https://orcid.org/0000-0003-3909-182X
This editorial refers to ‘Effects of lignocaine vs. opioids on antiplatelet activity of ticagrelor: the LOCAL trial’, by H. Fernando et al., https://doi.org/10.1093/eurheartj/ehab557.
Advantages and disadvantages of opioid and non-opioids analgesics in patients undergoing percutaneous coronary interventions. Among patients undergoing percutaneous coronary interventions, analgesics are used to relieve chest pain, enhance patient comfort and improve patient compliance (i.e., reduce movements, deep breaths or talking). Opioid and non-opioids analgesics each have their advantages and disadvantages, the clinical implications of some remain to be defined.
Opioid analgesics represent the cornerstone of medical treatment for pain relief among patients with cardiovascular disease, including those undergoing percutaneous coronary intervention (PCI).1–3 In particular, opioid analgesics are commonly administered for pain relief in patients with ongoing chest pain, such as in patients with acute coronary syndrome (ACS), but also to enhance patient comfort during elective procedures (Graphical Abstract).1 , 3 Opioid analgesics also modulate activation of the sympathetic nervous system, decreasing cardiac workload mainly by reducing systemic vasoconstriction and heart rate.1 , 2 In turn, this can facilitate operators in performing the PCI. Nevertheless, opioid analgesics have several side effects including hypotension, bradycardia, respiratory depression, and gastrointestinal (GI). GI side effects include nausea, vomiting and impaired GI motility. Importantly, such GI side effects can affect absorption and onset of action of orally administered drugs, including antiplatelet agents.4 , 5
Oral platelet P2Y12 inhibitors are key for the prevention of thrombotic complications in patients undergoing PCI, underscoring the importance of achieving prompt and reliable antiplatelet effects.1–3 Such considerations are of particular relevance with the ever-growing number of patients undergoing ad-hoc PCI following their diagnostic cardiac catheterization procedure, many of whom have not been pre-treated with an oral platelet P2Y12 inhibitor. However, a number of studies have consistently shown that opioid analgesics cause slower uptake and delayed onset of action of oral P2Y12 inhibitors leading to increased rates of high platelet reactivity (HPR) in the early hours after drug administration, thus exposing patients to a potentially increased risk of thrombotic complications.4–7 Although the clinical impact associated with the use of opioid analgesics in this setting remains controversial, the well-established association between HPR and thrombotic complications in patients undergoing PCI has impacted guideline recommendations from the European Society of Cardiology (ESC) for patients with ST-segment elevation ACS (STE-ACS) here their use has been downgraded from a Class I, level of evidence (LoE) C to a class IIa, LoE C.1 , 2 , 7 , 8 Moreover, both the Food and Drug Administration and the European Medicines Agency have provided updates to the product labels of oral P2Y12 inhibitors acknowledging the drug interaction with opioid analgesics, and suggest the use of parenteral antiplatelet agents in patients with ACS when these agents are co-administered. The impact of opioid analgesics on absorption and onset of action of oral P2Y12 inhibitors among patients undergoing PCI has sparkled interest in designing studies to overcome the above-mentioned drawbacks. These include studies aimed at antagonizing the GI effects of opioids (i.e., use of peripheral opioid receptor antagonists), which however have failed to achieve meaningful impact on antiplatelet drug absorption, and more importantly, investigating alternative, non-opioid, analgesic drugs.9–12
In the present issue of the European Heart Journal, Fernando and colleagues report the results of the Lignocaine vs. Opioids in Coronary intervention: assessing Antiplatelet activity and ticagrelor Levels (LOCAL) study. This was a prospective, single centre, double-blind, randomized, controlled pharmacokinetic (PK) and pharmacodynamic (PD) trial comparing the use of lignocaine vs. fentanyl among patients with non-ST elevation ACS (NSTE-ACS) undergoing PCI.9 Fentanyl is a synthetic opioid analgesic commonly used in patients undergoing cardiac catheterization that produces stronger and faster analgesic effects compared to morphine. Lignocaine (lidocaine) is a sodium channel blocker commonly used for local and regional anesthesia as well as for the treatment of ventricular arrhythmia (type Ib antiarrhythmic). Lignocaine blocks sodium channels, uncouples G protein, blocks N-methyl-D-aspartate (NMDA) receptor, reduces circulating inflammatory cytokines, and prevents secondary hyperalgesia and central sensitization.13 Accordingly, lignocaine is also used, albeit off label, for the treatment of various pain conditions, although its analgesic effects in patients with ACS are not fully defined and are hereby investigated.13
The LOCAL trial randomized 90 patients with NSTE-ACS undergoing coronary angiogram to receive intravenous fentanyl (n = 47), at a dosage of 0.75 µg/kg, or intravenous lignocaine (n = 43), at a dosage of 1 mg/kg as a slow intravenous push over 2 minutes followed or not by a further 0.5 mg/kg at the discretion of the physician.9 A total 70 patients were included in the PK/PD analysis and underwent integral ticagrelor tablet loading dose administration (180 mg) at the end of PCI. Blood samples for the PK/PD analyses were collected at baseline and at subsequent four time-points (30, 60, 120 and 240 minutes). The primary endpoint was plasma ticagrelor concentration at 2 hours post loading dose. There were several secondary endpoints, which included assessment of platelet reactivity by a number of assays, HPR rates, pain evaluation, and clinical outcomes. The authors found that the primary endpoint of plasma ticagrelor levels (including its major metabolite) at 2 hours post loading dose were significantly lower in the fentanyl than lignocaine arm (598 vs. 1008 ng/mL, P = 0.014). Such PK findings translated into more favorable PD effects as reflected by the enhanced platelet inhibition and lower HPR rates in patients treated with lignocaine compared to fentanyl. However, although platelet reactivity and HPR rates were significantly increased up to 2 hours in the fentanyl as compared to the lignocaine arm, these differences were no longer significant at 4 hours. Pain scores using an 11-point numerical rating (NRS) were similar in the two study arms. Moreover, the use of lignocaine was well-tolerated and not associated with relevant adverse events or side effects such as hypotension or bradyarrhythmias.
The strengths of the study are the rigorous design with strict inclusion and exclusion criteria to allow for a rather homogenous cohort of patients, the selection of critical time-points of blood sampling for PK/PD assessments and the use of multiple assays allowing for a comprehensive analysis. Nevertheless, there are several considerations that need to be made, particularly when translating the results of this study into clinical practice. First, this is a PK/PD study not powered for clinical outcomes. Thus, whether the presence of increased platelet reactivity limited to the first 2 hours after PCI leads to clinically significant outcomes remains elusive.8 Moreover, the clinical relevance of these PK/PD findings could be attenuated in the real world setting for the following reasons: 1) the loading dose of P2Y12 inhibitor commonly precedes the start of the PCI procedure (i.e., after the diagnostic angiogram), as also recommended in ESC guidelines, which would have likely translated into more time for ticagrelor to be absorbed and lessen the differences observed in the early hours post-PCI;3 2) a crushed formulation of ticagrelor, which accelerates drug absorption, is frequently used in patients with ACS and could have also mitigated differences between groups;14 3) in ACS patients who have not been pre-treated with an oral P2Y12 inhibitor, it is not infrequent that an intravenous antiplatelet agent be used (i.e., cangrelor or glycoprotein IIb/IIIa inhibitors) which would bridge this early gap in platelet inhibitory effects.15 Second, pain levels according to NRS were very low at baseline (2 and 1 in the fentanyl and lignocaine arms, respectively) and the maximal pain score was also low (3 in both groups). Moreover, two patients randomized to lignocaine also received fentanyl due to intolerable ischaemic chest pain despite administering two lignocaine doses. Therefore, these findings are insufficient to support the analgesic effectiveness of lignocaine. Third, although the study did not reveal relevant adverse events or side effects with lignocaine, the limited sample size of the study does not allow to rule out any safety concerns associated with its use in this clinical setting.13
The results of the LOCAL study are indeed informative and provide very encouraging PK/PD data that warrant further research in larger and more targeted patient populations to better assess its safety and analgesic effects. To this extent, the ongoing An open-label, non-inferiority randomized controlled trial of lidocAine vs. Opioids In MyocarDial Infarction (AVOID-2) study, will compare lignocaine to fentanyl among patients with STE-ACS (n = 300) with moderate-severe pain.11 Alternative non-opioid analgesic drugs, such as acetaminophen, have also showed promising, albeit non-conclusive, findings. The Effect of Opioids on P2Y12 Receptor Inhibition in Patients With ST-Elevation Myocardial Infarction Who Are Pre-treated With Crushed Ticagrelor (ON-TIME 3) trial, conducted in STE-ACS patients characterized by moderate-severe pain pre-treated with crushed ticagrelor, showed that despite there were no significant differences in the primary endpoint of platelet reactivity (albeit numerically lower), intravenous acetaminophen resulted in significantly higher ticagrelor plasma levels compared to fentanyl with similar and clinically meaningful degree of pain relief.10 Collectively, although the available evidence on the use of non-opioid analgesics in patients undergoing coronary angiography and PCI are thus far promising, whether they can be safely and effectively used as a mainstream treatment in this setting remains to be defined.
Conflict of interest: Dr Galli has no conflicts of interest to disclose. Dr Angiolillo has received payment as an individual for: reports receiving payments as an individual for: a) Consulting fee or honorarium from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; b) Participation in review activities from CeloNova and St. Jude Medical. Institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions and the Scott R. MacKenzie Foundation.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
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