J Cardiol Clin Res 4(4): 1067.
Submitted: 02 June 2016; Accepted: 02 July 2016; Published: 04 July 2016
Review Article
An Evidence-Based Review of Pain Management in Acute Myocardial Infarction
Abdikarim ABDI1 and Bilgen Basgut1,2*
1Department of Clinical Pharmacy, Near East University, Turkey
2Department of Pharmacology, Near East University, Turkey
*Corresponding author: Bilgen Basgut, Department of Clinical Pharmacy and Pharmacology, Near East University, North Cyprus, Mersin10, Turkey,
Email: bilgenbasgut@gmail.com
Since the turn of the twentieth century, morphine, an opioid analgesic, has played
an integral role in the management of pain in myocardial infarction (MI). This is
attributed to morphine’s effect on reducing blood pressure, slowing heart rate, and
relieving anxiety, which may decrease myocardial oxygen demand, added to the fact
that morphine has been studied extensively in pain management in many settings. For
this morphine kept considered amongst the first line therapies and most effective for
acute pain management in MI patients according to many guidelines.
However, observational data suggest that morphine administration during acute
myocardial infarction (AMI) may have negative consequences, while this practice also
lacks supporting rigorous evidence or studies designed to assess the effect of morphine
administration. Added to this recent evidence uncovered that morphine may impede
gastrointestinal absorption of oral antiplatelet drugs important in reducing mortality
in AMI.
These observations permit a comprehensive evaluation of the rationality of
administration of morphine in AMI, and whether better alternatives are available
in currently used analgesics or by using a morphine non-interacting P2Y12 receptor
inhibitor for AMI patients.
In this review we discuss the rationality of morphine use according to recent evidence
and the side effects and drug-drug interactions of morphine affecting MI patient with
the present alternatives based on the findings of experimental, observational and
randomized clinical studies.
Keywords: Pain management; Myocardial infarction; Dyspnoea; Coronary atherosclerosis
Myocardial infarction (MI) is a major cause of mortality and
disability worldwide. The term MI reflects cell death of cardiac
myocytes caused by ischemia, as a result of a perfusion imbalance
between supply and demand. It’s most obvious classical clinical
symptoms include various combinations of chest, upper
extremity, jaw, or epigastric discomfort on exertion or at rest
[1]. The discomfort associated with acute myocardial infarction
(AMI) usually lasts at least 20 minutes. Often, the discomfort is
diffuse, not localized, not positional, not affected by movement of
the region, and it may be accompanied by dyspnoea, diaphoresis,
nausea, or syncope. Relief of stressful symptoms as chest pain is
important, not only for patient well being, but also because stress
induces systemic circulatory effect that may worsen the ongoing
infarction [2].
Since 1923 when James MacKenzie first suggested use of
morphine and chloroform for treating cardiac patients with bed
rest until unconsciousness is achieved. Since then morphine has
been considered as one of the first line medications recommended
for pain control in AMI. This was attributed to morphine effect
on reducing blood pressure, slowing heart rate, and relieving
anxiety, which may decrease myocardial oxygen demand, added
to the fact that morphine has been studied extensively in pain
management in many other settings while opioids are generally
considered the first line therapies and most effective for acute
pain management [2,3].
Despite this, morphine use in the setting of AMI lacks
supporting rigorous evidence or studies designed to assess
the effect of morphine administration. Yet many international
guidelines such as the American College of Cardiology, the
American Heart Association, and the European Society of
Cardiology guidelines recommend morphine administration as a
standard therapy in pain management in AMI [4,5].
Added to the critique of lack of strong evidence, a large
observational study in 2005 reported that the use of morphine
either alone or in combination with nitroglycerin was associated
with higher mortality than nitroglycerin alone, whereas new
studies and trials may further explain this by associating
morphine use with attenuation of action of oral antiplatelet
medications [6,7].
These observations permit a comprehensive evaluation of the
rationality of administration of morphine in AMI, how it impacts
MI treatment and reperfusion therapy success, and whether
better alternatives exist for managing pain in AMI patients, which
warrant rigorously designed studies.
Ischemic pain of acute myocardial infarction
MI is defined as myocardial cell death due to prolonged
ischemia. Coronary atherosclerosis is a chronic disease with
stable and unstable periods. During unstable periods with
activated inflammation in the vascular wall, patients may
develop MI. The mechanism of MI often involves a complete
blockage of a coronary artery or more caused by a rupture of
an atherosclerotic plaque or less commonly due to coronary
artery spasms.
Due to the myocardial cell death or ischemia, MI is most
commonly accompanied by chest pain, tightness or discomfort
which may radiate to shoulders, arms, back, neck, or jaw. This
pain together with blood flow abnormalities, induce a massive
surge of catecholamine release from the sympathetic nervous
system leading to systemic circulatory effects such as an increase
in blood pressure, heart rate, and stroke volume. As a result these
changes may adversely further influence the balance between
myocardial metabolic requirement and supply and further result
in infarct extension [8,9].
The amount of myocardium that undergoes necrosis in
MI is an important predictor of morbidity and mortality. The
infarction does not occur instantaneously, it first develops
in the subendocardium and progresses as a wave-front of
necrosis from subendocardium to subepicardium over the
course of several hours. Transient coronary occlusion may cause
only subendocardial necrosis, whereas persistent occlusion
eventually leads to transmural necrosis. The goal of acute
coronary interventions generally is to interrupt this wave-front
and limit myocardial necrosis [10].
Restoration of arterial blood flow remains the only way to
salvage ischemic myocytes permanently, by either thrombolytic
enzymes or percutaneous coronary intervention (PCI) or by
Coronary artery bypass grafting (CABG), in addition to the
following interventions that can delay ischemic injury which
include oxygen, nitroglycerine, thrombolytic agents, β-blockers,
and pain management [9,10].
Concerns around morphine use
Beside the effectiveness of morphine in management of pain
and its clinical use to relieve chest pain in AMI; a practice first
documented back in 1912, and since then been the ultimate
practice supported with major therapy guidelines till today [11].
However strong criticisms to its use exist.
To start with, there have never been any randomized,
controlled, clinical trials or large scale observations evaluating
and supporting the efficacy or safety of morphine for use in ACS
while many guideline recommendations were not based upon
randomized clinical trials but only upon expert opinion which is
considered to be “poor” form of evidence.
Secondly morphine known side effects such as hypotension,
bradycardia and respiratory depression, may result in deleterious
outcomes in high doses especially in AMI patients who might
lack the coronary reserve required to withstand the stresses of
hypotension and hypoxemia [12-17].
The CRUSADE registry which is a retrospective, observational
study of 57 000 patients in which a total of 17,003 patients
(29.8%) received morphine within 24 hours of presentation,
revealed that administration of morphine either alone or in
combination with nitroglycerin was associated with higher
mortality for patients presenting with non-ST-segment elevation
myocardial infarction (NSTEMI) [6].
This analysis raised concerns regarding the safety of using
morphine in patients with NSTEMI and emphasized on the need
for randomized trials.
This outcome of morphine administration could be due to
morphine effect of blunting the severity of angina without actually
ameliorating the underlying pathophysiologic cause of chest pain
(i.e., coronary hypoperfusion) or due to morphine effect on oral
antiplatelet drugs absorption as shown in later studies [6]
.
In contrast a second observational study was carried, aiming
to assess the potential clinical impact of pre-hospital morphine
administration in ST-elevation myocardial infarction (STEMI)
patients from a nationwide French registry. 4,169 patients with
AMI were included 19% of them received morphine during prehospital
management, and the study concluded that pre-hospital
morphine use was not associated with an increase of in-hospital
complication and one-year mortality; and, could be more used as
recommended in the guidelines. [18].
In animal studies, morphine has been demonstrated quite
conclusively to increase myocardial infarction size as reported
by Markiewicz W. et al., 1982 [19] while contradictory to these
results, several other studies found morphine and particularly
selective delta receptor’s opioid agonists to show powerful
cardioprotective effects in numerous animal models and man
where in low doses it triggers a powerful endogenous system
that leads to a marked reduction in infarct size, called the
phenomenon of ischemic preconditioning [20,21].
So to develop a clear cause effect relationship, randomized
controlled clinical trials are necessary and warranted. As
recent trials uncovered a very important effect associated with
morphine use in MI that was not been noticed for the last decades
(Table 1).
Table 1 Studies regarding outcomes of morphine administration in AMI.
Authors/ year |
Study name |
Study Design |
Study Aim |
Population |
Results |
Thomas, Michael, et al; 1965 [12] |
Haemodynamic effects of morphine in patients with acute myocardial infarction |
Prospective clinical trail |
Haemodynamic effects of morphine in patients with acute myocardial infarction |
N=13 AMI patients |
Morphine associated with haemodynamic instability such as hypotension, bradycardia and respiratory depression. |
Meine, Trip J., et al; 2005 [6] |
"Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative." |
retrospective, observational registry enrolling patients |
evaluate the use of morphine within the first 24 hours after presentation in patients |
N=57039
NSTEMI |
Morphine associated with negative impact on mortality and clinical outcome. |
Iakobishvili Z , et al; 2010 [83] |
Effect of Narcotic Treatment on Outcomes of Acute Coronary Syndromes : (ACSIS) 2008 database |
Retrospective, observational
registry, focused on morphine. |
Evaluation of the effect of prehospital and in-hospital IV narcotics use on the in-hospital and 30-day outcomes among consecutive patients with various types of ACS. |
n = 765 STEMI
n= 993 NSTEMI |
Neutral regarding clinical outcome |
Puymirat, Etienne, et al ; 2015 [18] |
Correlates of pre-hospital morphine use in ST-elevation myocardial infarction patients and its association with in-hospital outcomes and long-term mortality: the FAST-MI (French Registry of STEMI & NSTEMI) programme. |
retrospective, observational registry |
the potential clinical impact of pre-hospital morphine administration in STEMI patients |
N= 4,169
19% (792) on morphine |
Pre-hospital morphine use was not associated with an increase of in-hospital complication and one-year mortality. |
De Waha, Suzanne, et al.; 2015 [27] |
Intravenous morphine administration and reperfusion success in ST-elevation myocardial infarction: insights from cardiac magnetic resonance imaging. |
Observational, focused
on morphine. |
To analyze the impact of IV morphine on ischemic
injury and salvaged myocardium assessed by cardiac
magnetic resonance imaging in patients with STEMI
reperfused by PPCI. |
n = 276 STEMI |
Suspected negative impact on clinical surrogate end-point. |
Table 1 Studies regarding outcomes of morphine administration in AMI.
×
Recently in 2013 Parodi and his colleagues while studying
prasugrel and ticagrelor loading doses in STEMI patients
observed that the onset of action of prasugrel and ticagrelor was
delayed by co-administration of morphine as a result of a drugto-drug
interaction (DDI) [22-24].
Later in the ATLANTIC study, in-ambulance administration
of ticagrelor in patients with STEMI transferred for primary PCI,
improved coronary reperfusion only in those patient groups who
did not receive morphine. [25].
The first randomized, double-blind, placebo-controlled,
cross-over trial was carried in 2014 by Eva-Luise Hobl and
her colleagues to examine the possible drug–drug interactions
between clopidogrel and morphine. They found that morphine
delays clopidogrel absorption, decreases plasma levels of
clopidogrel active metabolite, and retards and diminishes its
effects, which may lead to treatment failure in susceptible
individuals [7].
Further in a second trial, the IMPRESSION trial was performed
in 70 patients (35 in each study group) in a single-centre. The
study also found that morphine delays and attenuates ticagrelor
exposure and action in patients with MI [26].
Other researchers also recently found that IV morphine
administration prior to PCI to be independently associated with
suboptimal reperfusion success after PCI in patients with STEMI
[27].
Mechanisms and hypothesis behind morphine associated negative outcomes
In patients with MI, a number of medications of importance
in terms of mortality and morbidity are usually administered
all together, thereby raising the potential risk for drug-to-drug
interaction. As our knowledge of the morphine–antiplatelet
interaction has increased significantly over the last 3 years, recent
evidence may explain morphines administration associated
negative outcomes in AMI patients [6,28].
Drug interactions can occur due to pharmacokinetic
interactions including rate of absorption, metabolic pathways,
drug transport through membranes and protein binding. While
opioids provide highly effective pain relief, the therapeutic
activity of opioids is compromised by their gastrointestinal
adverse profıle. Opioids slow gastrointestinal tract motility and
decrease intestinal secretions both by a central nervous systemmediated
effect and an effect on the peripheral opioid receptors
in the GI tract. As this may induce also nausea and vomiting;
a well-known opioid-induced effects, it is also hypothesized
that low doses of opioids activate mu opioid receptors in the
chemoreceptor trigger zone (CTZ), thereby stimulating further
vomiting [29].
Opioid-induced bowel dysfunction is also another adverse
effect, which inturn reduce or delay absorption and decrease
peak plasma drug concentration levels (i.e. Cmax) of other orally
administered drugs [30].
Opioids such as methadone were early reported to affect
absorbtion of antiviral drugs as an example, by increasing their
exposure to inactivating gastric acids and by this decreasing their
bioavailability [7]. In the case of morphine in AMI, as reported by
Eva-Luise Hobl and her colleagues, morphine injection delayed
maximal plasma concentrations of clopidogrel (Tmax: 105 vs. 83
min, p = 0.025) and reduced both the Cmax of clopidogrel active
metabolite (from 171 to 113 ng/ml, p = 0.025) and the total
exposure as measured by the AUC0-n by 34% (16,840 vs. 11,103 ng
x h/ml, p = 0.001). As a result morphine administration delayed
clopidogrel absorption (p = 0.025) and delayed the maximal
inhibition of platelet aggregation on average by 2 h (n = 24; p
< 0.001). Residual platelet aggregation was higher 1 to 4 h after
morphine injection (n = 24; p < 0.005). Furthermore, morphine
delayed the inhibition of platelet plug formation under high
shear rates(P2Y-Innovance; n = 21; p < 0.004) and abolished the
3-fold prolongation in collagen adenosine diphosphate induced
closure times seen in extensive and rapid metabolizers (n = 16;
p = 0.001) [26].
Meanwhile Jacek Kubica et al reported from the IMPRESSION
trial that morphine also delay and attenuate ticagrelor exposure
and action in patients with MI by 36% decrease in exposure
(AUC(0 – 12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37%
(AUC(0 – 12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively,
with a concomitant delay in maximal plasma concentration of
ticagrelor (4 vs. 2 h; P = 0.004) [24,26].
Multiple regression analysis of the IMPRESSION trial showed
that lower AUC(0 – 12) values for ticagrelor were independently
associated with the administration of morphine (P = 0.004) and
the presence of STEMI (P = 0.014). While All three methods of
platelet reactivity assessment carried in this study showed a
stronger antiplatelet effect in the placebo group and a greater
prevalence of high platelet reactivity in patients receiving
morphine. Morphine was also concluded not to affect conversion
of ticagrelor to its active metabolite in AMI patients [26].
These effects of morphine on plazma concentration levels
of oral antiplatlet medications are hypothetically attributed to
decreased concentrations of the parent compound, probably
resulting from morphine-induced impaired gastric emptying,
lower intestinal motility and higher incidence of vomiting [28].
It is also hypothesized that patients who received morphine
might be subjects at higher risk of negative outcomes. Thus, it
is possible that in sicker patients, haemodynamic derangement,
adrenergic activation, and systemic vasoconstriction with the
reduction of blood volume to the abdomen may contribute to the
delayed drug adsorption and to the reduced platelet inhibition.
But the same morphine effect was also reported from the
IMPRESSION trial in healthy subjects [26].
Potent P2Y12-inhibitors (prasugrel and ticagrelor) were
hypothesized to provide an effective alternative to clopidogrel
when morphine is given, but in a later multicentre study the drugto-drug
interaction between morphine and antiplatelet agents
was observed in 300 STEMI patients undergoing PCI recieving
either prasugrel and ticagrelor. This association persisted even
after excluding patients who vomitted [31].
Cortisol, or hydrocortisone, is a steroid hormone
(glucocorticoid) that is vital to the endocrine system released
by the adrenal cortex to combat stress, opioid are well known
for their effect of inducing cortisol deficiency which may
advance to episodes of Addisonian crises [32]. Symptoms
include gastrointestinal effects, extreme weakness, mental
confusion, darkening of the skin, dizziness. nausea or abdominal
pain, vomiting and fever, though all dont appear spontaineosly.
A single 5-mg intravenous dose of morphine sulfate quickly
paralyzes cortisol production in opioid-naive men and
women, with a drop of more than 75% from baseline within
3 hours [33,34]. A meta-analysis of 11 trials (2,646 patients)
suggests a possible mortality decrease with corticosteroids.
Additional studies examining the effectiveness of replacement
corticosteroids, perhaps beginning concurrently with morphine
administration in patients with AMIs,are also warranted [35].
Other mechanisms that may result in the negative outcomes
associated with morphine administration in AMI, include
decrease in myocardial oxygen delivery, decrease of arterial
oxygenation, increase in arterial carbon dioxide, and perhaps
even cerebral hypoperfusion [36].
Suggested alternatives for analgesia in acute MI
Oral antiplatelet agents are the mainstay of pharmacological
treatment in patients with MI, while 30 % of these patients are
co-prescribed morphine which affects the absorption of the
first. Thus its of importance to review guidelines and further
charectorize and develop strategies to overcome this interaction
which could lead to treatment failure in susceptible patients.
In the following paragraphs we address the possible
alternatives and management of morphine antiplatelet
interaction [37,38].
Non-steroidal antiinflammatory drugs (NSAIDs)
Ketorolac and indoprofen were amongst the earliest Non
steriodal Antiinflammatory drugs (NSAIDs) analgesics suggesting
for pain management in MI [39,40]. NSAIDs are a group of agents
widely used for their anti-inflammatory, antipyretics, and
analgesics. Their maın mechanism of action is to inhibit a class of
enzymes known as cyclooxygenases (COX-1 & COX-2). According
to the isoenzyme they preferentially block, traditionally, they are
devided into COX-1 inhibitors which are very few with aspirin the
most commonly used, COX-2 inhibitors which include rofecoxib,
celecoxib, valdecoxib, parecoxib, etoricoxib, and lumaricoxib,
and non selective NSAIDs, which inhibit both COX-1 and COX-2
indiscriminately, and include diclofenac, naproxen, ibuprofen,
indomethacin, and piroxicam [41-44].
NSAIDs offer effective pain relief for the most common
forms of pain both acute and chronic ones, and are thus widely
used for relief of pain for a wide range of medical conditions
(44), but despite their widespread use, the US Food and Drug
Administration (FDA) in July 2015 strengthened warnings about
the risk of heart attack and stroke associated with nonsteroidal
antiinflammatory drugs (NSAIDs) [45]. The relationship between
NSAID use and cardiovascular events has long been subject
to numerous observational studies, clinical trials and metaanalyses,
with sometimes ambiguous conclusions [46,47].
The increased risk for cardiovascular events was first
demonstrated for COX-2 inhibitors but later found also associated
with most NSAIDs. A meta-analysis in 2006, of 138 randomized
trials was done in comparing the risk of vascular events of COX-2
inhibitors and traditional NSAIDs on 145,373 enrolled patients.
The analysis found COX-2 inhibitors as well as high-dose
diclofenac and ibuprofen to be associated with a higher risk of
vascular events, mainly MI, in contrast to high-dose naproxen
[48].
In a systematic review of community-based controlled observational
studies published 2011, the aim was to provide estimates
of the comparative risks with individual NSAIDs at typical
doses. The review included data from 21 cohort studies with
2.7 million exposed individuals and 30 case–controls, with a total
of 184,946 cardiovascular events. The highest overall cardiovascular
risks were seen with rofecoxib and diclofenac, while the lowest
with low dose ibuprofen and naproxen [49]. Naproxen was
reported also from a meta-analysis of 31 large-scale randomized
trials, to be least harmful compared to other NSAIDs and not being
associated with MI or cardiovascular death [50].
A large LANCET published meta-analysis came by in 2013,
aimed to characterize vascular and gastrointestinal effects of
NSAIDs, particularly in patients at increased risk of vascular
disease. The review concluded that the vascular risks of highdose
diclofenac, and possibly ibuprofen, were comparable to
COX-2 inhibitors, whereas high-dose naproxen was associated
with less vascular risk than other NSAIDs [51,52].
Its thought that NSAIDs increased cardiovascular risk is
due to either “platelet COX-1 to endothelial COX-2 inhibition
imbalance”, or to chronic renal COX-2 inhibition resulting in
hypertension, or both together. In the first case risk would be
immediate, in the second it would be time-dependent.
Also naproxen, ibuprofen and other NSAIDs may inhibit the
cardioprotection of aspirin when administered in close time
proximity with it. Bleeding is a concern too, coadministration
of antithrombotic treatments with all types of NSAIDs (except
aspirin) has been shown to increase the bleeding risk in patients
with MI [53,54].
Though the time course of the risk has not been clearly
elucidated, with arguments for an association with prolonged
duration of use only. Few evidence suggest NSAIDs to be
considered relatively safe drugs when prescribed at the most
effective dose and for the shortest duration of time, which was
defined to be 10 days or fewer in some studies, while others
studies indicate constant risk with also short term use of NSAIDs
[47,51].
For this though it may sound reasonable out of all NSAIDs to
evaluate short term naproxen (the least risky NSAID) compared
to narcotics for acute analgesia in MI patients, as some NSAIDS
shown to give better pain relief than morphine [46,47]. The FDA
Advisory Committee went to that current data does not support
the conclusion that naproxen has a lower risk of thrombotic
events than other NSAIDs; and that there is no latency period for
the risk of cardiovascular thrombotic events is associated with
NSAID use [46].
Hence NSAIDs though being effective analgesic agents, their
use is attenuated due to their associated cardiovascular events
risk and thus cannot be considered as alternatives for opioids
till new supporting evidence emerges, while The only NSAID
drug that should be given to such a patient before ACS has been
definitely ruled out is aspirin [55].
Five alternative strategies for analgesia in AMI
IV nitrates and Beta-blockers: As Ischemia being the main
etiology behind chest pain in AMI, reperfusion therapy in STEMI
and high risk NSTEMI patients is the most important component
of treatment, which strongly influences short- and long-term
patient outcomes.
In mild NSTEMI patients, immediate relief of ischemia and
prevention of recurrent MI and death is achieved with proper
antianginal, antiplatelet, and anticoagulant therapy. Of these
nitrates and beta-blockers (BBs) achieve a rapid reduction of
pain intensity [56,57].
It is reasonable to administer intravenous BBs at the time
of presentation to patients with STEMI who are hypertensive
or have an ongoing ischemia and no contraindications to beta
blockers use [5]. Early intravenous metoprolol followed by highdose
oral therapy had a neutral effect on the combined endpoint
of death, recurrent MI, or cardiac arrest. There were lower rates
of recurrent MI and ventricular fibrillation (VF) in the treated
groups, but with a significantly higher rate of cardiogenic shock
with metoprolol, especially on days 0 and 1 [5].
A Meta-analysis of randomized trials enrolling at least 100
patients was carried to evaluate BBs use in MI. Sixty trials with
102,003 patients were eligible, BBs reduced mortality in studies
carried before widely adopting the reperfusion therapy, but not
in the reperfusion era. In contemporary practice of treatment of
MI, BBs have no mortality benefit but reduce recurrent MI and
angina (short-term) at the expense of increase in heart failure,
cardiogenic shock and drug discontinuation. Current guidelines
recommend as a class 2 recommendations to administer
intravenous BBs at the time of presentation to patients with
STEMI and no contraindications to their use who are hypertensive
or have ongoing ischemia [5].
Nitrates are recommended for the relief of chest pain in both
AHA and ESC guidelines. They work by reducing LV preload and
increasing coronary blood flow which results in a decrease in
myocardial oxygen consumption and thus relief the symptoms of
ischemia. But in clinical practice it doesnot affect the myocardial
injury unless a significant vasospasm is present [5,56].
Guidelines reccommendations are mainly attributed to
preperfusion era trials which reported some beneficial effect
on mortality [58]. Also a retrospective study of 8,255 patients
of whom 1,662 (20%) received sublingual NTG, revealed
that the chest pain score (on a scale of 0–10) after recieving
NTG decreased from 6.9 to 4.4 (a mean difference of 2.5; 95%
confidence limit 2.4–2.8) [59].
İn contrast to this a recent multicenter randomized controled
trial reported that Sodium nitrite administered intravenously
immediately prior to reperfusion in patients with STEMI does not
reduce infarct size [60].
Thus we conclude from these evidence that nitrates can
ameliorate symptoms and signs of myocardial ischemia, whilst
they could be useful in absence of contraindications especially in
patients with persistant ischemia and concomitant hypertension
or heart failure [5,56].
IV Acetaminophen , still the safest Analgesic: Acetaminophen
(APAP) or Paracetamol, has been a mainstay for pain and fever
management for many years. Its has been used for decades ef-
fectively for the management of mild to moderate pain. its IV formulation
have been widely used in Europe since 2 decades and is
proposed for pain of sudden onset in people in the emergency department
though not sufficiently studied yet [61,62].
Parodi proposed the use of IV paracetamol in AMI. APAP
is highly safe and preferred in pain management particularly
in those with increased cardiovascular risk or kidney disease,
unlike NSAIDs [53]. Fourteen randomized controlled trials were
recently identified in MEDLINE and EMBASE, they had various
methodologic flaws, and the studies enrolled a sum of 1,472
patients.
In 8 of the forteen trials IV APAP was reported to be
comparable with other pain medications with no statistical
differennce in pain score, the medications compared included
different effective doses of morphine, oxycodone, tramadol,
piroxicam, topical 5% lidocaine and dexketoprofen.
In the other studies, IV APAP was repoted to be superior
compared to IV morphine and IM piroxicam, where it was
associated with significant reduction in pain scores. While the
incidence of side effects associated with IV APAP was very low.
A limitation to generalising these results is the fact that the level
of evidence for the individual trials ranged from very low to
moderate and thus limited evidence to support the use of APAP
for acute pain control in ED with “no studies” being yet done in
AMI patients [63].
Opiates May All be Equal, but They Are Not All the Same:
Opioids have similar properties to the opium from which they are
derived, while they target the same endorphin receptor, but still
they have many differences pharmacologically, experimentally,
clinically and from health economics point of view [64]. The
short acting synthetic opioid alfentanil is commonly used in
anaesthesia, it favoring charecteristics include its rapid onset of
action, of 1–2 minutes shown to be safe also for cardiac patients,
and better side effects profile than morphine (more controlable
due short duration of action). Furthermore, alfentanil seems to
liberate less histamine than morphine, which is hypothesized
to have a role in GI side effects of morphine including delayed
motility and thus alfentanil may less interact with oral antiplatelet
therapies [65-67].
A randomised double-blind clinical trial in which the effects
of alfentanil were compared with those of morphine in the
prehospital treatment of 40 haemodynamically stable patients
suffering from acute ischaemic-type chest pain. The study
reported that pain relief was faster (p < 0.005) in the alfentanil
group than in the morphine group. Alfentanil provided effective
analgesia during the follow-up period of 15 minutes with no
haemodynamic or respiratory side effects.
The study concluded that alfentanil is an effective analgesic
in the prehospital treatment of myocardial ischaemic pain.
Intranasal fentanyl also showed in another RCT to have no
significant difference in analgesia compared with intravenous
morphine for prehospital analgesia [67,68]. Neverless further
RCT are necessory to exclude or verify the magnitude of
interaction of Alfentanil if it occurs.
Tramadol was also shown to have a significant effect on
gastric empting which is measarble but smaller than morphine
and may thus have clinical and economic advantages in acute
pain management compared with morphine [69].
Tramadol has been in clinical use in Germany since the late
1970s and has proven effective in both experimental and clinical
pain without causing serious cardiovascular or respiratory side
effects. Its proposed for firstline management of postoperative
pain instead of morphine. It is also associated with a low
incidence of cardiac depression and significantly less dizziness
and drowsiness than morphine [70,71].
In contrast to morphine, tramadol has not been shown to
induce histamine release. At therapeutic doses, tramadol has no
effect on heart rate, left ventricular function or cardiac index [72].
Tapentadol is also an orally active, centrally acting synthetic
analgesic that is thought to exert its analgesic effects as tramadol
via a dual mechanisms of action (mu opioid receptor agonism
and norepinephrine reuptake inhibition).Tapentadol offers also
the prospect of reduced opioid-related gastrointestinal adverse
events and hence do not significantly increase the possibility of
delayed absorption of other drugs while maintaining adequate
analgesia [73,74].
Combinations .. More effective but less toxic: Tramadol
As being effective in moderate to severepain, while morphine
is thought to be more effective for severe acute pain a
combination drug containing tramadol hydrochloride 37.5 mg
and acetaminophen 325 mg may reasonably reduce the onset
time of analgesia and improves the degree of analgesia. The
combination could be studied in AMI as this product reduces the
incidence of tramadol related adverse events, while the addition
of acetaminophen improves pain relief and provides a faster
onset and longer duration of action with fewer adverse events
than either component separately [73].
Also Opioid-induced bowel dysfunction and effects on other
drugs can be effectively treated by combining morphine with
a peripherally acting opioid receptor antagonists. Examples
include oral naloxone or subcutaneous methylnaltrexone, such a
combination could lead to less peripharal side effects of morphine
and thus may favorably attenuate morpine’s delayed absorption
of oral antiplatelet medications [75,76].
Alternative Routes for P2Y12 receptor inhibitors:
Antiplatelet agents are the mainstay of pharmacological treatment
in patients presenting with an AMI, the novel and potentially
relevant drug-drug interaction (DDI) between morphine and
oral P2Y12 receptor inhibitors indicate that co-administration of
morphine should be avoided, if possible. As the DDI being mainly
attributed to morphine delay effect of oral absorption of P2Y12
receptor inhibitors, crushing prasugrel and ticagrelor tablets may
result in a better pharmacokinetic as was reported of crushed
clopidogrel in a healthy volunteers study. 300 mg clopidogrel was
administered and crushed via a nasogastric tube this resulted in
a faster and greater bioavailability of the drug compared with
whole tablets [77]. The same results were reported from The
MOJITO (Mashed Or Just Integral pill of TicagrelOr) study [78].
The study revealed that crushed ticagrelor tablet administration
in STEMI patients was feasible and provides earlier platelet
inhibition compared with standard integral tablets.
Also a study assessing STEMI patients undergoing PPCI (n
= 52) who were treated with a prasugrel 60-mg loading dose
(LD) either as whole or crushed tablets. PK/PD analyses were
performed at 7 time points. The study revealed crushed prasugrel
to lead to faster drug absorption, and consequently, more prompt
and potent antiplatelet effects compared with whole tablet
ingestion. Although the use of morphine was numerically higher
in the crushed group, this did not reach statistical significance.
Also morphine was used in though in 75% of the overall study
population and was not associated with any significant difference
on the primary endpoint. As well as during the overall 24-hours
of study time course, there was no treatment effect by morphine
interaction. Except that it was associated with modestly
reduced exposure to prasugrel active metabolite but not a
pharmacodynamic effect. This may suggest that beside the DDI
other mechanisms may play a major role in the pathophysiology
of delayed absorption of P2Y12 receptor inhibitors in patients
undergoing PCI [79,80].
Cangrelor, an intravenous direct-acting P2Y12 receptor
inhibitor, could be an ideal choice in patients with STEMI
receiving morphine. As it is difficult to achieve adequate platelet
inhibition at the time of PCI with oral agents due absorption delay
that affect the onset of effect of antiplatelet, IV Cangrelor optimize
treatment because it produces nearly maximal inhibition of
platelet aggregation within minutes [81].
It also of mentioning that newer P2Y12 receptor inhibitor
use is associated with a considerable economic burden on some
patients in comparison to generic clopidogrel which also worth
to be considered for cost effectiveness evaluation [82] (Table 2).
Table 2 Studies regarding antiplatelet use in AMI and effect of morphine.
Authors / year |
Study name |
Study Design |
Study Aim |
Population |
Results |
Zafar, M. Urooj, et al; 2009 [77] |
Crushed Clopidogrel Administered via Nasogastric Tube Has Faster and Greater Absorption than Oral Whole Tablets |
A prospective open-label crossover clinical trail |
To compare the absorption of 300 mg clopidogrel administered crushed via nasogastric (NG) tube versus whole tablets taken orally in healthy volunteers. |
N= 9 healthy subjects |
A 300 mg loading dose of crushed clopidogrel administered via NG tube provides faster and greater bioavailability than an equal dose taken orally as whole tablets |
Parodi, Guido, et al.; 2013 [22] |
Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. |
a randomized, 2-arm, prospective study |
To evaluate the impact of increased ticagrelor LD on
platelet inhibition as compared with the standard
prasugrel LD. |
n = 50 STEMI |
Morphine use is associated with a delayed activity of ticagrelor and prasugrel |
Morton, Allison C., et al; 2013 [85] |
Morphine delays the onset of action of prasugrel in patients with prior history of STEMI |
an open-label, crossover study |
To determine whether morphine delays the onset of action of prasugrel in patients with previous PPCI for STEMI. |
n = 11 post- STEMI |
Negative impact on pharmacodynamics
of prasugrel. |
Hobl EL et al ; 2014 [7] |
Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial |
a randomized, double-blind, controlled trial |
To examine possible drug– drug interaction between clopidogrel and morphine |
n = 24 healthy
subjects |
Negative impact on pharmacokinetics and
pharmacodynamics of clopidogrel |
Parodi, Guido, et al.; 2015 [25] |
Morphine Is Associated With a Delayed Activity of Oral Antiplatelet Agents in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention |
patient-level integrated analysis from 5 studies |
To assess platelet inhibition after a loading dose of the antiplatelet agents in STEMI patients according to morphine use. |
n = 300 STEMI
32% (95 patients) on morphine |
Morphine use is associated with a delayed onset of action of the oral antiplatelet agents. Even after excluding vomiting patients. |
Franchi, Francesco, et al; 2015 [86] |
Impact of morphine on pharmacokinetic and pharmacodynamic profiles of ticagrelor in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. |
a post-hoc analysis of a randomized study |
To assess the impact of morphine on pharmacokinetic
profiles of ticagrelor. |
n = 46 AMI,35% on morphine (16 patients) |
use of morphine alters PK profile and delays the PD effects of ticagrelor |
Silvain J et al ; 2015 [25] |
Impact of morphine administration on ticagrelor-induced platelet inhibition in ST-elevation myocardial infarction patients treated by primary pci: results from the PRIVATE-ATLANTIC study |
A sub analysis for randomized double blind placebo controlled trial |
to assess the pharmacodynamic (PD) and pharmacokinetic (PK) effect of ticagrelor pretreatment. |
n = 37 STEMI |
Suspected negative impact on
pharmacodynamics of ticagrelor. |
Kubica J et al ; 2015 [26] |
Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial |
a single-centre, randomized, double-blind tria |
To assess the influence of IV morphine on the
pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite in AMI patients |
n = 70 AMI |
Morphine delays and attenuates ticagrelor exposure (PK) and action (PD) in patients with myocardial infarction |
Hobl EL et al ; 2015 [80] |
Morphine interaction with prasugrel: a double-blind, cross-over trial in healthy volunteers |
randomized, double-blind, placebo-controlled, cross-over trial |
To clarify whether more potent P2Y12-inhibitors may provide an effective alternative, we examined drug–drug interactions between morphine and prasugrel. |
n = 12 healthy
subjects |
Negative impact on pharmacokinetics and
neutral on pharmacodynamics of prasugrel. |
Parodi, Guido, et al; 2015 [78] |
Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study. |
a prospective, 4-center, international, randomized, active-controlled study |
to evaluate the superiority of ticagrelor crushed pills versus integral tablets of equal dose in STEMI) patients |
n= 82 |
crushed ticagrelor tablet administration in STEMI patients is feasible and provides earlier platelet inhibition compared with standard integral tablets |
Hobl EL et al ; 2016 [87] |
Morphine decreases ticagrelor concentrations but not its antiplatelet effects: a randomized trial in healthy volunteers |
randomized, double-blind, controlled, crossover trial |
to evaluate the effects of morphine on the intestinal resorption, pharmacokinetics and pharmacodynamics of ticagrelor |
n = 24 healthy
subjects |
Morphine co-administration moderately decreases ticagrelor plasma concentrations but does not inhibit its pharmacodynamic effects |
Rollini, Fabiana, et al; 2016 [79] |
Crushed prasugrel tablets in patients with STEMI undergoing primary percutaneous coronary intervention: the CRUSH study. |
prospective, randomize, open-label study |
to determine whether crushing prasugrel is associated with more favorable drug bioavailability and platelet inhibitory effects compared with whole tablets in STEMI patients undergoing PPCI. |
n = 52 |
• Crushed prasugrel leads to faster absorption, and more potent antiplatelet effects.
• Morphine wasn’t associated with any significant difference on the primary endpoint.
• Morphine was associated with modestly reduced exposure to prasugrel active metabolite but not a pharmacodynamic effect in the uncrushed formulation group. |
Table 2 Studies regarding antiplatelet use in AMI and effect of morphine.
×
Almost for a century morphine, an opioid analgesic, had
been the ultimate and most effective management of chest pain
in AMI. Benefits were attributed to its lowering blood pressure,
heart rate and alleivating anxiety, as it is also reported to exert
cardioprotective effects, but still their use lacks supporting
rigorous evidence examining long term outcomes.
The CRUSADE study raised concerns regarding the safety of
using morphine in patients with NSTE ACS emphasizeing the need
for a randomized trials, smaller observations reported neutral
effect of morphine. While pharmacodynamic observations
published in 2013 suggested that the onset of action of prasugrel
and ticagrelor may be delayed by co-administration of morphine,
Morphine-P2Y12 inhibitors DDI was later confirmed by small
RCTs.
The interaction is mainly due Morphine effect of delaying
gastrointestinal motility and thus delaying the absorption of oral
antiplatelets. Other hypothesized theories include, that morphine
sulfate quickly paralyzes cortisol production in opioid-naive
men and women, whilst scientists linked morphine effects to its
histamine releasing effect.
In search for alternatives for morphine in AMI, NSAIDs though
being effective analgesic agents, their use is attenuated due to
their associated cardiovascular events risk, while naproxen was
reported to have minimum risk especially when administered
for a short duration <10 days though still it may inhibit the
cardioprotection of aspirin and thus strictly not recommended
till supporting evidence emerges.
It’s reasonable to initially administer intravenous beta
blockers and nitrates at the time of presentation to MI patients
with no contraindications, which may lead to significat pain relief.
Other alternatives as IV acetaminophen, was shown in small
studies to be atleast as equally effective as other analgesics, also
its combination with tramadol could be effective for moderate to
severe pain, as well as afentenyl, though all are not studied yet for
interaction with antiplatelets and use in AMI.
Modifying route of adminisration of antiplatelets is also
an alternative associated with better pharmacokinetic profile
for P2Y12 inhibitors, but not a pharmacodynamic effect when
coadministered with morphine suggesting that other mechanisms
may affect the pathophysiology of delayed absorption of P2Y12
inhibitors, which needs further rigorous evaluation.
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Cite this article: Abdikarim ABDI, Basgut B (2016) An Evidence-Based Review of Pain Management in Acute Myocardial Infarction. J Cardiol Clin Res 4(4): 1067.
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