Department of Pharmacy, Kagoshima University Hospital.
Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences.
Biol Pharm Bull. 2019;42(7):1185-1191. doi: 10.1248/bpb.b19-00105.
Opioid-induced respiratory depression is a potentially life-threatening adverse drug event. The purpose of this study was to evaluate the incidence of respiratory depression using the Japanese Adverse Drug Event Report (JADER) Database to obtain data to promote proper use of opioids. The JADER database from April 2004 to March 2017 was obtained from the Pharmaceuticals and Medical Devices Agency. We calculated the reporting odds ratios (RORs) of suspected opioids (morphine, fentanyl, oxycodone, tapentadol, methadone, tramadol, pentazocine, buprenorphine, and codeine phosphate hydrate), analyzed the daily dose at first appearance and the time-to-onset profile, and assessed the hazard type using the Weibull shape parameter. ROR analysis detected adverse event signals for all opioids. Morphine showed a large ROR value with statistical significance in elderly (≥70 years old) patients. The median daily doses of oral morphine and oxycodone for inducing respiratory depression were comparably low (30 mg/d as oral morphine equivalent dose), while that of transdermal fentanyl was 120 mg/d (oral morphine equivalent dose). On time-to-onset analysis using the Weibull distribution, those opioids were classified as the early failure type. The median time-to-onset of oral morphine, oral oxycodone and transdermal fentanyl was 5.5, 11 and 12.5 d, respectively, and almost 50% of cases were reported within 30 d. Taken together, our results suggest that it is important to monitor patients carefully for at least the first one week to one month, even if opioids are administered at a relatively low dose, especially in elderly patients administered morphine.
阿片类药物引起的呼吸抑制是一种潜在的危及生命的药物不良反应。本研究的目的是使用日本药物不良反应报告（JADER）数据库评估呼吸抑制的发生率，以获得数据来促进阿片类药物的合理使用。从 2004 年 4 月至 2017 年 3 月，从药品和医疗器械管理局获得了 JADER 数据库。我们计算了可疑阿片类药物（吗啡、芬太尼、羟考酮、酒石酸氢可酮、美沙酮、曲马多、喷他佐辛、丁丙诺啡和磷酸可待因）的报告比值比（ROR），分析了首次出现时的日剂量和发病时间曲线，并使用威布尔形状参数评估了危险类型。ROR 分析检测到所有阿片类药物的不良事件信号。吗啡在老年（≥70 岁）患者中表现出较大的 ROR 值且具有统计学意义。引起呼吸抑制的口服吗啡和羟考酮的中位日剂量相当低（30mg/d 作为口服吗啡等效剂量），而透皮芬太尼的中位日剂量为 120mg/d（口服吗啡等效剂量）。使用威布尔分布进行发病时间分析，这些阿片类药物被归类为早期失效类型。口服吗啡、口服羟考酮和透皮芬太尼的中位发病时间分别为 5.5、11 和 12.5d，近 50%的病例在 30d 内报告。总之，我们的结果表明，即使阿片类药物的剂量相对较低，也需要密切监测患者至少在第一周至一个月内的情况，特别是在接受吗啡治疗的老年患者中。
