Table 1.

Principal randomized trials testing the effect of drugs for pain relief on platelet inhibition

Trial	Year	N of patients	Randomization	Drug administration	Endpoints	Results of endpoints
Hobl et al. [5]	2014	24	Morphine vs placebo	Morphine 5 mg	AUC of clopidogrel active metabolite	Morphine reduced the AUC of clopidogrel active metabolite 34%, p = 0.001
IMPRESSION trial [6]	2016	70	Morphine vs placebo	Morphine 5 mg	AUC(0–12) for ticagrelor during the first 12 h after the administration of the LD	Ticagrelor 6307 ± 4359 vs. 9791 ± 5136 ng h/mL in morphine vs placebo; a difference of 36%, p = 0.003
PACIFY trial [7]	2017	70	Fentanyl vs routine care	IV fentanyl (dose at the discretion of treating providers)	Ticagrelor concentration during the 24 h after loading as assessed by the AUC(0–24)	2107 vs 3301 ng·h−1 mL in fentanyl vs no fentanyl, p = 0.05
PERSEUS trial [8]	2020	38	Fentanyl vs morphine	IV fentanyl (50–100 μg) or IV morphine (4–8 mg)	Platelet reactivity at 2 h after ticagrelor LD	At 2 h, mean P2Y12 reaction units were 173.3 ± 89.7 and 210.3 ± 76.4 in patients treated with fentanyl and morphine, p = 0.463
ON-TIME 3 trial [9]	2020	195	Acetaminophen vs fentanyl	Paracetamol (1000 mg) or fentanyl titrated based on the weight of the patient	Level of PRU measured immediately after primary PCI in patients treated with ticagrelor	Median PRU 104 (IQR 37–215) for acetaminophen vs. 175 (63–228) for fentanyl, p = 0.18

AUC area under the curve, h hour, IQR interquartile range, IV intravenous, LD loading dose, PCI percutaneous coronary intervention, PRU platelet reactivity units