Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: Comparison of those who do and do not experience withdrawal and concentration-effect relationships
Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: Comparison of those who do and do not experience withdrawal and concentration-effect relationships
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DOI：
10.1016/s0009-9236(99)90090-5
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发表时间：
1999-06-01
影响因子：
6.7
通讯作者：
Bochner, F
中科院分区：
文献类型：
--
作者：
Dyer, KR;Foster, DJR;Bochner, F
目的：为了确定血浆外消旋美沙酮浓度-效应关系的主观和客观的反应，以及是否药代动力学和/或药效学因素影响戒断severity.Methods：18例患者参加了一个公共的美沙酮维持计划，其中9人经历了显着的退出，接受恒定剂量的美沙酮每天一次，至少2个月。在给药间隔期间，采集13份血液样本以测量血浆外消旋美沙酮浓度（患者）;在11种情况下（所有参与者）定量主观（戒断严重程度，直接阿片类药物作用和疼痛阈值）和客观（瞳孔直径和呼吸频率）阿片类药物作用。使用S形E-max模型将血浆浓度和效应联系起来，并计算斜率因子（N）。在每小时的血浆浓度下降的速度从峰值到谷concentration.Results：血浆浓度和戒断严重程度和瞳孔直径之间呈反比关系，以及与主观阿片类药物的影响和痛阈的直接关系。戒断严重程度的平均N值为5.4 +/- 0.9，主观阿片类药物作用的平均N值为5.1 +/- 1.1，瞳孔直径的平均N值为1.2 +/- 0.1，疼痛阈值的平均N值为2.8 +/- 0.7。戒断严重程度与血浆浓度的最大下降速率相关（P <0.01）。有没有显着的退出，那些谁没有关于平均面积下的血浆浓度与时间曲线和给药前血浆浓度之间的差异，但最大的下降率更大的前一组（74.5与42.1 ng/mL/h）。结论：在这组长期美沙酮维持收件人，阿片类药物的反应与血浆外消旋美沙酮浓度的变化密切相关。对于主观反应，特别是戒断反应，血浆浓度的微小变化转化为效应的相对较大变化;因此，临床上重要的戒断反应是美沙酮浓度更快下降的结果。
Objective: To determine plasma racemic methadone concentration-effect relationships for subjective and objective responses and whether pharmacokinetic and/or pharmacodynamic factors influence withdrawal severity.Methods: Eighteen patients enrolled in a public methadone maintenance program, nine of whom experienced significant withdrawal, received constant doses of methadone once daily for at least 2 months. During an interdosing interval, 13 blood samples were collected to measure plasma racemic methadone concentrations (patients); subjective (withdrawal severity, direct opioid effects, and pain threshold) and objective (pupil diameter and respiratory rate) opioid effects were quantified on 11 occasions (all participants). The sigmoid E-max model was used to relate plasma concentrations and effects and to calculate the slope factor (N). The rate of decline in plasma concentration during each hour from the peak to the trough concentration was calculated.Results: There was an inverse relationship between plasma concentrations and withdrawal severity and pupil diameter, as well as a direct relationship with subjective opioid effects and pain threshold. The mean N values were 5.4 +/- 0.9 for withdrawal severity, 5.1 +/- 1.1 for subjective opioid effects, 1.2 +/- 0.1 for pupil diameter, and 2.8 +/- 0.7 for pain threshold. Withdrawal severity correlated with the maximum rate of decrease in plasma concentration (P < .01). There were no differences between those who reported significant withdrawal and those who did not with respect to mean area under the plasma concentration versus time curve and predose plasma concentration, but maximal rate of decline was greater in the former group (74.5 versus 42.1 ng/mL/h).Conclusions:In this group of long-term methadone-maintained recipients, opioid responses were strongly correlated with changes in plasma racemic methadone concentrations. For the subjective responses, notably withdrawal, small changes in plasma concentrations translate into relatively large changes in effect; therefore, clinically important withdrawal is a consequence of more rapid decline in methadone concentration.