Robert F. Kaiko

Pharmacokinetic‐pharmacodynamic relationships of controlled‐release oxycodone

Plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined after administration of 20 mg oral controlled‐release oxycodone tablets to four subject groups: young (aged 21 to 45 years) men, elderly (aged 65 to 79 years) men, young women, and elderly women. Area under the oxycodone and noroxycodone concentration‐time curve (AUC) values were comparable among the four groups. Compared with oxycodone, the oxymorphone AUC values were small, with significant differences between subject groups. AUC values were also calculated for the pharmacodynamic variable “drug effect,” scored on a 100 mm visual analog scale. The two groups with the highest oxycodone AUC values (young and elderly women) had the lowest oxymorphone AUC values and the greatest drug effect AUC values. The two groups with the lowest oxycodone AUC values (young and elderly men) had the highest oxymorphone AUC values and the lowest drug effect AUC values. These results support oxycodone, and not oxymorphone, as being primarily responsible for pharmacodynamic and analgesic effects.

Analgesic efficacy of controlled-release oxycodone in postoperative pain.

The efficacy and safety of graded doses (10, 20, and 30 mg) of controlled‐release (CR) oxycodone was compared with that of immediate‐release (IR) oxycodone (15 mg), immediate‐release oxycodone 10 mg in combination with acetaminophen 650 mg (APAP), and placebo in a single‐dose, double‐blind, randomized, parallel‐group study. The participants, 182 inpatients experiencing moderate to severe pain after abdominal or gynecologic surgery, provided hourly ratings of pain intensity and relief for 12 hours after administration. All active treatments were significantly superior to placebo for many hourly measurements and for the sum of pain intensity differences (SPID) and total pain relief (TOTPAR). A dose response was found among the three levels of CR oxycodone for pain relief and peak pain intensity difference (PID), with the 20‐ and 30‐mg doses being significantly better than the 10‐mg dose. For all active treatments, peak PID and peak pain relief occurred approximately 2 to 4 hours after administration. The median time to onset of relief was 32 minutes for oxycodone plus APAP, 41 minutes for IR oxycodone, and 46 minutes for CR oxycodone 30 mg. Duration of pain relief showed that the 10‐, 20‐, and 30‐mg doses of CR oxycodone had durations of action of 10 to 12 hours compared with IR oxycodone and oxycodone plus APAP (both approximately 7 hours). Typical adverse events, particularly somnolence, occurred in all active treatment groups. Treatment with CR oxycodone was safe and effective in this study, and its characteristics will be beneficial in the treatment of pain.

Steady-state bioavailability of controlled-release oxycodone in normal subjects

The steady-state bioavailability of a controlled-release (CR) oxycodone tablet was compared with that of an immediate-release (IR) oxycodone solution in a randomized, analytically masked, multiple-dose, crossover study in 24 normal subjects. Each subject received either one 10-mg CR oxycodone tablet every 12 hours for 4 days or 5 mL of a 1-mg/1 mL IR oxycodone solution every 6 hours for 4 days. Steady state was achieved after approximately 1 day of dosing. The mean (+/- SD) maximum plasma oxycodone concentrations for CR oxycodone and IR oxycodone were 15.1 +/- 4.7 ng/mL and 15.6 +/- 4.4 ng/mL, respectively. The time to maximum concentration (Tmax) was approximately twice as long for CR oxycodone (3.2 +/- 2.2 hours) as for IR oxycodone (1.4 +/- 0.7 hours) (P = 0.005). The area under the plasma concentration-time curve from 0 to 12 hours at steady state was 103.6 +/- 40.0 ng.h/mL for CR oxycodone and 99.0 +/- 35.8 ng.h/mL for IR oxycodone. Except for Tmax, there were no significant differences in pharmacokinetic parameters between treatments. Approximately twice as many adverse experiences, several of longer duration than noted with CR oxycodone, were reported with IR oxycodone. The bioavailability of the CR tablet was equal to that of the IR solution; however, the rate of oxycodone absorption from the CR tablet was slower than that from the IR solution, as shown by the Tmax value. The use of CR oxycodone will allow selection of the most clinically appropriate nonopioid analgesic, as well as independent titration and dosing, thereby enhancing therapeutic flexibility.

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.

The Bioavailability of Morphine in Controlled‐Release 30‐mg Tablets per Rectum Compared With Immediate‐Release 30‐mg Rectal Suppositories and Controlled‐Release 30‐mg Oral Tablets

The bioavailability of controlled‐release morphine 30‐mg tablets (MSC) administered orally or rectally and immediate‐release morphine (RMS) 30‐mg suppositories per rectum, was compared in this 14‐subject, randomized, single‐dose, analytically blinded, crossover study. Rectal MSC plasma morphine area under the curve from 0–24 hours (AUC0–24) was 50.8% of RMS and was similar for MSC administered by either route (rectal MSC = 90% oral MSC). Rectal MSC had a significantly delayed time to peak plasma level (5.4 vs 1.07 and 2.5 hrs for rectal MSC vs RMS and oral MSC, respectively) and a significantly attenuated time to maximum concentration (6.1 vs 25.4 and 9.7 ng/ml, respectively). Proctoscopy 24 hours after insertion revealed seven instances of mild, transient mucosal erythema or edema with rectal MSC and 12 with RMS. The number of nonlocal adverse effects was 14 with rectal MSC, 19 with RMS, and 18 with oral MSC. Further studies must determine the therapeutic consequences of pharmacokinetic differences and establish guidelines for rectal MSC use. The product is currently not recommended by the manufacturer for rectal administration.

Steady-State Pharmacokinetics of Controlled Release Oral Morphine Sulphate in Healthy Subjects

SummaryThe pharmacokinetics of oral morphine sulphate as controlled release tablets (‘MS-Contin’) and solution were compared at steady-state. Plasma morphine concentrations were determined over 24 hours following the last dose of each drug when given in a randomised, crossover fashion to healthy subjects. Radioimmunoassay was used, which was sensitive yet provided good specificity relative to high-performance liquid chromatography. Controlled release tablets had 86% the bioavailability of the solution. Although each dose of controlled release tablets was double that of the solution, their peak plasma concentrations were the same. Time to maximum concentration was 3 times longer for controlled release tablets with an absorption half-life twice that of the solution. Elimination of both drugs was similar and biphasic with the minor terminal portion at 10 times the half-life of the major early process. These data explain the analgesic duration of 12 hours observed in clinical studies and the lack of accumulation with morphine compared with methadone.

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 study of controlled-release oral morphine (Ms Contin) in an advanced cancer hospital

Abstract An oral controlled-release morphine sulfate tablet (MS Contin) was evaluated for efficacy and safety in advanced cancer patients with significant pain. Results supported the safety and efficacy of every-12-hours dosing with this drug. The mean daily morphine requirements of these patients was large (444.7 ± 96.7 mg) but not significantly greater than that required when treated with immediate-release oral morphine sulfate dosed every four hours. The global impression of patients and investigators was that this sustained-release sulfate preparation was better regarding analgesia and side effects relative to immediate release oral morphine and other prior analgesics.

Cocaine and morphine interaction in acute and chronic cancer pain

&NA; An evaluation of the analgesic, mood and side effects of the combination of intramuscular morphine and oral cocaine was conducted in 17 patients with postoperative pain and 19 others with chronic malignant pain for the purpose of assessing the therapeutic merits of so‐called ‘euphoriant’ elixirs in the management of pain in cancer patients. The study was designed as a randomized and double‐blind single dose but complete cross‐over comparison of the combination of 10 mg intramuscular morphine and 10 mg oral cocaine with morphine alone, cocaine alone, and placebo. While patients clearly discriminated between the analgesic effects of morphine and placebo, there were no differences in the analgesic responses to cocaine and placebo, or in responses to morphine and the combination of morphine and cocaine in either patient group. Side effects were predominantly morphine‐like and occurred in 59% of patients after the combination, 43% after morphine, 34% after cocaine and 25% after placebo. Interaction effects between cocaine and morphine were observed in terms of positive changes toward selected aspects of mood (e.g., cheerful, friendly) in postoperative patients but toward negative aspects of mood (e.g., sad, serious) in patients with chronic pain.