’d be interested in seeing it studied, but I hope no one is doing this because they believe it’s safer than fentanyl or morphine right now. References

Farag M, Spinthakis N, Srinivasan M, Sullivan K, Wellsted D, Gorog DA. Thromb Haemost. Morphine Analgesia Pre-PPCI Is Associated with Prothrombotic State, Reduced Spontaneous Reperfusion and Greater Infarct Size. Thromb Haemost. 2018 Feb 14 [Epub ahead of print]. doi: 10.1055/s-0038- 1629896. PMID: 29444530

Meine TJ, Roe MT, Chen AY, Patel MR, Washam JB, Ohman EM, Peacock WF, Pollack CV Jr, Gibler WB, Peterson ED; CRUSADE Investigators. Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. Am Heart J. 2005 Jun;149(6):1043-9. doi: 10.1016/j.ahj.2005.02.010. PMID: 15976786.

Leach A, Fisher M. Myocardial ischaemia and cardiac pain – a mysterious relationship. Br J Pain. 2013 Feb; 7(1): 23–30. doi: 10.1177/2049463712474648. PMID: 26516494. [Free Full Text at PMC]

Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, Ja"e AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ. 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes. Circulation. 2014;130:e344-e426. DOI: https://doi.org/10.1161/CIR.0000000000000134. Like 540