Oxymorphone (Opana®) Formulary Evaluation
Oxymorphone (Opana®) Formulary Evaluation
Part 2: Clinical Trials, Summary, and Recommendations
By Erica Oelfke, PharmD Candidate, Auburn (AL) University
Clinical Trial #1
Matsumoto AK, Babul N, Ahdieh H. Oxymorphone ER tablets relieve moderate to severe pain and improve physical function is osteoarthritis: Results of a randomized, double-blind, placebo and active-controlled Phase III Trial. J Pain 2005; 6:357-366.
Objectives: To compare oxymorphone ER and placebo on indices of pain, function, and safety in patients with chronic osteoarthritis (OA) pain.
Study design: Phase III, four-week, parallel-group, multicenter randomized control trial.
- Oxymorphone ER 40 mg (n = 141): Patients received oxymorphone ER 20 mg every 12 hours during weeks 1 and 2, and increased to 40 mg during weeks 3 and 4.
- Oxycodone CR 20 mg (n = 125): Patients received oxycodone 10 mg every 12 hours during weeks 1 and 2 and increased to 20 mg every 12 hours during weeks 3 and 4.
- Patients randomized to oxymorphone ER 20 mg (n = 119) or placebo (n = 124) continue the same treatment for the entire four weeks.
- Multiple analysis of covariance for single continuous outcome variables
- Least square means: treatment groups
- Pair-wise difference between least square means
- Fisher's exact test: analysis of AEs
A difference was observed for the change from baseline to week 3 for the 40 mg dose vs. placebo (LSMD from placebo = -9 [95% CI: -16.2 to -1.8]; P = 0.0015).
Pain intensity assessed by the API VAS decreased with all treatments during week 1, with the greatest decrease observed in oxymorphone ER treatments at week 3; similar decreases in pain intensity were observed at week 4.
A difference was observed for the change from baseline at week 3 for 20 mg vs. placebo.
Oxycodone CR 20 mg demonstrated some numerical improvements in pain control at week 3 and continued to improve at week 4.
Oxymorphone ER 20 mg or 40 mg every 12 hours showed 39% and 44% reduction, respectively, in mean daily API VAS scores compared to placebo; oxycodone CR 20 mg showed improvements in pain control from baseline, but was not significant when compared to placebo.
Both oxymorphone treatments reported two- to threefold greater pain relief vs. placebo after week 1.
Mean reduction from baseline was greatest in the oxymorphone ER 40 mg group at weeks 3 and 4 vs. placebo.
LSMD from baseline in WOMAC pain subscale for patients treated with oxymorphone ER 40 mg at weeks 3 and 4 was -58 (95% CI: -92 to -24; P = 0.001) and -57 (95% CI: -93 to -22; P = 0.002).
LSMD from baseline in WOMAC pain subscale for oxymorphone ER 20 mg at weeks 3 and 4 was -44 (90% CI: -78 to -11; P = 0.010) and -42 (90% CI: -77 to -7; P = 0.018).
No significant effect was observed during weeks 3 and 4 with oxycodone CR 20 mg.
Quality of life was improved during weeks 3 and 4 for oxymorphone ER 40 mg (P < 0.05).
Both oxymorphone groups showed significant reduction in pain, physical function subscales, and WOMAC pain and composite indices.
Oxymorphone ER 40 mg showed improvements in physical components for weeks 3 and 4.
Gastrointestinal and central nervous system effects were most common. There was a clinically meaningful greater incidence of nausea, vomiting, and pruritus in the groups taking oxymorphone ER compared with the group taking oxycodone CR.
Oxymorphone ER 20 mg and 40 mg every 12 hours demonstrated appropriate pain relief and improved physical function in comparison to placebo in patients with chronic OA pain. Oxymorphone has the potential to provide OA patients increased control over pain, which may lead to an increase in quality of life. This present study failed to confirm that oxycodone CR 20 mg twice daily is effective for controlling moderate-to-serve pain in patients with OA in comparison to oxymorphone ER 20 mg.
Clinical Trial #2
Gimbel J, Ahdieh H. The efficacy and safety of oral immediate-release oxymorphone for post-surgical pain. Anesth Anal 2004; 99:1472-1477.
Objectives: To evaluate the analgesic efficacy and dose response of three doses of oxymorphone IR compared with placebo and to assess the safety of oxymorphone IR compared with oxycodone IR and placebo in acute moderate-to-severe post-surgical pain.
Study design: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-ranging study consisting of two segments: an eight-hour single-dose phase and a multiple-dose phase that extended the study to 49 hours.
- Men and nonpregnant, nonlactating women (18-75 years) receiving primary total hip or knee replacement surgery (including an osteotomy).
- Scoring I to II on the ASA physical status classification system.
- Patients must have developed moderate pain intensity (> 45 mm on a 100 mm VAS) within six hours of discontinuing patient controlled analgesia or within nine hours of the last post-surgical dose of IM opioid.
- Allergy to opioids
- Physical, medical, or psychological condition contraindicated for opioid use, including drug or alcohol dependence.
- Undergoing medical procedures or treatments that might adversely affect the study or interpretation of the results.
- Use of nonsteroidal anti-inflammatory drugs other than celecoxib or rofecoxib was prohibited within 48 hours of surgery.
- During the eight-hour single-dose phase, patients were administered a single dose of oxymorphone IR 10 mg, 20 mg, or 30 mg; oxycodone IR 10 mg; or placebo.
- Patients who completed the single-dose phase entered the multiple-dose phase and those who previously received placebo were randomized to active treatment. During the multiple-dose phase, all patients received study medication every 4-6 hours for the remainder of the 48 hours.
Single-dose Phase: Total pain relief during the eight-hour single-dose interval (TOTPAR); area under the current pain relief scores TOTPAR; and the sum of pain intensity differences from baseline to hours 4, 6, and 8. These were assessed using categorical and VAS scales. In addition, the sum of combined pain relief and pain intensity difference during the intervals from 0-4h, 0-6h, and 0-8h was assessed categorically.
- An analysis of covariance model: TOTPAR and SPID.
- Ranked sum test: patient and physician global evaluation of study medication.
- Last-observation-carried-forward method: early withdrawals.
- Withdrawals for lack of efficacy totaled 27% among patients receiving oxymorphone IR, compared with 41.7% who received oxycodone 10 mg and 47.4% who received placebo.
- Adverse experiences accounted for 3.4%, 8.5%, and 12.3% of withdrawals among patients treated with oxymorphone 10 mg, 20 mg, and 30 mg compared with 0% of those who received oxycodone 10 mg and 3.5% with placebo.
- In the multiple-dose phase. The most common reasons for withdrawal were typical opioid-related adverse events (n = 19; 12% and 10% of patients treated with oxymorphone IR and oxycodone IR, respectively) and lack of efficacy (n = 17; 11.2% and 8% of patients treated with oxymorphone IR and oxycodone IR, respectively).
- Mean TOTPAR scores for all doses of oxymorphone IR were higher compared to placebo. Oxymorphone showed a higher dose-response relationship in a regression model (TOTPAR) by using the arithmetic dose as the regressor and reached an analgesic plateau at the 20 mg dose.
- Oxymorphone IR at 10 mg, 20 mg, and 30 mg was higher compared to placebo for SPID as well as SPRID. All three doses of oxymorphone IR were higher compared to placebo for the time-specific endpoints, pain intensity difference, and pain relief.
- Oxycodone IR was better compared to placebo; however, there were no significant differences noted for efficacy measures.
- The median time to pain relief was shorter in all oxymorphone IR groups (one hour) compared to placebo (1.5 hours).
- Fifty percent pain relief was achieved by 90.2% of patients in the oxymorphone IR 20 mg group, 82.4% of patients in the oxymorphone IR 10 mg group, 77.2% in the oxymorphone IR 30 mg group, and 69.1% in the oxycodone IR 10 mg group, compared with 59.1% in the placebo group.
- During the multiple-dose phase, the worst pain recalled from the previous day or night ranged from 2 to 2.3 among the active treatment groups on day 1, with improvements on day 2 (1.4-1.7) and day 3 (1.2-1.4).
Serious adverse events in five patients (postoperative ileus, hypotension, increased sweating, respiratory distress and related symptoms, depressed consciousness and somnolence) may be related to oxymorphone IR 20 mg or 30 mg. No abnormal lab results, vital signs, or physical examinations noted.
The author concludes that oxymorphone IR was superior to placebo and achieved an analgesic dose-response plateau at 20 mg. During the multiple-dose phase, pain scores improved on days 2 and 3, which indicated pain relief was obtained with oxymorphone IR with multiple doses over consecutive days. Oxymorphone IR may have a greater potency when compared to morphine. Oxymorphone exhibits more lipid solubility and increased selectivity and affinity for µ-opioid receptors and is more potent when administered parenterally. Appropriate studies are needed to require established potencies of the IR formulations. This study demonstrates that oxymorphone IR 10 mg, 20 mg, or 30 mg provides effective dose-related relief of moderate-to-severe acute pain that can be maintained over consecutive days with multiple dosing.
Oxymorphone hydrochloride, a semi-synthetic opioid agonist, modulates pain and exhibits significant specificity at the opioid µ receptor, with less binding at the κ receptor, similar to morphine. Opioids selective for the µ receptors should display a decrease in respiratory function and inhibit the release of acetylcholine and dopamine. Opioids more selective for the κ receptors increase psychotomimesis and diuresis.
Both the µ and κ agonists increase sedation, display more analgesia, and slow gastrointestinal function. Drugs that are relatively selective at standard doses may interact with other receptor subtypes when given at higher doses, leading to changes in their pharmacological profile. Similarly, oxymorphone has similar binding affinity at the µ and κ receptors, in comparison to other strong opiates.
Morphine is used on a frequent basis in the hospital. Physicians and nurses have more clinical experience dealing with morphine in comparison to oxymorphone. Direct comparative studies with other opioids are desirable before warranting oxymorphone's use in the hospital. There is potential for medication errors when administering this drug, such as dosage error and look alike/sound alike drugs. The complete interaction of alcohol with oxymorphone is unknown; therefore, coadministration with oxymorphone should be avoided. In addition, morphine may be administered in multiple dosage forms compared to oxymorphone, which only is available in three forms.
Direct comparative studies of oxymorphone to morphine are needed to determine a specific therapeutic advantage. Ordering and use of oxymorphone would require additional controlled drug inventory and paperwork for both pharmacy and nursing staff.
Finally, the cost of a typical dose of oxymorphone IR is $13.80 per day compared to the price of a similar morphine regimen, which is $1.08 per day.
An automatic interchange regimen is recommended for conversion to morphine equivalent doses (see Table).
Recommendation to add oxymorphone at this time to the formulary is not warranted due to the possibility of medication errors, increased cost, additional CII controls, and unknown interaction with alcohol. Morphine is used more frequently at Huntsville Hospital and physicians and nurses have more clinical experience dealing with morphine than oxymorphone. There are also other narcotic analgesics on the formulary with a relatively rapid onset of action.
Finally, direct comparative studies are needed to determine if oxymorphone would provide a clinical advantage over similar opiate agonists.Matsumoto AK, Babul N, Ahdieh H. Oxymorphone ER tablets relieve moderate to severe pain and improve physical function is osteoarthritis: Results of a randomized, double-blind, placebo and active-controlled Phase III Trial. J Pain 2005; 6:357-366.
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