R. Grandy

Analgesic efficacy and potency of two oral controlled‐release morphine preparations

MS Contin tablets and Oramorph SR tablets are two forms of oral controlled‐release morphine sulfate available for the alleviation of pain. Our objective was to compare their analgesic effects in a relative potency assay. In this study, 151 patients undergoing caesarean section or abdominal hysterectomy and reporting moderate or severe postoperative pain received a 30 or 90 mg dose of either drug in a balanced, randomized, double‐blind, parallel‐group, single‐dose experimental design. Patients provided self‐ratings of analgesia. Relative potency for pain relief were calculated from log dose‐effect curves. For total pain relief (rated by visual analog scales) over 12 hours, the log dose relative potency estimate for MS Contin tablets/Oramorph SR tablets was 1.9 (95% confidence limits, 0.89 to 11.1); for peak pain relief (visual analog scales) the relative potency estimate was 1.7 (95% confidence limits, 0.65 to 48.3). Overall, the 90 mg dose of MS Contin was more effective than 30 or 90 mg doses of Oramorph SR and the 30 mg dose of MS Contin at hours 6 to 12. Adverse experiences (mainly drowsiness) were mostly mild to moderate, with no significant differences in their overall incidence or severity between equivalent doses. MS Contin tablets provided greater peak, total, and duration of analgesia, without higher incidence of adverse experiences.

Controlled-release morphine bioavailability (MS Contin tablets) in the presence and absence of food.

The bioavailability of a single, orally administered, 30-mg controlled-release morphine tablet (MS Contin Tablet; The Purdue Frederick Company, Norwalk, Conn.) was compared after fasting or a high fat meal in this single dose, randomized, crossover study involving 24 healthy male subjects. There was no significant (p greater than 0.05) difference in the mean extent of morphine absorption over 24 hours in the presence or absence of food (area under the plasma concentration vs. time curve [AUC(0,24)], fed = 107% of fasted). Time to maximal concentration (Tmax) was similar (p greater than 0.05) in the two treatment groups; the mean Tmax for fed volunteers was 2.5 hours versus 2.4 hours for fasted volunteers. The two regimens did not differ significantly (p greater than 0.05) with regard to maximal morphine concentration (Cmax); mean Cmax for fed subjects was 8.22 ng/ml whereas mean Cmax for fasted subjects was 8.53 ng/ It was concluded that consumption of a high fat meal did not affect either the rate or extent of morphine absorption, or any of the other pharmacokinetic parameters tested, following administration of MSC.

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

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 < 0.05) more effective, and with significantly (P < 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 × 30 mg tablet and 2 × 15 mg tablets (study 1), MSC 2 × 30 mg tablets and 1 × 60 mg tablet (study 2), and MSC 3 × 30 mg tablets and 1 × 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.

Clinical Pharmacokinetics of Controlled‐Release Oxycodone in Renal Impairment

Clinical Pharmacology & Therapeutics (1996) 59, 130–130; doi: 10.1038/sj.clpt.1996.18

A Bioequivalence Study of Oral Controlled‐Release Morphine Using Naltrexone Blockade

Twenty‐three normal volunteers who received morphine sulphate (MS Contin) with naltrexone completed this randomized, analytically blinded, two‐way crossover comparison of the bioavailability of one 200‐mg oral controlled‐release morphine sulfate tablet with two 100‐mg MSC tablets. Morphine effects were blocked by three 100‐mg doses of naltrexone. The first dose of naltrexone was given 24 hours before MSC dosing, followed by a second dose at the time of MSC dosing and a third dose 24 hours after MSC administration. Compared with two 100‐mg MSC tablets, the 200‐mg tablet was 96% bioavailable (90% confidence interval, 88.14–105.74%). The 90% confidence intervals for mean Cmax and AUC0–24 for one 200‐mg MSC tablet were within ±20% of the Cmax and AUC0–24 of two 100‐mg tablets, indicating the two dosage forms are bioequivalent. Single 200‐mg doses of MSC given with the naltrexone blockade were generally well tolerated, and adverse effects were similar to those reported for naltrexone alone and for lower doses of morphine without naltrexone. Naltrexone proved safe and effective in blocking the effects of controlled‐release morphine, permitting bioequivalence studies of a high dose of morphine in normal volunteers.