Conditions: Coronary Artery Disease
Keywords: Percutaneous Coronary Intervention Blood Platelets Fentanyl
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 212
Healthy volunteers: no

Brief summary:
With potent analgesic properties, perceived hemodynamic benefits and limited alternatives, opiates are the analgesic mainstay for acute coronary syndrome (ACS) patients reporting peri-procedural pain or nitrate-resistant chest pain. However, large observational studies suggest that opiate administration during ACS may result in adverse cardiovascular outcomes. Complimenting this, a number of recent mechanistic studies have demonstrated delayed and attenuated effects of oral dual anti-platelet therapy (DAPT) on platelet inhibition endpoints among subjects receiving intravenous morphine. These studies support the hypothesis that morphine delays the gastrointestinal absorption of DAPT medications. However, no data exist on the impact of intravenous fentanyl, a systemic opioid analgesic routinely administered during percutaneous coronary intervention (PCI) procedures, on the platelet inhibition effects of DAPT. The investigators hypothesize that, similar to morphine, fentanyl administered at the time of PCI will reduce and delay the effect of DAPT on platelet function. As such, the primary aim of this study is to test the impact of intravenous fentanyl on residual platelet reactivity by randomizing patients undergoing PCI to a strategy of peri-procedural benzodiazepine plus non-systemic local analgesia or to the current standard of benzodiazepine plus intravenous fentanyl. Given the critical need for rapid and robust inhibition of platelet function during PCI, this trial has true potential to change clinical practice, particularly if the investigators demonstrate reduced DAPT absorption and elevated residual platelet reactivity among patients receiving fentanyl during PCI.

Detailed description:

Arms:
arm 1: IV midazolam and Local Anesthetic, with removal of IV fentanyl from peri-procedural analgesia (which is otherwise routinely given) arm 2: IV midazolam and Local Anesthetic and IV fentanyl for peri-procedural analgesia

Interventions: intervention 1: Removal of Fentanyl from peri-procedural analgesia intervention 2: Fentanyl intervention 3: Lidocaine intervention 4: Midazolam
Intervention descriptions: intervention 1: Removal of Fentanyl from peri-procedural analgesia (which is otherwise routinely given for PCI) intervention 2: IV peri-procedural analgesia intervention 3: Local Anesthetic intervention 4: IV sedation

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
TITLE: The Platelet Aggregation After tiCagrelor Inhibition and FentanYl Trial (PACIFY) 
 
NCT: NCT02683707 
 
DATE: 07/20/16 
 
PI: William McEvoy 


 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 1 of 10 
 
Date: ___7/20/16/______    
Principal Investigator: __William McEvoy___ 
Application Number: ___IRB00089755 __ 
 
 
 
JHM IRB - eForm A – Protocol 
 
 
 
 Use the section headings to write the JHM IRB eForm A, inserting the appropriate material 
in each. If a section is not applicable, leave heading in and insert N/A. 
 When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at 
the top of JHM IRB eForm A. 
 
*************************************************************************************************** 
1. 
Abstract 
With potent analgesic properties, perceived hemodynamic benefits and limited alternatives, opiates 
are the analgesic mainstay for acute coronary syndrome (ACS) patients reporting peri-procedural 
pain or nitrate-resistant chest pain. However, large observational studies suggest that opiate 
administration during ACS may result in adverse cardiovascular outcomes. Complimenting this, a 
number of recent mechanistic studies have demonstrated delayed and attenuated effects of oral dual 
anti-platelet therapy (DAPT) on platelet inhibition endpoints among subjects receiving intravenous 
morphine. These studies support the hypothesis that morphine delays the gastrointestinal absorption 
of DAPT medications. However, no data exist on the impact of intravenous fentanyl, a systemic 
opioid analgesic routinely administered during percutaneous coronary intervention (PCI) 
procedures, on the platelet inhibition effects of DAPT. We hypothesize that, similar to morphine, 
fentanyl administered at the time of PCI will reduce and delay the effect of DAPT on platelet 
function. As such, the primary aim of this study is to test the impact of intravenous fentanyl on 
residual platelet reactivity by randomizing patients undergoing PCI to a strategy of peri-procedural 
benzodiazepine plus non-systemic local analgesia or to the current standard of benzodiazepine plus 
intravenous fentanyl. Our study will address a major gap in knowledge. PCI analgesia with fentanyl 
is often administered concurrently with loading doses of DAPT, particularly in ACS. Given the 
critical need for rapid and robust inhibition of platelet function during PCI, our research study has 
true potential to change clinical practice, particularly if we demonstrate reduced DAPT absorption 
and elevated residual platelet reactivity among patients receiving fentanyl during PCI. As such, this 
research could result in a paradigm shift in the analgesia management of PCI and have a profound 
impact on optimization of post-PCI cardiac outcomes. 
 
2. 
Objectives  
Primary Objective: We will test the hypothesis that randomization to fentanyl will be associated 
with higher residual platelet reactivity, as determined by mean P2Y12 reactivity units (PRUs) at 2 
hours, among persons undergoing PCI with IV fentanyl analgesia (as well as aspirin and 
ticagrelor), compared to subjects randomized to undergo PCI with non-systemic analgesia.  
Secondary Objective: To test the hypothesis that fentanyl administered during PCI will adversely 
impact the pharmacokinetics of ticagrelor, as determined by the area under the curve of active 
metabolite measured using liquid chromatography tandem mass spectrometry. 
Secondary Objective: To test for differences in patient reported pain scores and biomarkers of 
myocardial injury, comparing PCI patients randomized to peri-procedural benzodiazepine plus 
non-systemic local analgesia or to the current standard of benzodiazepine plus intravenous 
fentanyl. 
 


 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 2 of 10 
 
Figure 1- Morphine Lowers Plasma Concentrations of 
Clopidogrel Active Metabolite. **p≤0.01 JACC 2014;63:630–5 
3. 
Background   
Morphine has long played a central role in the management of ACS 1-4. However, a 2005 
observational study suggested that patients receiving morphine for pain relief in ACS had worse 
outcomes 5. In this context, recent research 
demonstrates that intravenous morphine delays 
and inhibits the absorption of oral DAPT with 
resultant delay in the time to maximal platelet 
inhibition 6-9. Hobl et al. administered a loading 
dose of 600mg clopidogrel together with either 
placebo or 5mg morphine intravenously in a 
randomized, double-blind, cross-over mechanistic 
trial 6. Morphine injection delayed clopidogrel 
absorption (Tmax: 105 vs. 83 min, p = 0.025) and 
reduced the total exposure to its active metabolite 
by 34% (p = 0.001, figure 1). Morphine also 
resulted in higher residual platelet aggregation 
and delayed maximal inhibition of platelets by 2 
hours (n = 24; p<0.001) 6. Similar results have 
recently been reported for subjects receiving 
ticagrelor. 9, 10 Morphine’s association with 
emesis, inhibition of gastric emptying and 
reduced GI motility is hypothesised as the cause.  
 
Delayed and reduced absorption of DAPT in 
ACS patients is likely to translate into worse 
cardiovascular outcomes because maximal 
inhibition of platelet function is necessary to 
treat intracoronary atherosclerotic plaque 
rupture and thrombosis, as well as to minimize 
the risk of in-stent thrombosis among patients 
who receive coronary stents at the time of PCI. In keeping with this, morphine has also recently 
been associated with suboptimal reperfusion after PCI in patients with ACS (figure 2). 11 As a 
consequence, 2015 European guidelines now state, “in ACS patients whose ischemic symptoms are 
not relieved by nitrates and beta-blockers, opiate administration is reasonable…, with the caveat 
that morphine may slow intestinal absorption of oral platelet inhibitors.”4 
 
However, no data exist as to the impact of fentanyl, another IV opiate, on DAPT absorption and 
platelet inhibition. This represents a major gap in current knowledge. Indeed, fentanyl is used for 
analgesia in the vast majority of PCI procedures in Europe and the US, often being administered 
concurrently with loading doses of DAPT. It is known that fentanyl has similar effects to morphine 
on GI motility 12 and that the typical fentanyl PCI dose, 25-50mcg, is equipotent with the morphine 
dose used by Hobl and Kubica in two recent trials (5mg). 6, 9 Given the critical need for rapid and 
robust inhibition of platelet function among patients receiving intracoronary stents during PCI, this 
research proposal has true potential to change clinical practice, particularly if our results confirm 
reduced DAPT absorption and elevated residual platelet reactivity among patients receiving 
fentanyl during PCI. As such, this research could result in a paradigm shift in the analgesia 
management of PCI and have a profound impact on optimization of post-PCI clinical outcomes.  
 
 
 
 
Figure 2- Morphine adversely impacts post PCI infarct size 
& myocardial salvage index by MRI. Clin Res Card 2015;104:727–34 
min 


 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 3 of 10 
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
This is an open-label randomized controlled trial. We will accrue 70 patients undergoing loading of 
oral DAPT (aspirin and ticagrelor 180mg [the latter only being administered if a stent procedure is 
necessary]) as part of routine clinical care. This may require that up to 300 patients will need to be 
approached for consent. The reason for this is that only about 1 in 4 patients who undergo left heart 
catheterization actually need DAPT loading for stent placement (many do not need stents) and it is 
impossible to know who these patients will be before the catheterization procedure is performed. 
 
Consenting patients will be randomized, 1:1, to peri-procedural intravenous benzodiazepine plus 
non-systemic local analgesia or to the current standard of peri-procedural intravenous 
benzodiazepine plus intravenous fentanyl plus local analgesia (figure).  
 
Peri-procedural analgesia is part of routine clinical care, thus, the primary research procedure in this 
study is the randomization to the type of analgesia (fentanyl vs. no fentanyl).  
 
Subsequent to randomization, clinical care will then proceed as per normal practice (e.g. patients 
requiring coronary stenting will undergo the procedure at the discretion of the interventional 
cardiologist). However, because ticagrelor is a newer DAPT option and is less commonly given at 
our hospital than clopidogrel, we will require that patients enrolled into our study not be switched 
from ticagrelor to clopidogrel within the first 12 hours of the initial ticagrelor load in the 
catheterization lab (this is due to theoretical concerns that clopidogrel loading is less effective 


 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 4 of 10 
 
within the first 12 hours of ticagrelor loading due to competition for platelet receptors). As such, we 
require all patients enrolled into the study to be admitted for observation for 12-24 hours after 
enrolment. Ticagrelor was chosen for this study as it is a potent and fast-acting agent, has been 
demonstrated to be superior to clopidogrel, and will allow us to answer the main research question 
as to whether, or not, fentanyl delays the GI absorption of oral anti-platelet agents. 
 
In order to address our research objectives, enrolled patients will need to undergo sampling of blood 
after randomization (figure). While such blood sampling is typical in routine clinical care, we will 
also be obtaining blood for the sole purposes of research. Blood will be sampled at 0, 0.5, 1, 2, 4, 
and 24 hours after randomization. Where possible, blood will be drawn from existing IV access. For 
research purposes, we will also obtain patient-reported procedural pain data using the visual analog 
scale and the numeric rating scale at 2 hours (NRS). 13  
 
b. Study duration and number of study visits required of research participants. 
 
The duration of the study will be over 24 hours. The only study visit required is the admission 
during which the PCI is being performed as part of routine clinical care. Of note, patients 
undergoing PCI are routinely kept in the hospital for a minimal of 24 hours. 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Patients will not be blinded to the analgesia strategy (benzodiazepine sedation and local vs 
systemic analgesia) as the coronary angiogram is being performed as part of routine clinical care 
and it will not be possible to blind medical providers to the medications administered during the 
procedure. However, the collaborators who perform the analyses of blood samples will be 
blinded to the randomized allocation in order to minimize ascertainment bias. 
 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. 
 
All subjects enrolled will receive standard clinical care. The only change from standard practice 
is the 50% chance of being randomized to peri-procedural intravenous benzodiazepine plus non-
systemic local analgesia. This will consist of benzodiazepine and local anaesthetic (e.g. 
subcutaneous lidocaine), as described below. We believe this is ethically justifiable for the 
following reasons; 1) the procedural pain is typically minimal, with the vast majority of patients 
undergoing radial approach to left heart cath; 2) benzodiazepine and local anesthetic are well 
known to provide effective comfort for patients who can’t receive opiates (e.g. due to allergy); 
3) those patients who complain of breakthrough pain in the non-systemic analgesia arm are 
allowed receive bail-out IV opiates in our research protocol; and 4) our hypothesis is that IV 
opiates may themselves be causing indirect harm in the setting of PCI by attenuating the 
effects of DAPT. Indeed- in the context of research demonstrating that morphine reduces and 
delays the effect of DAPT on platelet inhibition- our primary hypothesis is that the impact of 
intravenous fentanyl on platelet inhibition outcomes will be similar. However, because no 
studies have evaluated this question, there is a state of clinical equipoise. The only way to 
answer this pressing clinical question is to randomize patients to non-systemic analgesia, while 
ensuring patient discomfort is no different, and to compare platelet function results in these 
patients to a similar group of patients who are randomized to the current standard of peri-
procedural intravenous benzodiazepine plus intravenous fentanyl. 
 
 
 


 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 5 of 10 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
There is no placebo or non-treatment group in this randomized trial.  
 
f. Definition of treatment failure or participant removal criteria. 
 
Treatment failure will be defined as subject-report of uncontrolled pain or discomfort during the 
PCI procedure. As part of routine care patients are regularly asked to report any pain during the 
procedure. In all instances, and most notably in the group randomized to initial intravenous 
benzodiazepine plus non-systemic analgesia, post randomization analgesia will be managed as 
per usual by the procedural team. Specifically, the study protocol only provides initial guidance 
on analgesia, based on the randomized allocation. Once the initial analgesia has been provided, 
should patients subsequently report uncontrolled pain or discomfort, the treating team can 
administer any analgesia that they feel is clinically indicated, including intravenous fentanyl in 
either arm of the study. There are no protocol-based removal criteria. However, participants can 
remove themselves at any time from the study as participation is voluntary.  
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
When the study ends or should participation end prematurely, all subjects enrolled will undergo 
routine treatment as per usual best practice. Participants will be analyzed on an intention to treat 
basis. Therefore, participants will be analyzed based on their initial randomized analgesia 
allocation and whether or not their participation in the study ended prematurely. 
 
5. 
Inclusion/Exclusion Criteria 
 
Key inclusion criteria are: undergoing clinically indicated PCI; >18 years of age; able for PO 
medications and to provide informed consent. Key exclusion criteria: pregnant; any 
DAPT(clopidogrel, prasugrel, ticagrelor) within 14 days of enrollment; known coagulation 
disorders; active treatment with oral anticoagulant or low molecular weight heparin; impaired renal 
or hepatic function; platelets < 100 x10 3 /mcl; planned use of GP2b3a for PCI; Prior TAVR or 
planned TAVR post PCI; and contraindications to ticagrelor or opiates. 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
Subjects randomized to the current standard of peri-procedural intravenous benzodiazepine plus 
intravenous fentanyl will receive an initial dose of 1 mg of midazolam and 25-50 mcg of 
fentanyl. Subsequent doses of either medicine can be provided as necessary. The rationale for 
this dosing schedule is that it is the standard of care. Furthermore, 25-50mcg of fentanyl is 
equipotent with the morphine dose used by Hobl and Kubica in two recent trials (5mg). 6, 9 
Subjects randomized to the research strategy of peri-procedural intravenous benzodiazepine plus 
non-systemic analgesia will receive an initial dose of 1 mg of midazolam (with titrations 
allowed as necessary) and local anaesthetic (e.g. subcutaneous lidocaine). The rationale for this 
strategy is to maintain comfort during the case without exposing the subjects to opiates. 
 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed. 
N/A 


 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 6 of 10 
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  
N/A 
 


 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 7 of 10 
 
Date: ___7/20/16______    
Principal Investigator: __William McEvoy___ 
Application Number: _ IRB00089755__ 
 
7. 
Study Statistics 
a. Primary outcome variable. 
 
In both randomized groups P2Y12 reactivity units (PRUs), measured using VerifyNow, will be 
determined at 0, 0.5, 1, 2, 4, and 24 hours. The primary outcome will be mean PRU at 2 hours.  
 
b. Secondary outcome variables. 
 
Additional secondary platelet outcomes will include light transmission aggregometry (LTA) at 2 
hours, and also time-averaged PRU using mixed effects models. Given we hypothesize fentanyl 
may impair platelet inhibition due to reduced gastrointestinal absorption of ticagrelor, we will 
also compare ticagrelor pharmacokinetics in both arms, as determined by the area under the 
curve of active metabolite by liquid chromatography mass spectrometry (at 0, 0.5, 1, 2, 4 and 24 
hours). We will also determine the impact of fentanyl on myocardial injury, as measured by 
high-sensitivity Troponin-I in the serum. In all 300 patients consented, we will also compare 
patient reported pain among both groups using the visual analog scale and the numeric rating 
scale (NRS). (12) These simple to perform subjective assessments can measure clinically 
meaningful differences in pain (e.g. a difference of 30% on the NRS). (12) 
 
 


 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 8 of 10 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
Based on prior data 14, we anticipate a 2 hour PRU of ~230 (Standard Deviation of 25) among 
patients receiving 180 mg ticagrelor without opiate and estimate a conservative effect size of 
20% increase in 2hr PRU among those who receive fentanyl 8, 15. These calculations yield a 
sample size estimate of ≤23 subjects per group (approx. 50 total) to achieve 90% power (2 sided 
alpha 0.05). Accounting for drop out and unanticipated increases in 2hr PRU variability, and to 
provide power for subgroup analyses, we will accrue 70 patients who undergo DAPT loading in 
total. In all analyses a value of p < 0.05 will be considered statistically significant. 
 
d. Early stopping rules. 
 
N/A 
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
 
It is possible that the non-systemic analgesia arm could report increased peri-procedural pain, 
however IV opiates are permitted at any time, for any participant, based on break-through pain 
reported during the case. The other main medical risks are the bleeding and bruising from 
venipuncture. Where possible we will draw blood from IV access to minimize venipuncture. As 
our research protocol includes the administration of ticagrelor as the anti-platelet agent used for 
the stenting procedure, some providers may wish to transition their patients from ticagrelor to 
other anti-platelet agents (such as clopidogrel or prasugrel) after completion of participation in 
our study. This change may be motivated by clinical or patient preference reasons. However, if 
the provider elects to make such a change after the participant has completed the study, we will 
require them to not change to either clopidogrel (starting with a 600mg load) or prasugrel 
(starting with a 60mg load) within the first 12 hours of the initial ticagrelor load (specifically, 
they will need to wait until 12 hrs has passed from the last ticagrelor dose and then load with the 
alternative agent at the time the next dose of ticagrelor would have been due. This requirement 
will minimize the risk that patients who are switched from ticagrelor to an alternative anti-
platelet agent will not be exposed to the potential risk of suboptimal platelet inhibition in the 
period around which this change is made. 
 
b. Steps taken to minimize the risks. 
 
As already mentioned, blood will be drawn from existing iv heparin locks when available. 
Furthermore, we plan to minimize difference in pain by applying effective non-systemic 
analgesia that will consist of a rigorous pain relief strategy of potent benzodiazepine and 
effective local anaesthetic (e.g. subcutaneous lidocaine). In addition, patients can request more 
pain relief (including opiates) after the initial randomized analgesia has been allocated and can 
withdraw at any time from the study. 
 
c. Plan for reporting unanticipated problems or study deviations. 
 
Any unanticipated problems will be reported to the IRB. 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
Date will be stored on a secure and encrypted P.I.’s computer. 
 


 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 9 of 10 
 
e. Financial risks to the participants. 
 
There are no financial risks to the participants 
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
There are no guaranteed individual benefits for the participant. However, given the critical 
need for rapid inhibition of platelet function during PCI, this research proposal has true 
potential to change clinical practice, particularly if our results confirm reduced DAPT 
absorption and elevated residual platelet reactivity among patients receiving IV fentanyl 
during PCI. As such, this research could result in a paradigm shift in the analgesia 
management of PCI and have a profound impact on optimization of post-PCI clinical 
outcomes. 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, proposed 
bonus, and any proposed reductions or penalties for not completing the protocol. 
 
Subjects will not be compensated for participation in this study. 
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them. 
 
The research performed on the blood samples will be paid for by the P.I. and not billed to 
the patient. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 10 of 10 
 
REFERENCES 
 
1. 
Moore F. Intravenous morphine in coronary thrombosis. The Lancet. 1930:959-960 
2. 
Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG. Aha/acc guideline for the management of patients 
with non-st-elevation acute coronary syndromes: A report of the american college of cardiology/american heart 
association task force on practice guidelines. J Am Coll Cardiol. 2014;64:138-228 
3. 
O'Gara PT, Kushna FG, Ascheim DD. Accf/aha guideline for the management of st-elevation myocardial infarction: 
Executive summary: A report of the american college of cardiology foundation/american heart association task force on 
practice guidelines. Circulation. 2013:529-555 
4. 
Authors/Task Force M, Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, 
Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, 
Storey RF, Windecker S. 2015 esc guidelines for the management of acute coronary syndromes in patients presenting 
without persistent st-segment elevation: Task force for the management of acute coronary syndromes in patients 
presenting without persistent st-segment elevation of the european society of cardiology (esc). European heart journal. 
2015 
5. 
Meine TJ, Roe MT, Chen AY. Association of intravenous morphine use and outcomes in acute coronary syndromes: 
Results from the crusade quality improvement initiative. Am Heart J. 2005:1043-1049 
6. 
Hobl EL, Stimpfl T, Ebner J, Schoergenhofer C, Derhaschnig U, Sunder-Plassmann R, Jilma-Stohlawetz P, Mannhalter 
C, Posch M, Jilma B. Morphine decreases clopidogrel concentrations and effects: A randomized, double-blind, placebo-
controlled trial. Journal of the American College of Cardiology. 2014;63:630-635 
7. 
Hobl EL, Reiter B, Schoergenhofer C, Schwameis M, Derhaschnig U, Lang IM, Stimpfl T, Jilma B. Morphine 
interaction with prasugrel: A double-blind, cross-over trial in healthy volunteers. Clinical research in cardiology : 
official journal of the German Cardiac Society. 2015 
8. 
Parodi G, Bellandi B, Xanthopoulou I, Capranzano P, Capodanno D, Valenti R, Stavrou K, Migliorini A, Antoniucci D, 
Tamburino C, Alexopoulos D. Morphine is associated with a delayed activity of oral antiplatelet agents in patients with 
st-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention. Circulation. 
Cardiovascular interventions. 2015;8 
9. 
Kubica J, Adamski P, Ostrowska M, Sikora J, Kubica JM, Sroka WD, Stankowska K, Buszko K, Navarese EP, Jilma B, 
Siller-Matula JM, Marszall MP, Rosc D, Kozinski M. Morphine delays and attenuates ticagrelor exposure and action in 
patients with myocardial infarction: The randomized, double-blind, placebo-controlled impression trial. European heart 
journal. 2015 
10. 
Hobl EL, Reiter B, Schoergenhofer C, Schwameis M, Derhaschnig U, Kubica J, Stimpfl T, Jilma B. Morphine 
decreases ticagrelor concentrations but not its antiplatelet effects: A randomized trial in healthy volunteers. European 
journal of clinical investigation. 2015 
11. 
de Waha S, Eitel I, Desch S, Fuernau G, Lurz P, Urban D, Schuler G, Thiele H. Intravenous morphine administration 
and reperfusion success in st-elevation myocardial infarction: Insights from cardiac magnetic resonance imaging. 
Clinical research in cardiology : official journal of the German Cardiac Society. 2015;104:727-734 
12. 
Wallden J, Lindberg G, Sandin M, Thorn SE, Wattwil M. Effects of fentanyl on gastric myoelectrical activity: A 
possible association with polymorphisms of the mu-opioid receptor gene? Acta anaesthesiologica Scandinavica. 
2008;52:708-715 
13. 
Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual analog scale for pain (vas pain), numeric 
rating scale for pain (nrs pain), mcgill pain questionnaire (mpq), short-form mcgill pain questionnaire (sf-mpq), chronic 
pain grade scale (cpgs), short form-36 bodily pain scale (sf-36 bps), and measure of intermittent and constant 
osteoarthritis pain (icoap). Arthritis care & research. 2011;63 Suppl 11:S240-252 
14. 
Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, Antonino MJ, Patil SB, Karunakaran A, 
Kereiakes DJ, Parris C, Purdy D, Wilson V, Ledley GS, Storey RF. Randomized double-blind assessment of the onset 
and offset of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The 
onset/offset study. Circulation. 2009;120:2577-2585 
15. 
Scott KM, Caldwell PH, Barnes EH, Barrett J. "Teaching by humiliation" and mistreatment of medical students in 
clinical rotations: A pilot study. The Medical journal of Australia. 2015;203:185