Dale Ola, Piribauer Maria, Kaasa Stein, Moksnes Kristin, Knobel Heidi, Klepstad Pål
Pain and Palliation Research Group, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
J Pain Symptom Manage. 2009 Jan;37(1):68-76. doi: 10.1016/j.jpainsymman.2007.12.016. Epub 2008 May 27.
The European Association for Palliative Care guidelines for treatment of cancer pain recommend a double dose (DD) of immediate-release morphine at bedtime instead of single doses (SD) repeated every four hours throughout the night. A previous open controlled study reported more side effects after DD than after SD. The present study was a randomized, double-blind, crossover study comparison of DD and SD of immediate-release morphine during the night, followed by an open pharmacokinetic study. The primary outcome was average pain intensity during the night, as measured on an 11-point numerical rating scale. Secondary outcomes were morning pain, number of rescue medications, adverse effects (nausea, xerostomia, tiredness, sleep quality, and number of awaking episodes) and patient preference. Morphine and metabolites were quantified by a validated liquid chromatography-tandem mass spectrometry method. Nineteen patients completed the clinical study; 13 participated in the pharmacokinetic follow up. Average pain during the night for DD vs. SD was close to statistical significance (mean 0.8 and 1.4, respectively, P=0.058; mean [95% confidence interval] for the difference was 0.50 [0.02, 1.0]). A similar trend was observed for strongest night pain (P=0.069) and sleep quality (P=0.077). Only two patients required rescue morphine. Four patients had no treatment preference; nine and six favored DD and SD, respectively. DD patients displayed higher area under the curve for morphine and morphine-6-glucuronide during the first part of the night. Although DD tended to perform slightly better than SD, a difference in average pain during the night of 0.50 has little clinical significance, and the two procedures are, therefore, clinically equivalent. It is speculated whether the initial higher exposure to morphine-6-glucuronide may have clinical significance.
欧洲姑息治疗协会癌症疼痛治疗指南推荐在睡前服用双倍剂量（DD）的即释吗啡，而非在夜间每四小时重复服用单剂量（SD）。此前一项开放性对照研究报告称，双倍剂量组的副作用比单剂量组更多。本研究是一项随机、双盲、交叉研究，比较夜间即释吗啡双倍剂量和单剂量的效果，随后进行一项开放性药代动力学研究。主要结局是夜间平均疼痛强度，采用11点数字评分量表进行测量。次要结局包括早晨疼痛、急救药物使用次数、不良反应（恶心、口干、疲劳、睡眠质量和觉醒次数）以及患者偏好。吗啡及其代谢物通过经过验证的液相色谱 - 串联质谱法进行定量。19名患者完成了临床研究；13名患者参与了药代动力学随访。双倍剂量组与单剂量组夜间的平均疼痛接近统计学显著性差异（分别为均值0.8和1.4，P = 0.058；差异的均值[95%置信区间]为0.50[0.02, 1.0]）。在最强夜间疼痛（P = 0.069）和睡眠质量（P = 0.077）方面观察到类似趋势。只有两名患者需要急救吗啡。四名患者没有治疗偏好；分别有九名和六名患者倾向于双倍剂量和单剂量。在夜间的第一部分，双倍剂量组患者的吗啡和吗啡 - 6 - 葡萄糖醛酸的曲线下面积更高。尽管双倍剂量组的表现往往略优于单剂量组，但夜间平均疼痛差异0.50的临床意义不大，因此这两种方法在临床上是等效的。推测吗啡 - 6 - 葡萄糖醛酸最初的较高暴露是否具有临床意义。
