Gourlay Geoffrey K, Cherry David A, Onley Margaret M, Tordoff Simon G, Conn David A, Hood Gillian M, Plummer John L
Pain Management Unit, Flinders Medical Centre,; Bedford Park, South Australia, 5042 Australia.
Pain. 1997 Feb;69(3):295-302. doi: 10.1016/S0304-3959(96)03269-1.
Twenty-four patients with severe pain related to cancer completed a randomised, double-blind, double-dummy, crossover study examining morphine pharmacokinetics and pharmacodynamics when the same 24-h morphine dose was administered using two modified release oral morphine formulations; either one dose of Kapanol (a new sustained release polymer coated pellet formulation administered in capsule form, Glaxo Wellcome group of companies) per 24 h, or MS Contin (Purdue Frederick Company, Connecticut, USA) administered at 12-h intervals. The morphine dose was optimised for each patient using an immediate release morphine solution in the lead-in period to provide the most favourable balance between pain relief and side-effects. Patients were then randomly allocated to receive their 24-h morphine dose as either Kapanol or MS Contin in period 1. Patients recorded daily measures of pain relief and morphine related side-effects (morphine pharmacodynamics) in a diary. Patients were admitted to the Pain Management Unit on the morning of day 7 (+/- 1 day) and frequent blood samples were collected for 24 h following the 10:00 h dose to fully characterise the pharmacokinetic profile for morphine and its metabolites at steady state. Morphine pharmacodynamics and the amount and timing of rescue medication (dextromoramide) were also recorded during this time. Period 2, which commenced at 10:00 h on day 8, was identical to period 1 except the modified release formulations were changed. The pharmacokinetic profile of Kapanol exhibited a significantly higher Cmin (minimum plasma morphine concentration), less fluctuation in plasma morphine concentration throughout the dosing interval, a longer Tmax (time associated with the maximum morphine concentration) and a greater time that the plasma morphine concentration was > or = 75% of Cmax (an index of the control the formulation exerts over the morphine release rate) compared to that of MS Contin. Some of these pharmacokinetic differences (e.g., Cmin and fluctuation in plasma morphine concentration) were surprising given that the dosing interval for Kapanol (24 h) was double that of MS Contin (12 h). There was no significant difference between the Kapanol and MS Contin treatment phases in any of the pharmacodynamic parameters, morphine related side-effects, the percentage of patients taking rescue medication as well as the amount or time to the first dose of rescue analgesia on day 7 in periods 1 and 2, patient or investigator assessments of global efficacy at the end of periods 1 and 2, or patient treatment preference at the end of the study. Once a day Kapanol provided the same degree of pain relief and morphine related side-effects as 12-h MS Contin.
24例患有与癌症相关的重度疼痛的患者完成了一项随机、双盲、双模拟、交叉研究，该研究旨在考察当使用两种缓释口服吗啡制剂给予相同的24小时吗啡剂量时吗啡的药代动力学和药效学；即每24小时服用一剂卡帕诺（一种以胶囊形式给药的新型缓释聚合物包衣微丸制剂，葛兰素威康集团公司生产），或每12小时服用美施康定（美国康涅狄格州普渡弗雷德里克公司生产）。在导入期使用速释吗啡溶液为每位患者优化吗啡剂量，以在疼痛缓解和副作用之间提供最有利的平衡。然后患者被随机分配在第1阶段接受卡帕诺或美施康定作为其24小时吗啡剂量。患者在日记中记录每日疼痛缓解情况以及与吗啡相关的副作用（吗啡药效学）。患者在第7天上午（±1天）入住疼痛管理单元，并在10:00给药后的24小时内采集多次血样，以全面表征吗啡及其代谢产物在稳态时的药代动力学特征。在此期间还记录了吗啡药效学以及急救药物（右吗拉胺）的用量和时间。第2阶段于第8天10:00开始，与第1阶段相同，只是更换了缓释制剂。与美施康定相比，卡帕诺的药代动力学特征表现为显著更高的Cmin（血浆吗啡最低浓度）、在给药间隔期间血浆吗啡浓度波动更小、更长的Tmax（与最大吗啡浓度相关的时间）以及血浆吗啡浓度≥Cmax的75%的时间更长（该指标反映制剂对吗啡释放速率的控制）。鉴于卡帕诺的给药间隔（24小时）是美施康定（12小时）的两倍，其中一些药代动力学差异（例如，Cmin和血浆吗啡浓度波动）令人惊讶。在第1阶段和第2阶段的第7天，卡帕诺和美施康定治疗阶段在任何药效学参数、与吗啡相关的副作用、服用急救药物的患者百分比以及首次给予急救镇痛的剂量或时间方面均无显著差异，在第1阶段和第2阶段结束时患者或研究者对总体疗效的评估以及在研究结束时患者的治疗偏好方面也无显著差异。每日一次的卡帕诺提供的疼痛缓解程度以及与吗啡相关的副作用与每12小时一次的美施康定相同。
