Effects of lignocaine vs. opioids on antiplatelet activity of ticagrelor: the LOCAL trial

Opioids, mostly fentanyl, are the standard of care for managing myocardial ischaemic pain but they impair the early bioavailability of oral P2Y12 inhibitors, which are used in the treatment of myocardial infarction (MI), leading to delayed onset of antiplatelet activity, and therefore limiting their use. Lignocaine is a potential alternative but its effect on the bioavailability of P2Y12 inhibitors is unknown.

The aim of this study was to compare the effects of lignocaine and fentanyl on the onset of the antiplatelet activity of ticagrelor in patients undergoing coronary angiography and percutaneous coronary intervention (PCI).

This is the first study to evaluate lignocaine as an alternative to fentanyl for analgesia in patients undergoing coronary angiography and PCI. Lignocaine does not impair the bioavailability or delay the antiplatelet effect of ticagrelor. The tolerability of lignocaine, compared with fentanyl was similar, and there was no significant difference in 30-day major adverse events.

Lignocaine may be an effective and well tolerated alternative to fentanyl when used as procedural analgesia. Opioids should only be used for breakthrough pain unresponsive to other analgesic approaches. Investigating alternatives to opioids in the treatment of acute ischaemic chest pain, such as STEMI, is warranted.

The Lignocaine versus Opioids in Coronary Intervention: Assessing Antiplatelet Activity and Ticagrelor Levels (LOCAL) trial (U1111-1231-1375) was a prospective, single-centre, double-blind, randomised controlled trial. Patients (n=90) were randomised to IV fentanyl citrate (initial  dose 0.75 µg/kg if aged under 70 years, otherwise 0.5 µg/kg, with additional doses at the discretion of the interventional cardiologist and 0.5 µg/kg at the end of the procedure) or lignocaine hydrochloride (initial dose 1 mg/kg [maximum dose of 100 mg] as a slow IV push over 2min with a further 0.5mg/kg at the discretion of the cardiologist); crossover to fentanyl only if sufficient analgesia was not achieved. Patients with indications for antiplatelet therapy were given oral ticagrelor (180 mg) at the end of the procedure. Participants ranked their pain at the beginning, worst point, and at 2 h after the procedure using an 11-point numerical rating scale (NRS).

Plasma ticagrelor concentration at 2 h in the lignocaine group compared to the fentanyl group using intention-to-treat analysis.

• Area under the ticagrelor plasma concentration-time curve between 0 and 4 h
• Platelet inhibition assessed by VerifyNow (VFN), Multiplate Analyzer (MPA), flow cytometry assays at all time points, and vasodilator-stimulated phosphoprotein phosphorylation (VASP) at 2 h post-ticagrelor administration
• Percentage of patients with high on-treatment platelet reactivity (HTPR) at the above time points
• Pain NRS scores in both groups at the start and end of the procedure
• Adverse effects in each group requiring intervention
• Major adverse cardiac events (MACE) at 30 days in each group

Males and non-pregnant females over 18 years of age with a diagnosis of UA or STEMI who have provided informed consent for angiography and PCI

• Out of hospital cardiac arrest
• STEMI
• Cardiogenic shock

• Of the 90 participants, 70 had an indication for dual antiplatelet therapy
• Plasma ticagrelor levels 2 h post-administration were significantly lower in the fentanyl arm compared with the lignocaine arm (598 vs. 1008 ng/mL, p=0.014)
• The area under the ticagrelor plasma–time curve in the first 4 h post-administration was significantly lower in the fentanyl compared to lignocaine arm (1228 vs.2753 ng h/mL, p<0.001). The same was true for AR-C124910XX (201 vs. 447 ng h/mL, p=0.001)
• Ticagrelor plasma levels were significantly lower in the fentanyl arm at all time points except baseline and 240min
• Levels of AR-C124910XX were significantly lower in the fentanyl arm at all time points except at baseline
• For all time points after baseline, all tests of platelet reactivity showed significantly higher rates of platelet reactivity in the fentanyl arm compared with the lignocaine arm (p<0.001 for all time points)
• Pain scores were not significantly different between the two groups at the start of the procedure. Two patients in the lignocaine arm crossed over to fentanyl during the procedure due to intolerable chest pain despite administration of two lignocaine doses
• Safety events were similar in the two groups. There was a trend towards greater nausea and vomiting in the fentanyl arm. No patients developed sustained bradyarrhythmias, cardiogenic shock, or neurotoxicity
• There was no difference in the prevalence of 30-day major adverse events between the fentanyl or lignocaine groups
• Patient satisfaction with procedural pain relief was high and did not differ between groups (94% vs. 97% for fentanyl and lignocaine respectively)

These findings suggest that lignocaine may be a safe and effective alternative analgesic agent to fentanyl in patients undergoing coronary angiography and PCI, and does not diminish the early antiplatelet effects of ticagrelor. The study replicates previous findings that that fentanyl interferes with the absorption and early antiplatelet responses of ticagrelor. Lignocaine was well tolerated and patient satisfaction was high.

• The study was too small to determine whether lignocaine is safe in routine clinical practice
• Inter-assay variability was seen in the different platelet function tests