Double-blind, randomized comparison of the analgesic and pharmacokinetic profiles of controlled- and immediate-release oral oxycodone in cancer pain patients.

Thirty patients with cancer pain completed a double-blind crossover study comparing controlled-release (CR) and immediate-release (IR) oxycodone. In open-label titration (2 to 21 days), these patients were stabilized on IR oxycodone qid. They were then randomized to double-blind treatment with CR oxycodone q12h or IR oxycodone qid for 3 to 7 days followed by crossover at the same daily dose. Mean (+/- SD) pain intensity (0 = none to 10 = severe) decreased from a baseline of 6.0 +/- 2.2 to 2.7 +/- 1.1 after titration with IR oxycodone dosed qid. Pain intensity remained stable throughout double-blind treatment: 2.7 +/- 1.9 with CR oxycodone and 2.8 +/- 1.9 with IR oxycodone. Acceptability of therapy and pain scores correlated with plasma oxycodone concentrations for each interval and were similar for both medications (IR and CR oxycodone). Adverse events were similar for both formulations. Following repeat dosing under double-blind conditions, oral CR oxycodone administered q12h provided analgesia comparable to IR oxycodone given qid.

Opioid formulations: tailoring to the needs in chronic pain.

Opioids are one of the standard therapies used in the management of chronic pain. They were first widely adopted for the treatment of chronic pain associated with cancer and are now considered important in the alleviation of non-cancer and neuropathic pain. Around-the-clock (ATC) medication has been found to be an effective approach in treating chronic pain. Guidelines issued by the American Pain Society (1999) note that in most cases the preferred route of administering opioids is oral, because of convenience, flexibility, and relative steadiness of the opioid concentrations in the blood. The advantages of ATC therapy and oral medication are some of the reasons for the development of controlled-release, oral formulations of opioids (e.g. morphine, oxycodone, hydromorphone, and hydrocodone). The reduced dosing frequency makes the oral medication more convenient for patients, making it easier for them to comply with the dosing regimen. ATC therapeutic coverage and the possible increased compliance afforded by controlled-release formulations can make opioids even more effective in managing chronic pain.

Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release form for the purpose of titrating to stable pain control?

Two separate trials compared controlled-release (CR) oral oxycodone (administered every 12 hours) with immediate-release (IR) oxycodone (4 times a day) to determine whether patients with chronic pain could be titrated to stable pain control as readily with the CR as with the IR formulation. In one study, 48 patients with cancer pain were randomized to open-label titration with either CR or IR oxycodone (maximum dose, 400 mg/day) for a period of up to 21 days. In a study of similar design, 57 patients with low back pain were titrated with either CR or IR oxycodone (maximum dose, 80 mg/day) for a period of up to 10 days. The majority of patients in both studies were converted to oxycodone from other opioid analgesics. Results of both studies showed no difference between CR and IR oxycodone with respect to both the percentage of patients achieving stable pain control, the time to achieve stable pain control, and the degree of pain control achieved. Among cancer patients, 85% achieved stable analgesia, 92% with the CR formulation and 79% with the IR formulation. Among noncancer patients, 91% achieved stable pain control, 87% with the CR formulation and 96% with the IR formulation. The most commonly reported adverse effects in both studies were similar for the two formulations and were those anticipated with opioids: nausea, vomiting, constipation, somnolence, dizziness, and pruritus. Nausea and vomiting were the most frequently cited reasons for treatment discontinuations. These studies suggest that dose titration can be accomplished as readily with oral CR oxycodone as with IR oxycodone in patients with chronic, moderate to severe pain.

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.

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.

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

Characterization and validation of a pharmacokinetic model for controlled-release oxycodone.

1. Oxycodone is a strong opioid agonist that is currently available in immediate-release (IR) formulations for the treatment of moderate to severe pain. Recently, controlled-release (CR) oxycodone tablets were developed to provide the benefits of twice-a-day dosing to patients treated with oxycodone. The purpose of this investigation was to develop and validate a pharmacokinetic model for CR oxycodone tablets in comparison with IR oxycodone solution. 2. Twenty-four normal male volunteers were enrolled in a single-dose, randomized, analytically blinded, two-way crossover study designed to compare the pharmacokinetics of two 10 mg CR oxycodone tablets with 20 mg IR oxycodone oral solution. Pharmacokinetic models describing the oxycodone plasma concentration vs time profiles of CR tablets and IR solution were derived using NONMEM version IV. The predictive performance of the models was assessed by comparison of predicted oxycodone plasma concentrations with actual oxycodone plasma concentrations observed in a separate group of 21 volunteers who received repeated doses of IR and CR oxycodone for 4 days. 3. The unit impulse disposition function of oxycodone was best described by a one-compartment model. Absorption rate of the IR solution was best described by a mono-exponential model with a lag time, whereas absorption rate of the CR tablet was best described using a bi-exponential model. The absorption profile of the CR tablets was characterized by a rapid absorption component (t1/2abs = 37 min) accounting for 38% of the available dose and a slow absorption phase (t1/2abs = 6.2 h) accounting for 62% of the available dose. Two 10 mg tablets of oral CR oxycodone hydrochloride were 102.7% bioavailable relative to 20 mg of IR oxycodone hydrochloride oral solution. The population model derived after administration of a single dose accurately predicted both the mean and range of oxycodone concentrations observed during 4 days of repeated dosing. The mean prediction error was 2.7% with a coefficient of variation of 54%. 4. The absorption characteristics of CR oxycodone tablets should allow effective plasma concentrations of oxycodone to be reached quickly and for effective concentrations to be maintained for a longer period after dosing compared with the IR oral solution. The CR dosage form has pharmacokinetic characteristics that permit 12 hourly dosing.

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.

Differential effects of food on the bioavailability of controlled-release oxycodone tablets and immediate-release oxycodone solution.

The effects of a high-fat meal on the bioavailability of oxycodone hydrochloride, administered as a recently developed 40 mg controlled-release (CR) tablet or a 20 mg immediate-release (IR) solution, were evaluated in a randomized crossover study in 22 normal male and female subjects. Serial blood samples were collected for 36 h after dosing and analyzed for oxycodone by a validated method using gas chromatography/mass spectrometry. There was no significant food effect with CR oxycodone as judged by 90% confidence interval (CI) analysis of AUC0-infinity and Cmax values under fed and fasted conditions. For the IR solution, both oxycodone bioavailability and peak plasma oxycodone concentration were significantly altered by consumption of the high-fat meal, with the mean value for AUC0-infinity increasing to 120% (CI = 109-132%) and the mean value for Cmax decreasing to 82% (CI = 47-91%) of values observed in the fasted condition. Adverse events reported for both formulations were mostly mild to moderate in severity and typical of those observed with opioids.

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.

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.

Relative bioavailability of controlled-release oral morphine sulfate during naltrexone blockade.

The effect of naltrexone hydrochloride on the bioavailability of 60 mg controlled-release oral morphine sulfate in normal volunteers was determined using a randomized, 2-way crossover, analytically blinded study design. Although naltrexone did not qualitatively alter the concentration-time curve for controlled-release morphine, the area under the plasma morphine concentration-time curve from 0-24 h (AUC0-24) was significantly greater (p < 0.01) for morphine given with naltrexone (265 ng x h/ml) than for morphine given alone (215 ng x h/ml). Compared to morphine given alone, the apparent absorption half-life of morphine was decreased from 0.94-0.58 h (p = 0.01) and Cmax was increased from 28.17 ng/ml to 32.26 ng/ml (p = 0.04) during naltrexone blockade, whereas the Tmax and apparent elimination half-life of morphine were not significantly affected. The minimal differences in morphine bioavailability indicate naltrexone may be useful in comparative bioavailability studies of high-dose opioids in opioid-naive normal volunteers.

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.

The relationship of dose to the antihypertensive response of verapamil-sustained release in patients with mild to moderate essential hypertension. The Verapamil-SR Study Group.

The dose-response relationship of verapamil-SR was studied in 221 hypertensive patients. This double-blind, parallel-group, placebo-controlled study compared placebo to 60 mg, 120 mg, 240 mg and 480 mg daily of verapamil-SR. After 6 weeks of therapy, peak diastolic blood pressure was similar in the placebo group and the verapamil-SR 60 mg group, 93.0 and 92.0 mmHg, respectively. The 120 mg, 240 mg and 480 mg verapamil-SR groups produced significantly lower diastolic blood pressure, 89.8, 85.3 and 83.7 mmHg (P less than 0.01), respectively. At trough, placebo and verapamil-SR 60 mg groups and 120 mg groups had diastolic blood pressures of 96.6, 97.0 and 97.1 mmHg, respectively. Diastolic blood pressure with the 240 mg dose (92.4 mmHg) was significantly lower than with the 120 mg dose (P less than 0.01). The 480 mg dose resulted in a diastolic blood pressure of 88.6 mmHg, which was significantly lower than the 240 mg dose (P less than 0.01). The responder rate with 240 mg at peak was 82%. The trough to peak ratio was 0.58. Plasma concentrations were highly correlated with dose (r greater than 0.8; P less than 0.01); but not with diastolic blood pressure (r greater than 0.4; P less than 0.01). Headache and constipation, although not significantly different from placebo, were the most commonly reported adverse reactions in the verapamil-SR groups, 6.3% (placebo--6.7%) and 5.1% (placebo--4.4%), respectively. Graded doses of verapamil-SR produced a dose-response curve in hypertensive patients with a greater than 80% responder rate at the 240 mg dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental changes in the interactions of cholinergic and beta-adrenergic agonists on electrophysiologic properties of canine cardiac Purkinje fibers.

The parasympathetic nervous system attenuates the effects of sympathetic interventions on the hearts of mature animals. Whereas the vagal mediator, acetylcholine (ACh), alone has minor effects on electrophysiologic properties of the ventricular conducting system, in the presence of sympathetic amines, it induces an accentuated antagonism. Because there are developmental changes in both sympathetic and parasympathetic effects on the heart we studied the parasympathetic and sympathetic interaction in isolated neonatal canine Purkinje fibers (PF), and compared the results to those in adult PF. PF were exposed to isoproterenol (Iso) alone (1 X 10(-9), 1 X 10(-7) and 1 X 10(-5) M) to ACh alone (1 X 10(-7) or 1 X 10(-5) M) and to Iso in the presence of ACh. In adult PF, superfusion with Iso, 10(-5) M, alone shortened action potential duration to 50% repolarization from a control value of 215 +/- 9 to 200 +/- 9 ms (p less than 0.01). Simultaneous superfusion of adult PF with Iso 10(-5) and Ach 10(-5) M decreased the extent of action potential shortening produced by Iso, so that action potential duration to 50% repolarization shortened from a control value of 221 +/- 8 to only 214 +/- 12 ms (p less than 0.01). The response to superfusion with Iso and Ach (10(-5) M) differed significantly from that with Iso alone (p less than 0.01). In contrast, exposure of neonatal PF to Iso (10(-5) M) prolonged action potential duration to 50% repolarization from a control value of 157 +/- 7 to 180 +/- 5 ms (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of labetalol on limb haemodynamics in patients following coronary artery bypass graft surgery.

Labetalol is a competitive inhibitor of alpha- and beta-adrenergic receptors and has an antihypertensive action. To determine limb haemodynamic effects, we measured calf blood flow and venous capacitance by venous occlusion plethysmography before and after oral labetalol in 10 patients 3-7 days following coronary bypass surgery. Vascular resistance was calculated as the ratio of mean arterial pressure to arterial flow. The peak effect of labetalol was taken as the point of maximum blood pressure decline, and this interval was selected for evaluation of the limb haemodynamic response. Ninety to 120 min after administration of 100-200 mg of labetalol the mean blood pressure fell from 88 +/- 3 to 79 +/- 3 mm Hg; (P less than 0.005). The mean arterial blood flow registered 5.1 +/- 1.0 ml 100 ml-1 limb tissue min-1 which was not significantly different from the control value of 4.4 +/- 0.8 ml 100 ml-1 limb tissue min-1. The calculated index of limb vascular resistance was not affected by labetalol administration, averaging 37 +/- 12 mm Hg 100-1 ml limb tissue min-1 before labetalol and 30 +/- 11 mm Hg ml-1 100 ml limb tissue min-1 at the time of peak hypotensive effect. There was a slight but statistically significant increment in limb venous volume to 1.9 +/- 0.3 from 1.5 +/- 0.3 ml 100 ml-1 limb tissue (P less than 0.025). Placebo administration produced no consistent changes in blood pressure, arterial blood flow, vascular resistance or venous capacitance.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute effects of oral labetalol on myocardial conduction after coronary artery bypass grafting.

Cardiac electrophysiologic effects of a single oral dose of labetalol were determined in seven patients 4 to 9 days after a coronary artery bypass graft. Surface ECG and bipolar electrograms recorded from temporary pacing wires affixed to the normal right ventricle and abnormal left ventricle at the time of surgery were used to determine conduction intervals. Electrophysiologic parameters were recorded during fixed-rate atrial pacing. Sinus heart rate and blood pressure were monitored. Three patients received 100 mg and four patients received 200 mg labetalol. The drug had no significant effect on intraventricular conduction intervals or QRS duration. It did not significantly influence sinus heart rate or AV conduction time, but in two patients there was prolongation in AV conduction that may have been drug-induced. Labetalol induced a modest but significant decrease in systolic and diastolic blood pressure. In another study propranolol, unlike labetalol, had prolonged AV and intraventricular conduction in the abnormal left ventricle, but not in the normal right ventricle. The absence of these effects with labetalol may reflect lesser local anesthetic effect on intraventricular conduction and an alpha-adrenergic blocking effect that interferes with beta-blockade-induced prolongation of AV conduction.