Dawes Joy M, Cooke Erin M, Hannam Jacqueline A, Brand Katherine A, Winton Pamela, Jimenez-Mendez Ricardo, Aleksa Katarina, Lauder Gillian R, Carleton Bruce C, Koren Gideon, Rieder Michael J, Anderson Brian J, Montgomery Carolyne J
Department of Anaesthesia, Great Ormond Street Hospital, London, UK.
Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
Paediatr Anaesth. 2017 Jan;27(1):28-36. doi: 10.1111/pan.13020. Epub 2016 Oct 25.
Oral morphine has been proposed as an effective and safe alternative to codeine for after-discharge pain in children following surgery but there are few data guiding an optimum safe oral dose.
The aim of this study was to characterize the absorption pharmacokinetics of enteral morphine in order to simulate time-concentration profiles in children given common oral morphine dose regimens.
Children (2-6 years, n = 34) undergoing elective surgery and requiring opioid analgesia were randomized to receive preoperative oral morphine (100 mcg·kg , 200 mcg·kg , 300 mcg·kg ). Blood sampling for morphine assay was performed at 30, 60, 90, 120, 180, and 240 min. Morphine serum concentrations were determined by liquid chromatography-mass spectroscopy and pharmacokinetic parameters were calculated using nonlinear mixed effects models. Current data were pooled with published time-concentration profiles from children (n = 1059, age 23 weeks postmenstrual age - 3 years) administered intravenous morphine, to determine oral bioavailability (F), absorption lag time (T ), and absorption half-time (T ). These parameter estimates were used to predict concentrations in children given oral morphine (100, 200, 300, 400, 500 mcg·kg ) at different dosing intervals (3, 4, 5, 6, 8, 12 h).
The oral morphine formulation had F 0.298 (CV 36.5%), T 0.45 (CV 63.6%) h and T 0.71 (CV 55%) h. A single-dose morphine 100 mcg·kg achieved a mean C 10 mcg·l . Repeat 4-hourly dosing achieved mean steady-state concentration 13-18 mcg·l ; concentrations associated with good analgesia after intravenous administration. Serum concentration variability was large ranging from 5 to 55 mcg·l at steady state.
Oral morphine 200 mcg·kg then 100 mcg·kg 4 h or 150 mcg·kg 6 h achieves mean concentrations associated with analgesia. There was high serum concentration variability suggesting that respiration may be compromised in some children given these doses.
口服吗啡已被提议作为儿童手术后出院疼痛时可替代可待因的一种有效且安全的药物，但几乎没有数据指导最佳安全口服剂量。
本研究的目的是描述肠内吗啡的吸收药代动力学，以便模拟给予常见口服吗啡剂量方案的儿童的时间 - 浓度曲线。
接受择期手术且需要阿片类镇痛的儿童（2 - 6岁，n = 34）被随机分组，接受术前口服吗啡（100 mcg·kg、200 mcg·kg、300 mcg·kg）。在30、60、90、120、180和240分钟进行采血以检测吗啡。通过液相色谱 - 质谱法测定吗啡血清浓度，并使用非线性混合效应模型计算药代动力学参数。将当前数据与已发表的静脉注射吗啡的儿童（n = 1059，月经后年龄23周 - 3岁）的时间 - 浓度曲线汇总，以确定口服生物利用度（F）、吸收滞后时间（T）和吸收半衰期（T）。这些参数估计值用于预测给予口服吗啡（100、200、300、400、500 mcg·kg）且给药间隔不同（3、4、5、6、8、12小时）的儿童的浓度。
口服吗啡制剂的F为0.298（CV 36.5%），T为0.45（CV 63.6%）小时，T为0.71（CV 55%）小时。单剂量100 mcg·kg的吗啡达到的平均C为10 mcg·l。每4小时重复给药达到的平均稳态浓度为13 - 18 mcg·l；这是静脉给药后与良好镇痛相关的浓度。稳态时血清浓度变异性很大，范围为5至55 mcg·l。
口服吗啡200 mcg·kg然后每4小时100 mcg·kg或每6小时150 mcg·kg可达到与镇痛相关的平均浓度。血清浓度变异性很高，表明给予这些剂量时一些儿童的呼吸可能会受到影响。
