Robert Francis Kaiko

Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomized, double-blind, parallel-group study.

Controlled‐release oral formulations of oxycodone and morphine are both suitable analgesics for moderate to severe pain. They were compared in cancer‐pain patients randomized to double‐blind treatment with controlled‐release oxycodone (n = 48) or controlled‐release morphine (n = 52) every 12 h for up to 12 days. Stable analgesia was achieved by 83% of controlled‐release oxycodone and 81% of controlled‐release morphine patients in 2 days (median). Following titration to stable analgesia, pain intensity (0/none to 3/severe) decreased from baseline within each group (p≤ 0.005), from 1.9 (0.1) to 1.3 (0.1), mean (SE), with controlled‐release oxycodone, and from 1.6 (0.1) to 1.0 (0.1) with controlled‐release morphine (no significant between‐group differences). Typical opioid adverse experiences were reported in both groups. Hallucinations were reported only with controlled‐release morphine (n = 2). Visual analog scores (VAS) for ‘itchy’ and ‘scratching’ were lower with controlled‐release oxycodone (p≤ 0.044), as was peak‐to‐trough fluctuation in steady‐state plasma concentration (p = 0.004). The correlation between plasma concentration and dose was stronger (p = 0.026) for oxycodone (0.7) than morphine (0.3). The relationship between pain intensity (VAS) and plasma concentration was more positive for oxycodone (p = 0.046). There was a positive relationship between morphine‐6‐glucuronide concentrations and urea nitrogen and creatinine levels (p = 0.0001). Controlled‐release oxycodone was as effective as controlled‐release morphine in relieving chronic cancer‐related pain, and as easily titrated to the individuals need for pain control. While adverse experiences were similar, controlled‐release oxycodone was associated with less itching and no hallucinations. Controlled‐release oxycodone provides a rational alternative to controlled‐release morphine for the management of moderate to severe cancer‐related pain.

Comparison of controlled-release and immediate-release oxycodone tablets in patients with cancer pain.

PURPOSE This study compared the clinical efficacy of oxycodone hydrochloride controlled-release (CR) tablets administered every 12 hours with immediate-release (IR) oxycodone tablets administered four times daily in patients with cancer-related pain. PATIENTS AND METHODS Cancer patients who required therapy for moderate to severe pain were randomized to CR oxycodone every 12 hours (n=81) or IR oxycodone four times daily (n=83) for 5 days in a multicenter, double-blind study. Pain intensity was assessed four times daily (categorical scale of none, slight, moderate, and severe); acceptability of therapy was assessed twice daily (categorical scale of very poor, poor, fair, good, and excellent). RESULTS Pain intensity remained slight during the study, with mean oxycodone doses of 114 mg/d (range, 20 to 400 mg/d) for CR and 127 mg/d (range, 40 to 640 mg/d) for IR. Acceptability of therapy was fair to good with both treatments. While standard conversion ratios provided an acceptable dose for many patients, a protocol amendment that allowed initial titration and use of rescue medication reduced the discontinuation rate for lack of acceptable pain control (from 34% to 4% with CR and from 31% to 19% with IR before and after amendment, respectively) without increasing the discontinuation rate for adverse events (from 8% to 7% with CR and from 13% to 11% with IR). Fewer adverse events were reported with CR (109) than with IR (186) oxycodone (P=.006). CONCLUSION CR oxycodone every 12 hours was as effective as IR oxycodone four times daily in managing moderate to severe cancer-related pain and was associated with fewer reports of adverse events.

Long-Term Administration of Controlled-Release Oxycodone Tablets for the Treatment of Cancer Pain

We conducted a study of the safety of controlled-release (CR) oxycodone tablets (OxyContin Tablets) administered chronically to patients with cancer-related pain in a usual clinical setting. These patients had participated in 1 of 2 double-blind, active-control studies. Our study was an open, 3-month treatment study that included 87 patients. Patients received CR oxycodone tablets every 12 hr in a manner that reflected typical clinical practice. Supplemental immediate-release (IR) oxycodone was available PRN for breakthrough pain. Patients recorded medication use, adverse events, and evaluations of pain intensity and acceptability of therapy in a daily diary. Forty-four patients (51%) completed all 12 weeks of study; 43 patients (49%) discontinued participation. At baseline and throughout the study period, the overall mean pain-intensity score was slight to moderate. A comparison of initial and final doses showed a significant but modest increase in total daily CR oxycodone dose. An increase or decrease in titration of the oxycodone dose occurred for 66 patients (84%) at least once during the 12-week study period, primarily for increased pain. Forty-four patients (56%) did not undergo dose titration when the latter was indicated. Half of the patients used IR oxycodone rescue almost daily; the mean number of rescue doses per day was 1.5. Despite stable pain control and an increasing total daily CR oxycodone dose, the percentage of patients reporting common opioid-related adverse events decreased over the course of the study. CR oxycodone tablets administered every 12 hr were successfully used to manage cancer pain over a 12-week period. Importantly, side effects diminished over time without a concomitant change in efficacy.

The Use of Controlled-Release Oxycodone for the Treatment of Chronic Cancer Pain: A Randomized, Double-Blind Study

To compare the effectiveness and safety of controlled-release (CR) oxycodone tablets with immediate-release (IR) oxycodone in patients with chronic cancer pain, a multicenter, randomized, double-blind, parallel-group study was performed in 111 patients with cancer pain. Patients were treated with 6 to 12 tablets or capsules of fixed-combination opioid/nonopioid analgesics per day at study entry. Patients received 30 mg of CR oxycodone tablets every 12 hr or 15 mg of IR oxycodone four times daily for 5 days. No titration or supplemental analgesic medications were permitted. The mean (+/- SE) baseline pain intensity (0 = none, 1 = slight, 2 = moderate, 3 = severe) was 1.5 +/- 0.1 for the CR oxycodone-treated group and 1.3 +/- 0.1 for the group given IR oxycodone (P > 0.05). The 5-day mean pain intensity was 1.4 +/- 0.1 and 1.1 +/- 0.1 for the CR and IR groups, respectively (P > 0.05). Discontinuation rates were equivalent (33%). There was no significant difference between treatment groups in the incidence of adverse events. This study demonstrates that cancer pain patients given 6 to 12 tablets or capsules of fixed-dose combination analgesics can be equally well treated with CR oxycodone administered every 12 hr or IR oxycodone four times daily at the same total daily dose. CR oxycodone offers the benefits of twice daily dosing.

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.

Relative variability in bioavailability of oral controlled-release formulations of oxycodone and morphine.

A retrospective analysis compared the coefficients of variation associated with the maximum plasma concentration (C max ) and the extent of absorption (area under the curve [AUC] from 0 hour to the last observation) for oral, controlled-release tablet formulations of oxycodone (OxyContin) and morphine (MS Contin). Data from fasting, male subjects aged 18 to 45 years were taken from five controlled-release oxycodone (N = 82) and seven controlled-release morphine (N = 101) single-dose, bioequivalence studies. The coefficients of variation of C max and AUC were approximately 33% less for controlled-release oxycodone than for controlled-release morphine (P = .005). The variation from the minimum to maximum value was two to three times less for controlled-release oxycodone than for controlled-release morphine. Among healthy male subjects, the absorption of oxycodone from oral controlled-release oxycodone was significantly more consistent than the absorption of morphine from oral controlled-release morphine in terms of both maximum absorption and extent of absorption.

Analgesic Onset and Potency of Oral Controlled‐Release (CR) Oxycodone and CR Morphine

Clinical Pharmacology & Therapeutics (1996) 59, 130–130; doi: 10.1038/sj.clpt.1996.19

A Double-blind, Placebo-Controlled, Repeated Dose, Dose-Response Evaluation of Controlled-Release (CR) Oxycodone in Patients with Osteoarthritis

Clinical Pharmacology & Therapeutics (1996) 59, 129–129; doi: 10.1038/sj.clpt.1996.17