Oxymorphone HCl (Opana) for the Relief: CLINICAL STUDIES Adams et al.

Posted by James

A randomized, three-period, four-sequence, crossover study assessed the pharmacokinetics of four dose levels of oxymorphone ER in 24 healthy volunteers. Patients were randomly assigned to receive three of four possible doses of oxymorphone ER tablets: 5, 10, 20, and 40 mg. The three eight-day administration periods were separated by seven-day washout periods.

To protect against potential opioid-related effects, the researchers gave the patients naltrexone 50 mg once a day, beginning on the evening before the first dose of oxymorphone ER on day one and continuing until the evening of day seven. Plasma was collected for up to 48 hours after a single dose on the first day and during a 12-hour dosage interval at steady state.

Dose proportionality and linearity were confirmed after single doses and at steady state. Trough concentrations of oxymorphone and its metabolites, measured before administration of the morning dose on days six to eight, indicated that steady-state conditions were achieved after three days of dosing every 12 hours. After single doses, the mean oxymorphone ER area-under-the-concen-tration-versus-time curve (AUC) was 4.54 with 5 mg, 8.94 with 10 mg, 17.80 with 20 mg, and 37.90 ng • hour/ml with 40 mg.

The mean terminal elimination half-life of oxymorphone ER was 11.30 hours with 5 mg, 9.83 with 10 mg, 9.89 with 20 mg, and 9.35 hours with 40 mg.

The maximum plasma concentration (C_max) for oxymorphone ER, which was the highest level observed during a dosage interval, was 0.27 with 5 mg, 0.65 with 10 mg, 1.21 with 20 mg, and 2.59 ng • hour/ml for 40 mg.

Linear pharmacokinetic parameters at steady state were supported by the nearly linear progression for all concentration-dependent variables as the dosage increased from 5 to 40 mg every 12 hours and by the absence of any meaningful differences in oxymorphone clearance across the four dosages. At steady state, the mean AUC concentration for oxymor­phone ER was 5.60 with 5 mg, 9.77 with 10 mg, 19.3 with 20 mg, and 37 ng • hour/ml with 40 mg every 12 hours.
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The plasma levels of metabolites also increased in a linear fashion after single-dose administration and at steady state. Therefore, the pharmacokinetic profile of oxymorphone ER demonstrated linearity and dose proportionality under single-dose and steady-state conditions for the parent compound and its metabolites at doses of 5 to 40 mg.

Gimbel et al.

A multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-ranging study compared three oxymorphone IR doses (10, 20, and 30 mg) with placebo for efficacy and safety in patients with acute moderate-to-severe postsurgical pain.

Total pain relief, which was determined via a five-point scale, at all doses of oxymorphone IR was statistically superior to placebo. A dose-dependent relationship was significant for oxymor-phone IR, which reached an analgesic plateau at the 20-mg dose.

The median time to pain relief was significantly shorter in all of the oxymor-phone IR groups (one hour) than in the placebo groups (1.5 hours) (P < 0.05). When dose intervals were averaged from the first to the third day for all patients, the longest median dose interval was observed with a dose of 30 mg: 9 hours, 39 minutes. For the other three active-treatment groups, the median dose intervals ranged from 7 hours to 7 hours, 44 minutes.

The most frequent adverse drug events (ADEs) with oxymorphone IR were mild-to-moderate opioid side effects such as nausea, vomiting, and somnolence. Serious ADEs occurred in 15 of the 464 patients enrolled. Five of these serious ADEs were considered possibly related (hypotension, excessive diaphoresis, somnolence) or probably related (coma) to oxymorphone IR 20 or 30 mg. There were no meaningful changes in any laboratory results, vital signs, or physical examination findings.

This study established the analgesic efficacy and safety of single and multiple doses of oxymorphone IR. All three doses were superior to placebo. Significant pain relief, achieved with oxymor-phone IR during the single-dose phase, was maintained with multiple doses over consecutive days. The median time to pain relief for patients taking oxymor-phone IR was one hour, and ADEs were similar to those associated with oxy-codone CR.

In conclusion, oxymorphone IR 10, 20, and 30 mg provided effective, dose-related relief of moderate-to-severe acute pain that was maintained over consecutive days with multiple dosing.