Moolenaar F, Meijler W J, Frijlink H W, Visser J, Proost J H
Department of Pharmacokinetics and Drug Delivery, Groningen University Institute of Drug Exploration, The Netherlands.
Eur J Clin Pharmacol. 2000 Jun;56(3):219-23. doi: 10.1007/s002280000133.
To compare the efficacy, safety and pharmacokinetics of a newly developed controlled-release suppository (MSR) with MS Contin tablets (MSC) in cancer patients with pain.
In a double-blind, randomised, two-way cross-over trial, 25 patients with cancer pain were selected with a morphine (M) demand of 30 mg every 12 h. Patients were divided into two groups. Group 1 received active MSC (30 mg) and placebo MSR, followed by placebo MSC and active MSR (30 mg) each for a period of 5 days. Group 2 started with active MSR and placebo MSC, followed by active MSC and placebo MSR, each for a period of 5 days. Blood for determination of plasma concentration of morphine (M) and its 3- and 6-glucuronides (M3G, M6G) was collected, and area under the plasma concentration-time curve (AUC)0-12 h, peak plasma concentration (Cmax), time to reach Cmax (tmax), and CO and C12 of M, M6G and M3G were determined on day 5 and day 10. Intensity of pain experienced by each patient was assessed every 2 h on a 0-10 scale, while side effects and rescue medication were recorded.
Twenty patients (ten patients in each group) completed the study. A pronounced inter-patient variability in plasma concentrations of M, M3G and M6G was observed after administration of both forms. Apart from the C0 and C12, no significant differences in AUC0-12 h, tmax and Cmax of morphine between the rectal and oral route of administration were found. In the case of the metabolites, it was found that AUC0-12 h and Cmax of M6G, and AUC0-12 h, Cmax, C0 and C12 of M3G after rectal administration were significantly lower than after oral administration. However, apart from the tmax of M6G, none of the pharmacokinetic parameters of M, M6G or M3G met the criteria for bioequivalence. There were no significant (P = 0.44) differences in pain intensity score between the oral and rectal forms within the two groups, regardless of the treatment sequence. No treatment differences in nausea, sedation or the demand on escape medication (acetaminophen tablets) between the rectal and oral forms were observed.
The newly developed controlled-release M suppository is safe and effective and may be a useful alternative for oral morphine administration in patients with cancer pain.
比较新研发的控释栓剂（MSR）与美施康定片（MSC）在癌症疼痛患者中的疗效、安全性及药代动力学。
在一项双盲、随机、双向交叉试验中，选取25例每12小时吗啡（M）需求量为30mg的癌症疼痛患者。患者分为两组。第1组先接受活性美施康定片（30mg）和安慰剂MSR，然后接受安慰剂美施康定片和活性MSR（30mg），各为期5天。第2组先接受活性MSR和安慰剂美施康定片，然后接受活性美施康定片和安慰剂MSR，各为期5天。采集血样以测定吗啡（M）及其3-和6-葡萄糖醛酸苷（M3G、M6G）的血浆浓度，在第5天和第10天测定M、M6G和M3G的血浆浓度-时间曲线下面积（AUC）0-12h、血浆峰浓度（Cmax）、达峰时间（tmax）以及C0和C12。每2小时以0-10分的量表评估每位患者的疼痛强度，同时记录副作用和急救药物。
20例患者（每组10例）完成了研究。两种剂型给药后，观察到M、M3G和M6G的血浆浓度在患者间存在显著差异。除C0和C12外，直肠给药和口服给药途径的吗啡AUC0-12h、tmax和Cmax未发现显著差异。对于代谢物，发现直肠给药后M6G的AUC0-12h和Cmax以及M3G的AUC0-12h、Cmax、C0和C12均显著低于口服给药后。然而，除M6G的tmax外，M、M6G或M3G的药代动力学参数均未达到生物等效性标准。两组内口服和直肠剂型的疼痛强度评分无显著差异（P = 0.44），与治疗顺序无关。直肠和口服剂型在恶心、镇静或急救药物（对乙酰氨基酚片）需求方面未观察到治疗差异。
新研发的控释吗啡栓剂安全有效，可能是癌症疼痛患者口服吗啡给药的有用替代方法。
