Objectives: Central nervous system adverse events (AEs) occur when oxycodone is used in combination with benzodiazepines, antidepressants and anticonvulsants. There have been no reports of central nervous system AEs with oxycodone alone or in combination with oxycodone. Based on USA Food and Drug Administration Adverse Event Reporting System (FAERS) data, this study aims to explore the risk signals of central nervous system AEs with oxycodone alone or in combination with benzodiazepines, antidepressants and anticonvulsants, and to provide a reference for the safe and rational use of this drug.
Methods: Extracted AEs data from the FAERS for oxycodone alone and in combination with benzodiazepines, antidepressants, and anticonvulsants from Q1 2004 to Q2 2021. The risk signal mining analysis of AEs was performed using the proportional imbalance method and Bayesian method. Number of reports ≥3 and lower 95% CI limit of reporting odds ratio (ROR)>1; number of reports ≥3, proportional reporting ratio (PRR)≥2 and χ2≥4; lower information components (IC) lower 95% CI limit (IC025)>0; empirical Bayes geometric mean (EBGM) lower 95% CI limit (EBGM05)>2, and N>0 were defined as positive signals.
Results: A total of 5 793 reports of central nervous system AEs with oxycodone alone were tapped, and 366, 622, and 740 reports of combined benzodiazepines, antidepressants, and anticonvulsants, respectively. Consumers and physicians were the main reporting population. The age distribution of oxycodone alone was mainly from 61 to 80 years old. The age distribution of oxycodone in combination with related drugs was mainly from 46 to 60 years old. The risk of AEs was greater in women than in men, and the United States was the predominant reporting country. Oxycodone alone was strongly associated with myoclonus [ROR=2.92, 95% CI 2.28 to 3.76); PRR=2.92, χ2(77.49); IC=1.52, IC025(0.65); EBGM=2.89, EBGM05(2.33)], delirium [ROR=4.69, 95% CI 4.24 to 5.21; PRR=4.66, χ2(1 052.64); IC=2.17, IC025(1.81); EBGM=4.50, EBGM05 (4.13)], mental disorder [ROR=2.95, 95% CI 2.53 to 3.44; PRR=2.94, χ2(206.93); IC=1.56, IC025(0.96); EBGM=2.95, EBGM05(2.58)], and acute central respiratory depression [ROR=2.87, 95% CI 2.68 to 3.08); PRR=2.82, χ2(971.62); IC=1.52, IC025(1.33), EBGM=2.87, EBGM05 (2.76)]. Combination of benzodiazepines was most strongly associated with mental disorder [ROR=10.08, 95% CI 9.38 to 10.78; PRR=9.90, χ2(64.06); IC=3.33, IC025 (1.65); EBGM=10.08, EBGM05(5.61)], and tremor [ROR=3.09, 95% CI 2.76 to 3.42); PRR=3.08, χ2(48.93); IC=1.63, IC025 (1.17); EBGM=3.09, EBGM05(2.34)]. Combination of antidepressants was most strongly associated with delirium [ROR=13.23, 95% CI 12.23 to 14.23; PRR=12.87, χ2(43.86); IC=3.69, IC025(1.36); EBGM=12.23, EBGM05 (5.32)] and somnolence [ROR=6.74, 95% CI 6.15 to 7.33); PRR=6.73, χ2(53.42); IC=2.75, IC025(1.52); EBGM=6.73, EBGM05(4.10)]. Combination of anticonvulsants was most strongly associated with myoclonus [ROR=17.89, 95% CI 17.46 to 18.32; PRR=17.72, χ2(971.39); IC=4.16, IC025(2.70); EBGM=17.89, EBGM05(12.46)] and delirium [ROR=4.86, 95% CI 4.45 to 5.27); PRR=4.82, χ2(69.49); IC=2.28, IC025 (1.51); EBGM=4.86, EBGM05(3.44)].
Conclusions: Based on pharmacovigilance studies of the FAERS database, clinical medication monitoring of oxycodone alone and in combination with benzodiazepines, antidepressants, and anticonvulsants should be strengthened to be alert to the occurrence of central nervous system-related AEs.
目的: 羟考酮与苯二氮䓬类药物、抗抑郁药及抗惊厥药联用时，会出现中枢神经系统不良事件(adverse events，AEs)。本研究基于美国食品药品监督管理局不良事件报告系统(Food and Drug Administration Adverse Event Reporting System，FAERS)数据，挖掘羟考酮单用及联用苯二氮䓬类药物、抗抑郁药和抗惊厥药的中枢神经系统AEs的风险信号，为该药的安全合理使用提供参考。方法: 提取FAERS中2004年第1季度至2021年第2季度的单用羟考酮及联用苯二氮䓬类药物、抗抑郁药及抗惊厥药的AEs数据，采用比例失衡法及贝叶斯法进行AEs风险信号挖掘分析。报告数≥3且报告比值比(reporting odds ratio，ROR) 95% CI下限>1；报告数≥3，比例报告比值比(proportional reporting ratio，PRR)≥2且χ2值≥4；信息成分(information components，IC)95% CI下限(IC025)>0；经验贝叶斯几何平均数(empirical Bayes geometric mean，EBGM)95% CI下限(EBGM05)>2，N>0被定义为阳性信号。结果: 共挖掘到单用羟考酮中枢神经系统AEs报告数为5 793例，合用苯二氮䓬类药物、抗抑郁药、抗惊厥药报告数分别为366、622、740例。消费者和医师是主要上报人群。单用羟考酮的年龄主要分布在61~80岁。羟考酮联用相关药物年龄主要分布在46~60岁。女性发生AEs的风险大于男性，报告国家以美国为主。单用羟考酮与肌阵挛[ROR=2.92，95% CI 2.28~3.76；PRR=2.92，χ2(77.49)；IC=1.52，IC025(0.65)；EBGM=2.89，EBGM05(2.33)]、谵妄[ROR=4.69，95% CI 4.24~5.21；PRR=4.66，χ2(1052.64)；IC=2.17，IC025(1.81)；EBGM=4.50，EBGM05(4.13)]、精神异常[ROR=2.95，95% CI 2.53~3.44；PRR=2.94，χ2(206.93)；IC=1.56，IC025(0.96)，EBGM=2.95，EBGM05(2.58)]、急性中枢性呼吸抑制[ROR=2.87，95% CI 2.68~3.08；PRR=2.82，χ2(971.62)；IC=1.52，IC025(1.33)；EBGM=2.87，EBGM05(2.76)]的关联性强；联用苯二氮䓬类药物与精神异常[ROR=10.08，95% CI 9.38~10.78；PRR=9.90，χ2(64.06)；IC=3.33，IC025(1.65)；EBGM=10.08，EBGM05(5.61)]、震颤[ROR=3.09，95% CI 2.76~3.42；PRR=3.08，χ2(48.93)；IC=1.63，IC025(1.17)；EBGM=3.09，EBGM05(2.34)]的关联性最强；联用抗抑郁药与谵妄[ROR=13.23，95% CI 12.23~14.23；PRR=12.87，χ2(43.86)；IC=3.69，IC025(1.36)；EBGM=12.23，EBGM05(5.32)]、嗜睡[ROR=6.74，95% CI 6.15~7.33；PRR= 6.73，χ2(53.42)；IC=2.75，IC025(1.52)；EBGM=6.73，EBGM05(4.10)]的关联性最强；联用抗惊厥药与肌阵挛[ROR=17.89，95% CI 17.46~18.32；PRR=17.72，χ2(971.39)；IC=4.16，IC025(2.70)；EBGM=17.89，EBGM05(12.46)]、谵妄[ROR=4.86，95% CI 4.45~5.27；PRR=4.82，χ2(69.49)；IC=2.28，IC025(1.51)；EBGM=4.86，EBGM05(3.44)]的关联性最强。结论: 基于对FAERS数据库的药物警戒研究，应加强羟考酮单用及联用苯二氮䓬类药物、抗抑郁药、抗惊厥药的临床用药监测，警惕中枢神经系统相关AEs的发生。.
Keywords: Food and Drug Administration Adverse Event Reporting System; adverse events; oxycodone; signal mining.