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Impact of opioids on P2Y12 receptor inhibition in patients with ST-elevation myocardial infarction who are pre-treated with crushed ticagrelor: Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial

Comment by Marta Kaluzna-Oleksy

European Heart Journal - Cardiovascular Pharmacotherapy (2022) 8, 4–12 doi:10.1093/ehjcvp/pvaa095

Interventional Cardiology


To search for effective pain relief and fast and optimal platelet inhibition by investigating an alternative analgesic, intravenous (iv) acetaminophen (paracetamol), when compared with iv fentanyl in ST-segment elevation myocardial infarction (STEMI) patients with ongoing chest pain who all received crushed ticagrelor in a pre-hospital setting.


The Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial is an investigator-initiated, prospective, open-label, trial.

STEMI patients (defined as on-going chest pain >30 min and <12 h duration and ST-segment elevation >0.1 mV in at least two contiguous leads) as diagnosed by the paramedic team with a pain score of 4 or higher at a 10-step numeric rating pain score, were included. 195 patients who were scheduled to undergo primary percutaneous coronary intervention (PCI) and were pre-treated with crushed ticagrelor, were randomised in a 1:1 fashion to iv acetaminophen (N=98) or iv fentanyl (N=97) administrated in the ambulance.

Data on intensity of pain and data on platelet inhibition, including pharmacokinetics and pharmacodynamics, were collected in four time points (T1, T2, T3, T4).

Primary endpoint: The level of platelet reactivity units (PRU) measured immediately post-primary PCI (T2 = immediately after primary PCI or 1-h post-angiography).

Key secondary endpoints:

  • pain reduction on a 10-step numeric rating pain scale between the level of pain at arrival of the ambulance at the patient site and the level of pain before or immediately post-primary PCI,
  • the level of PRU at other time points,
  • high on-treatment platelet reactivity (HPR) defined as PRU >208 immediately post-primary PCI
  • the concentrations of ticagrelor, its active metabolite and the cumulative concentrations of ticagrelor and its active metabolite at all time points.


  • The primary endpoint was not significantly different between the study arms [median 104 (IQR 37–215) vs. 175 (IQR 63–228), P = 0.18], Hodges– Lehmann estimator 20 (95% confidence interval -6.0 to 55.0).
  • The ticagrelor concentration was higher in the acetaminophen arm at the start of primary PCI [151 (IQR 32–509) vs. 60 ng/mL (IQR 13– 206), P = 0.007], immediately after primary PCI [326 (IQR 94–791) vs. 115 ng/mL (IQR 38–326), P = 0.002] and at 1h after primary PCI [488 (IQR 281–974) vs. 372 ng/mL (IQR 95–635), P = 0.002], but not for T4 (6h post-primary PCI or 7h post-angiography)
  • Acetaminophen resulted in the same extent of pain relief when compared with fentanyl between the moment of randomisation and start of primary PCI [reduction of 3 points (IQR 1–5), P = 0.67] and moment of randomisation and end of primary PCI [reduction of 5 points (IQR 3–7), P = 0.96]
  • Exploratory endpoints: four MACE in the fentanyl arm, which included one stent thrombosis (15 min post-primary PCI), two re-infarctions (10h and 6 days post-primary PCI), and one Bleeding Academic Research Consortium (BARC) type 3 bleeding event (7 days post-primary PCI), and two MACE in the acetaminophen arm, which included one re-infarction (3h post-primary PCI) and one bleeding BARC type 3 event (5 days post-primary PCI).

Main messages

The main message of the ON-TIME 3 trial is, that iv acetaminophen, compared with iv fentanyl, did not result in significantly lower platelet reactivity but was associated with higher plasma concentrations of crushed ticagrelor and resulted in effective pain relief. These findings suggest the negative impact of fentanyl, and possibly other opioids, on platelet inhibition after pre-loading with crushed ticagrelor and aspirin in the ambulance.

Opioids are widely used in daily practice but delay the intestinal drug absorption of P2Y12 inhibitors. They may cause also nausea and vomiting, what further reduce the uptake of oral platelet inhibitors. In a PCI situation, receiving morphine showed higher platelet reactivity, which is associated with ischaemic events like stent thrombosis, and should be prevented.

There has been a long debate about the use of opioids in patients with STEMI where the optimal platelet inhibition is one of the most important goals of the treatment. Despite of the fact, that more investigators emphasized the adverse effects of opioids in STEMI patients and the pain-relieving effects of this group of drugs is remained unclear, opioids like morphine and fentanyl, are still recommended in the European and American guidelines on the management of STEMI, but their class of recommendation has been recently reduced from classes I to IIa (level of evidence C) in the European guideline.  

Other analgesics may be an alternative for opioid use in STEMI patients. It is known that non-steroidal anti-inflammatory drugs increase cardiovascular events. An alternative can be use of acetaminophen (paracetamol), which with the intravenously (iv) form is quickly effective. However, so far no evidence exists about the effects of acetaminophen on platelet inhibition in STEMI patients. The presented trial is unique since it compares an opioid drug to a non-opioid analgesic drug for pain relief in STEMI patients in a pre-hospital setting and confirms the adverse effects of fentanyl on the absorption of ticagrelor.

Admittedly, the presented study was not blinded, but open-label, but evaluating the use of drugs in ambulatory setting makes it very useful in daily practice and shows acetaminophen as a safe and effective “pain-killer” in STEMI patients.

The optimal pain-reducing therapy strategy in myocardial infarction patients, especially STEMI patients remains still unclear. The results of this study, as well as previous reports, suggest that opioids should be avoided, especially when we can administrate such substance as acetaminophen, which is effective in relieving pain in patients with STEMI, without the side effects associated with opioid use.


The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.


The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.