双氯芬酸（麦角胺）明显干扰阿司匹林对急性和慢性疼痛患者血小板抑制作用的病例对照研究。

Dipyrone (metamizole) markedly interferes with platelet inhibition by aspirin in patients with acute and chronic pain: A case-control study.

机构信息

From the Department of Anaesthesiology (AS, PK, GP, RW); Institute of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany (LR, TH).

出版信息

Eur J Anaesthesiol. 2017 May;34(5):288-296. doi: 10.1097/EJA.0000000000000581.

DOI:10.1097/EJA.0000000000000581

PMID:28030443

Abstract

BACKGROUND

Nonopioid analgesic drugs may interfere with platelet inhibition by aspirin. Recent in vitro and clinical studies in patients with cardiovascular disease have suggested that this pharmacodynamic interaction may also occur with dipyrone, a nonopioid analgesic popular in Europe, Asia and South America.

OBJECTIVE

Dipyrone is used extensively in acute and chronic pain. This study was undertaken to provide clinical data, so far missing, on its interactions in this group of patients.

DESIGN

A case-control study.

SETTING

Primary care in one European university hospital centre.

PATIENTS

In total, 27 patients with stable cardiovascular, cerebrovascular or peripheral arterial disease and acute or chronic pain were identified and given dipyrone for at least 5 days in combination with low-dose aspirin. In total, 10 comparable patients on low-dose aspirin alone served as controls.

MAIN OUTCOME MEASURES

Platelet-rich plasma was prepared to determine arachidonic acid-induced aggregation (aggregometry) and thromboxane formation (immunoassay). Platelet sensitivity to aspirin was examined in vitro. The presence of dipyrone (metabolites) in plasma was confirmed by HPLC. Additional in vitro measurements examined the aspirin/dipyrone interaction in healthy donors.

RESULTS

Inhibition of aggregation was observed in only six of 27 patients receiving aspirin with dipyrone, with absence of complete inhibition by antiplatelet therapy showing in 78% of patients. In contrast, aggregation was completely inhibited in nine of 10 control patients (P < 0.001). Platelet thromboxane synthesis was higher in patients receiving dipyrone + aspirin compared with controls (387 ± 89 vs. 7 ± 1 ng ml, P < 0.001). Aspirin added in vitro failed to inhibit aggregation and thromboxane synthesis in platelet-rich plasma from dipyrone-treated patients. In vitro measurements with blood from healthy individuals confirmed that dipyrone dramatically reduces inhibition of platelet thromboxane synthesis by aspirin.

CONCLUSIONS

Dipyrone given for 5 days or longer blunts platelet inhibition by low-dose aspirin in the majority of recipients.

TRIAL REGISTRATION

German Clinical Trials Register: DRKS ID DRKS00000204. Universal Trial Number (UTN): U1111-1113-3946.

摘要

背景

非阿片类镇痛药可能会干扰阿司匹林对血小板的抑制作用。最近在心血管疾病患者中的体外和临床研究表明，这种药效学相互作用也可能发生在双氯芬酸身上，双氯芬酸是一种在欧洲、亚洲和南美洲广受欢迎的非阿片类镇痛药。

目的

双氯芬酸被广泛用于急性和慢性疼痛。本研究旨在提供迄今为止在这组患者中缺失的关于其相互作用的临床数据。

设计

病例对照研究。

地点

一家欧洲大学医院中心的初级保健。

患者

共确定了 27 例患有稳定的心血管、脑血管或外周动脉疾病以及急性或慢性疼痛的患者，并给予双氯芬酸至少 5 天，同时给予小剂量阿司匹林。总共 10 例接受小剂量单独阿司匹林的可比患者作为对照。

主要观察指标

制备富含血小板的血浆以确定花生四烯酸诱导的聚集（聚集测定）和血栓烷形成（免疫测定）。体外检测血小板对阿司匹林的敏感性。通过 HPLC 证实血浆中双氯芬酸（代谢物）的存在。额外的体外测量检查了健康供体中阿司匹林/双氯芬酸的相互作用。

结果

在接受阿司匹林加双氯芬酸治疗的 27 例患者中，仅 6 例观察到聚集抑制，78%的患者抗血小板治疗无完全抑制。相比之下，在 10 例对照患者中，9 例完全抑制了聚集（P<0.001）。与对照组相比，接受双氯芬酸+阿司匹林治疗的患者血小板血栓烷合成更高（387±89 与 7±1ng/ml，P<0.001）。体外加入阿司匹林未能抑制双氯芬酸治疗患者的富含血小板血浆中的聚集和血栓烷合成。来自健康个体的体外测量证实，双氯芬酸可显著降低阿司匹林对血小板血栓烷合成的抑制作用。