The United States experience with oral controlled-release morphine (MS contin tablets).parts i and ii. review of nine dose titration studies and clinical pharmacology of 15-mg, 30-mg, 60-mg, and 100-mg tablet strengths in normal subjects

Abstract

The results of nine US multicenter, sequential crossover, dose titration studies of controlled-release oral morphine (MS Contin 30 mg tablets [MSC], Purdue Frederick, Norwalk, CT) are reviewed in Part I. The studies demonstrated the prolonged analgesic efficacy of the preparation in the treatment of patients with moderate to severe cancer-related pain. Approximately 93% of the patients achieved satisfactory to excellent analgesia on a 12-hour regimen when appropriate dose titration was allowed. The remaining patients were successfully maintained on an 8-hour regimen. The preparation was well-tolerated and comparable in safety to immediate-release oral morphine. In global evaluations, MSC was judged to be significantly (P less than 0.05) more effective, and with significantly (P less than 0.05) fewer side effects than both the prestudy opioid analgesics and 4-hour immediate-release oral morphine. Patients had a broad range of morphine requirements (mean daily MSC dose, 240 mg; range, 60 mg/day to 1800 mg/day); therefore various MSC tablet strengths were developed. Part II presents three studies in which the MSC formulations (15-mg, 60-mg, and 100-mg tablets) were compared to the 30-mg tablet within three randomized, single-dose, two-way crossover, analytically blinded bioavailability protocols, to determine bioequivalence and dose proportionality. The maximum morphine concentration, time of maximum morphine concentration, and area under the plasma morphine versus 12-hour and 24-hour time curve (AUC 0.12; AUC 0.24) were determined in each study. There were no significant differences between the values associated with MSC 1 X 30 mg tablet and 2 X 15 mg tablets (study 1), MSC 2 X 30 mg tablets and 1 X 60 mg tablet (study 2), and MSC 3 X 30 mg tablets and 1 X 100 mg tablet (study 3, values adjusted to dose of 90 mg), except for one marginally significant difference in study 3 (AUC 0.24; P = 0.04) which was not clinically or biopharmaceutically significant. The results showed that MSC 15-mg, 30-mg, 60-mg, and 100-mg dosage strengths are bioequivalent and dose proportional, and, therefore, therapeutically interchangeable. It was concluded that with routine assessment of the patient and adherence to the principles of analgesic dosing, MSC can be successfully used to control cancer-related pain. Furthermore, the availability of various MSC tablet strengths can be expected to facilitate the analgesic management of a patient population with widely differing opioid requirements.

Peak Plasma Concentrations After Oral Morphine

“…15,16 Only one paper confirmed having patients with hepatic impairment; 17 the subjects were five alcoholic cirrhotics. One report containing details of three studies 18 stated that the number of subjects in each study was between 20 and 24; for the purposes of our analysis, each study was assumed to have 20 subjects. One report 19 was a followup of an included study 10 and therefore contained duplicated data; only the new data was used from the later report.…”

A Pharmacokinetic Study to Compare Two Simultaneous 400 μg Doses with a Single 800 μg Dose of Oral Transmucosal Fentanyl Citrate

“…These results are similar to other opioid dose titration studies examining the pharmacokinetics of orally administered opioids. 4,5 In a study review done by Kaiko et al, it was shown that two 15-mg controlled-release oral morphine tablets were the same as one 30-mg tablet, two 30-mg tablets equaled one 60-mg tablet, and three 30mg tablets equaled one 100-mg tablet with respect to pharmacokinetic parameters. 5 The mean plasma morphine versus time curves for these three study comparison groups were very similar.…”

“…4,5 In a study review done by Kaiko et al, it was shown that two 15-mg controlled-release oral morphine tablets were the same as one 30-mg tablet, two 30-mg tablets equaled one 60-mg tablet, and three 30mg tablets equaled one 100-mg tablet with respect to pharmacokinetic parameters. 5 The mean plasma morphine versus time curves for these three study comparison groups were very similar. The differences in AUC, Tmax, and Cmax for these different dosage groups were not statistically significant.…”

A case report of rash induced by cefoperazone sodium and sulbactam sodium plus metronidazole sodium chloride combined with morphine hydrochloride

“…High-dose administration of opioids can cause rash and itching. Growing evidence shows that the stimulation caused by the direct degranulation and activation of mast cells and the activation of opioid receptors lead to the release of histamine, causing skin reactions such as flushing, rash, urticaria, and itching (10)(11)(12).…”