Conditions: Fentanyl Platelet Reactivity
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: yes

Brief summary:
The goal is to determine whether fentanyl and morphine have similar effects in reducing aspirin's effect upon platelets in emergency department patients with chest discomfort. Morphine has been shown to worsen outcomes in heart attack patients due to reduction of oral anti-platelet agent effectiveness and so many providers have switches to using fentanyl. However, it is largely unknown whether fentanyl has similar effects.

Detailed description:
Patients presenting to the emergency department with chest discomfort who are being administered aspirin will be offered enrollment in this study. At the time of their zero and two hour troponin we will also draw platelet aggregration studies to determine the effects of aspirin upon platelets. Narcotic medicines slow the absorption of aspirin. Morphine has therefore been shown to decrease the effectiveness of aspirin. Many providers therefore use fentanyl instead, however little is known about the effects of fentanyl upon aspirin. We will therefore compare the platelet reactivity of patients receiving morphine, fentanyl, or no narcotics

Arms:
arm 1: not receiving any narcotics arm 2: the second group will be those receiving morphine arm 3: the 3rd group will be those receiving fentanyl

Interventions: intervention 1: Morphine intervention 2: Fentanyl
Intervention descriptions: intervention 1: second group will be receiving morphine intervention 2: third group receiving fentanyl

Protocol document:
Prot_SAP_000.pdf: 
Title: A comparison of PLAtelet response to Aspirin between emergency department patients with chest pain 
receiving Fentanyl or Morphine (PLAAFM) 
NCT #: NCT05367336 
Date: 2/18/2025 
 
 
 
 


Introduction or Background  
Problem and Purpose Statement-Objective of the Research 
The aim of this project was to determine whether fentanyl and morphine have similar effects in reducing aspirin’s effect 
upon platelets in emergency department patients with chest discomfort.  Morphine has been shown to worsen 
outcomes in heart attack patients due to reduction of oral anti-platelet agent effectiveness and so many providers have 
switched to using fentanyl.  However, it is largely unknown whether fentanyl has similar effects. 
 
Theoretical Framework-Present Knowledge, Literature Review 
Patients experiencing heart attacks or unstable angina (commonly known as acute coronary syndrome (ACS)) commonly 
experience discomfort and pain.  Nitroglycerin is typically the first medicine given for discomfort because it has dilatory 
effects upon vasculature to reduce the blood pressure and relax blood vessels to decrease myocardial demand.  
However, in some patients it is contraindicated and in many patients it is only partially efficacious in reducing 
discomfort.  Narcotics are commonly given.  Classically morphine was given in ACS as it is also thought to have 
venodilatory properties and could perhaps also relax the patient to decrease the sympathetic demands of the fright-
fight-flight responses experienced by patients having heart attacks.  Narcotics have several common side effects, and 
one of these is decreased gastrointestinal (GI) transit time, commonly manifested as constipation.  However, this 
decreased GI transit time also can slow the absorption of oral medications.  Oral anti-platelet therapy (starting with 
aspirin and commonly including dual anti-platelet therapy with clopidogrel as well) is also part of the treatment of 
patients with ACS as reducing clot propagation in the coronary arteries can decrease the size of an infarct.  Interference 
with oral anti-platelet therapy has been observed with morphine (2) contributing to worse outcomes in patients 
receiving morphine (1).  Delayed onset of action or decreased absorption has also been demonstrated with stronger 
anti-platelet drugs such as clopidogrel (3) and prasugrel (4) in association with morphine.  Many physicians have 
therefore switched to using fentanyl, and fentanyl has been found to be equally efficacious in pain control in potential 
ACS (7).  The PACIFY trial (5) evaluated the effects of fentanyl upon the stronger anti-platelet agent ticagrelor and found 
statistical significance at 2 hours with a lower peak concentration, and delayed onset of the peak concentration of 
ticagrelor when fentanyl was given.  The PACIFY trial did not compare the effects of morphine to fentanyl.  The PERSEUS 
trial was a small study of 38 patients (6) which showed no difference between fentanyl and morphine at 2 hours with 
regards to ticagrelor absorption but that there was a difference at 4 hours.   There has not to our knowledge been any 
study of fentanyl’s effect on aspirin absorption.   
 
Research Questions or Hypothesis 
It is unlikely that a sufficient sample of patients with acute coronary syndrome (ACS) can be obtained to prospectively 
compare fentanyl to morphine, as the administration of other anticoagulants would confound the results. Therefore, the 
study will focus on chest pain patients in the emergency department. The hypothesis is that both morphine and fentanyl 
will reduce the effectiveness of aspirin. 
 
Methodology 
Given the challenges in obtaining a sufficient sample of patients with acute coronary syndrome (ACS) to prospectively 
compare fentanyl to morphine, the study will focus on chest pain patients in the emergency department. These patients 
typically have blood drawn initially and again two hours later to check for elevation and changes in troponin levels, a 
cardiac muscle protein detectable when cardiac muscle is being injured. These blood draws will be supplemented by 
evaluating platelet aggregation at the 0 and 2-hour marks. 
 
There are many measures and techniques in evaluation of platelet function.  Light Transmission Aggregometry (LTA) 
looks at changes in light transmittance through serum as platelets aggregate, leading to increased light transmission as 
more platelets aggregate.  Aspirin interferes with arachidonic acid mediated aggregation because of its effects upon 
COX-1 conversion of arachidonic acid to thromboxane A2.  Arachidonic acid is therefore the best trigger to use to 
evaluate aspirin’s effect upon platelets, as opposed to epinephrine, ADP, or several others used to evaluate the stronger 
anti-platelet oral and IV agents that act in different places in the platelet activation cascade (8).  
 
 
 


Research Design  
Patients who have 0 and 2 hour troponins ordered will have their chart reviewed by the research coordinator for 
candidacy in the study (see below for inclusion/exclusion). If the patient meets study entry criteria then platelet 
aggregation studies using arachidonic acid will be added on to the 0 and 2 hour lab draw. 
 
The study will compare the 0 and 2-hour platelet aggregation scores of patients receiving aspirin who are undergoing 
two sets of troponin tests. The first group will consist of patients not receiving any narcotics, the second group will 
include those receiving morphine, and the third group will include those receiving fentanyl. The treating clinician will 
determine the appropriate pain treatment plan for each patient. 
 
Sample/Participants  
The research coordinator will perform chart review on Emergency Department patients presenting with chest 
discomfort.  If there are 2 sets of troponins ordered and no exclusion criteria then the research coordinator will 
approach the patient for consent. 
 
Inclusion criteria:  Adult Emergency Department patients undergoing 0 and 2 hour troponin testing who have been 
administered aspirin within 30 minutes of the initial blood draw.  Initially all patients undergoing this testing will be 
candidates for the study.  We will attempt to enroll 80 patients in the each of the 3 arms.  Determination of which (if 
either) narcotic is administered will be up to the clinician.  As we reach the enrollment goals our research coordinator 
will discuss with the clinicians the expected pain plan to tailor enrollment of patients in the treatment arms that are still 
needed 
 
Exclusion criteria:  Patients not expected to get a 2 hour troponin; patients already on aspirin, clopidogrel, or stronger 
anti-coagulants; patients who arrived via EMS given it can be difficult to find the run reports to determine whether 
patient received fentanyl in the pre-hospital period; pregnant patients; patients on chronic narcotics; patients already 
once enrolled in this study, inability to provide consent in English 
 
With regards to at risk populations, Economically Disadvantaged, Nursing home residents, prisoners, homeless patients 
are all commonly encountered in the ED.  However, the request of 1 or 2 blue top tubes (totaling about a teaspoon of 
blood) is not an onerous ask.  Since narcotic use (or non-use) will be wholly up to the provider and not impacted by this 
study we see no problems with including them. 
 
Setting-Where is this taking place? 
Emergency Department in St Joseph. 
Instrumentation-Data collection  
If consent is given to obtain the labs then the research coordinator will extract basic demographic information into a 
spreadsheet (name, MRN, age, sex, race, ethnicity), as well as the results of the labs including the CBC data already 
obtained (hemoglobin and platelet count).  We will record the patients’ creatinine to also help describe our population.  
Finally the platelet aggregation data that we are studying will be recorded, as well as confirmation with the patient that 
they are not on anti-platelet medicines such as aspirin, clopidogrel (Plavix), aspirin-dipyridamole (Aggrenox), prasugrel 
(Effient), ticagrelor (Brilinta).  We will record time and dosing of aspirin administration, time and dosing of narcotic 
medicines (morphine, fentanyl, dilaudid). 
 
This spreadsheet would be maintained on SH-Lakeland servers in a location only accessible to the research coordinator 
and PI. 
 
Ethical Considerations 
There are not significant risks to this study. Two blue-top tubes of blood will be required for this study. One is already 
drawn and generally discarded as part of the initial rainbow of blood that’s drawn. 2.7ml of blood is used to fill a blue 
top tube, a trivial amount. Because these labs are not used clinically, we will seek grant funding to cover these expenses. 
 


Because this study does not pose risks we make no plans for injury compensation. This blood test is approved for 
research purposes only and is not used for clinical decision making so we are not concerned about incidental findings 
with regard to potential outlier values. 
 
The aim of this study is to provide better understanding of commonly used medicines’ potential for unintended 
consequences. 
 
Procedures 
The duration of participation is limited to the two blood draws. 
 
Data Analysis Procedure  
In the PACIFY trial, at 2 hours, patients receiving fentanyl had a PRU value of 113 +/- 94 on the platelet aggregation study 
(light aggregometry using ADP) after receiving Brilinta (ticagrelor), versus 71 +/- 66 in those not receiving fentanyl.  With 
an alpha of 0.05 and beta of 0.8, 57 patients would be required to demonstrate statistical significance if there is a similar 
magnitude of effect.  In the PERSEUS trial at 2 hours, patients receiving fentanyl had a PRU value of 173 +/-90 after also 
receiving Brilinta (ticagrelor), versus 210 +/- 76 in those receiving morphine and Brilinta (ticagrelor).  74 patients would 
be required to show statistical significance in direct comparison of morphine vs fentanyl.  The aim is to enroll 80 patients 
in each arm (no narcotic, morphine, and fentanyl). 
 
Two-tailed T-testing will be used to look for differences in the 2 hour platelet reactivity response rates between those 
receiving morphine versus those not receiving narcotics and between those receiving fentanyl and those not receiving 
narcotics. 
 
If the data is sent to the Spectrum Health SASS team for analysis MRN’s will be converted to a study ID so that the actual 
MRN will not be sent out. 
 
References 
1.  Duarte GS, Nunes-Ferreira A, Rodrigues FB, Pinto FJ, Ferreira JJ, et al.  Morphine in acute coronary syndrome:  
Systematic review and meta-analysis.  BMJ Open 2019;9:e025232 
2. Parodi G, Bellandi B, Xanthopoulou I, Capranzano P, Capodanno D, et al.  Morphine is associated with a delayed 
activity of oral antiplatelet agents in patients with ST-Elevation acute myocardial infarction undergoing primary 
percutaneous coronary intervention.  Circ Cardiovasc Interv.  2015;8:e001593 
3. Hobl E.L., Stimpfl T., Ebner J., et al. "Morphine decreases clopidogrel concentrations and effects: a randomized, 
double-blind, placebo-controlled trial". J Am Coll Cardiol 2014;63:630-635.  
4. Thomas M.R., Morton A.C., Hossain R., et al. "Morphine delays the onset of action of prasugrel in patients with 
prior history of ST-elevation myocardial infarction". Thromb Haemost 2016;116:96-102.  
5. McEvoy JW, Ibrahim K, Kickler TS, Clarke WA, Hasan RK, et al.  Effect of intravenous fentanyl on ticagrelor 
absorption and platelet inhibition among patients undergoing percutaneous coronary intervention: The PACIFY 
randomized clinical trial (Platelet aggregation with ticagrelor inhibition and fentanyl).  Circulation 
2018;137(3):307-9. 
6. S Degrauwe, M Roffi, F Carbone, N Lauriers, R Fesselet, O Muller, P G Masci, F Rigamonti, F Mach, M 
Valgimigli, J F Iglesias, 5918 
Influence of intravenous fentanyl versus morphine on ticagrelor absorption and platelet inhibition in 
patients with ST-segment elevation myocardial infarction undergoing primary PCI, European Heart 
Journal, Volume 39, Issue suppl_1, August 2018, ehy566.5918, 
7. Weldon ER, Ariano RE, Grierson RA.  Comparison of fentanyl and morphine in the prehospital treatment 
of ischemic type chest pain.  Prehosp Emerg Care 2016;20:45-51 
8. Gremmel T, Bhatt D, Michelson AD.  Laboratory monitoring of antiplatelet therapy, pp655-7.   Platelets.  2019