Research design considerations for clinical studies of abuse-deterrent opioid analgesics: IMMPACT recommendations.

Opioids are essential to the management of pain in many patients, but they also are associated with potential risks for abuse, overdose, and diversion. A number of efforts have been devoted to the development of abuse-deterrent formulations of opioids to reduce these risks. This article summarizes a consensus meeting that was organized to propose recommendations for the types of clinical studies that can be used to assess the abuse deterrence of different opioid formulations. Because of the many types of individuals who may be exposed to opioids, an opioid formulation will need to be studied in several populations using various study designs to determine its abuse-deterrent capabilities. It is recommended that the research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability, (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties of the formulation, (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse, and (4) postmarketing epidemiological studies.

Long-term tolerability and effectiveness of oxymorphone extended release in patients with cancer.

OBJECTIVE: To evaluate the long-term safety, tolerability, and effectiveness of oxymorphone extended release (ER) in patients with cancer-related pain. DESIGN: Post hoc analysis of two-1-year open-label extension studies. SETTING: Multiple US cancer treatment facilities. PATIENTS: Patients with cancer pain who had participated in two short-term crossover comparator trials of oxymorphone ER: one open-label and one double-blind randomized. INTERVENTIONS: Patients who had been taking oxymorphone ER continued the dose established in the previous study. Patients who had been taking a comparator opioid were switched to an equianalgesic dose of oxymorphone ER. All patients underwent individualized oxymorphone ER dose titration to optimize effectiveness and tolerability. ASSESSMENTS: Current, average, worst, and least pain scores were normalized to a 100-point scale. Patients rated treatment on a five-point global assessment of study medication (Poor = 1 to Excellent = 5). All adverse events (AEs) were recorded. RESULTS: Of the 80 patients who entered the extension trials, 26 completed 52 weeks, 7 discontinued owing to loss of effectiveness, and 20 discontinued owing to AEs, most of which were unrelated to study drug. No significant increase in mean (standard deviation [SDD average pain intensity was observed from baseline (30.5 [19.6], 100-point scale) to final visit (35.9 [21.1], p = 0.37). The most common AEs were concomitant disease progression (28.8 percent, n=23), nausea (22.5 percent, n=18), dyspnea (16.3 percent, n=13), fatigue (16.3 percent, n=13), and edema of the lower limb (15 percent, n=12). CONCLUSIONS: In these patients with pain related to cancer, oxymorphone ER was generally well tolerated and provided stable long-term pain control.

Titration with oxymorphone extended release to achieve effective long-term pain relief and improve tolerability in opioid-naive patients with moderate to severe pain.

OBJECTIVE: Assess the effectiveness and tolerability of a program of gradual dose titration with oxymorphone extended release (ER) for treatment of moderate to severe chronic pain in opioid-naive patients. DESIGN: Open-label, nonrandomized 6-month study with a titration/stabilization period of 50%) reductions of pain interference with quality-of-life measures. There was minimal dose escalation over the 5 months and low use of rescue medication. CONCLUSIONS: Oxymorphone ER provided effective pain relief from moderate to severe chronic pain in opioid-naive patients. Gradual titration was well tolerated, with a low rate of discontinuations caused by AEs.

Efficacy and tolerability of oxymorphone immediate release for acute postoperative pain after abdominal surgery: a randomized, double-blind, active- and placebo-controlled, parallel-group trial.

BACKGROUND: Patients are typically switched from parenteral opioids to oral opioids during the 24 to 48 hours after surgery. In June 2006, an oral immediate-release (IR) tablet formulation of oxymorphone was approved for the treatment of acute moderate to severe pain. Single doses of oxymorphone IR have been reported to provide significant pain relief after orthopedic surgery. OBJECTIVE: This study assessed the efficacy and tolerability of multiple fixed doses of oxymorphone IR in the treatment of acute postoperative pain after abdominal surgery. METHODS: This was a multicenter, randomized, double-blind, active- and placebo-controlled, parallel-group study in men and women aged >or=18 years undergoing abdominal surgery that required a >or=3-cm incision. Patients who discontinued short-acting parenteral opioids and developed moderate or severe pain (4-point categorical scale [none, mild, moderate, or severe] and pain intensity >or=50 mm on a 100-mm visual analog scale [from 0 = no pain to 100 = worst pain imaginable]) within 30 hours after abdominal surgery were randomized to receive oxymorphone IR 10 or 20 mg, oxycodone IR 15 mg, or placebo every 4 to 6 hours after the previous dose. The study included 2 efficacy assessments: a single-dose evaluation for up to 6 hours after the dose, and a multipledose evaluation for up to 48 hours after the first dose. Pain was assessed at 15-minute intervals during the hour after the first dose, hourly thereafter for the next 5 hours, and before each subsequent dose. The primary efficacy end point was the median time to study discontinuation for all causes. Assessment of tolerability was based on the proportion of study discontinuations due to treatment-emergent adverse events (AEs). RESULTS: Three hundred thirty-one patients were included in the study. Demographic characteristics were similar across all groups: 98.8% (327) of patients were women, and 80.1% (265) of the abdominal surgeries were hysterectomies. The mean (SD) age of the study population was 42.6 (9.3) years. The median time to study discontinuation for all causes was significantly longer for all active treatments compared with placebo (oxymorphone IR 10 mg, 17.9 hours; oxymorphone IR 20 mg, 20.3 hours; oxycodone IR 15 mg, 24.1 hours; placebo, 4.8 hours; P < 0.006). Oxymorphone IR 20 mg was significantly more effective than placebo over the 6-hour single-dose evaluation (P < 0.05). With multiple dosing, all active-treatment groups had significantly lower least squares mean current and average pain intensities compared with placebo (P < 0.004 and P < 0.005, respectively). The least squares means of the average pain intensity were significantly lower among patients treated with oxymorphone IR 10 mg, oxymorphone IR 20 mg, or oxycodone IR 15 mg compared with those who received placebo (39.7, 35.2, 39.8, and 50.1, respectively; P < 0.005). Discontinuations due to treatment-emergent AEs did not differ significantly between groups: 8.5% (7/82), 17.3% (14/81), 13.3% (11/83), and 12.9% (11/85) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, oxycodone IR 15-mg, and placebo groups, respectively. The proportions of patients reporting at least 1 treatment-emergent AE were 46.3% (38/82), 51.9% (42/81), and 54.2% (45/83) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, and oxycodone IR 15-mg groups, respectively, compared with 34.1% (29/85) in the placebo group (P = NS). The fixed-dose design was a study limitation, as it did not allow titration to effect and thus did not mirror clinical practice. CONCLUSION: In this predominantly female population undergoing abdominal surgery, oxymorphone IR given every 4 to 6 hours for up to 48 hours provided efficacious and tolerable analgesia for moderate to severe pain.

A 12-week, randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain.

OBJECTIVE: Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER) in opioid-naive patients with moderate to severe chronic low back pain (CLBP). DESIGN AND METHODS: Patients > or = 18 years of age were titrated with oxymorphone ER (5- to 10-mg increments every 12 h, every 3-7 days) to a well-tolerated, stabilized dose. Patients were then randomized to continue their oxymorphone ER dose or receive placebo every 12 h for 12 weeks. Oxymorphone immediate release was available every 4-6 h, as needed, for the first 4 days and twice daily thereafter. RESULTS: Sixty-three percent of patients (205/325) were titrated to a stabilized dose of oxymorphone ER, most (203/205) within 1 month. During titration, 18% discontinued from adverse events (AEs) and 1% from lack of efficacy. For patients completing titration, average pain intensity decreased from 69.4 mm at screening to 22.7 mm (p < 0.0001). After randomization, 68% of oxymorphone ER and 47% of placebo patients completed 12 weeks of double-blind treatment. Approximately 8% of patients in each group discontinued because of AEs. Placebo patients discontinued significantly sooner from lack of efficacy than those receiving oxymorphone ER (p < 0.0001). Pain intensity increased significantly more in the placebo group (least squares [LS] mean change 26.9 +/- 2.4 [median 28.0]) than in the oxymorphone ER group (LS mean change 10.0 +/- 2.4 [median 2.0]; p < 0.0001). Oxymorphone ER was generally well tolerated without unexpected AEs. Although limitations of a randomized withdrawal study include the potential for unblinding and opioid withdrawal in placebo patients, opioid withdrawal was limited to two patients in the placebo group and one in the oxymorphone ER group. CONCLUSIONS: Stabilized doses of oxymorphone ER were generally safe and effective over a 12-week double-blind treatment period in opioid-naive patients with CLBP.

Efficacy and safety of OPANA ER (oxymorphone extended release) for relief of moderate to severe chronic low back pain in opioid-experienced patients: a 12-week, randomized, double-blind, placebo-controlled study.

UNLABELLED: Opioid-experienced (N = 250) patients with chronic, moderate to severe low back pain (LBP) were converted from their prestudy opioid(s) to an approximately equianalgesic dose of OPANA ER (oxymorphone extended release). Patients continued slow titration, with 56% stabilized within 1 month to a dose of OPANA ER that reduced average pain to <40 mm on a visual analog scale with good tolerability. Stabilized patients (n = 143) were randomized to placebo or their stabilized dose of OPANA ER every 12 hours for a 12-week double-blind period. Pain intensity increased significantly more for patients randomized to placebo than for patients who continued their stabilized dose of OPANA ER; the increase from baseline (at randomization) to final visit was 31.6 mm for placebo versus 8.7 mm with OPANA ER (P < .0001). During double-blind treatment, placebo patients were approximately 8-fold more likely than OPANA ER patients to discontinue because of lack of efficacy (P < .001). Discontinuations as a result of adverse events were similar between groups, 10% with placebo and 11% with OPANA ER. Opioid-related adverse events included constipation (6%), somnolence (3%), and nausea (3%). Fifty-seven percent of opioid-experienced patients with chronic, moderate to severe LBP achieved a stable dose of OPANA ER that was efficacious and generally well-tolerated for up to 12 weeks. PERSPECTIVE: In a 12-week, double-blind, randomized, placebo-controlled trial in opioid-experienced patients with chronic, moderate to severe LBP, OPANA ER provided efficacious, long-term analgesia and was generally well-tolerated. OPANA ER may provide clinicians with a new treatment option for patients experiencing suboptimal analgesic responses or poor tolerability with other opioids.

A 2-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase III trial comparing the efficacy of oxymorphone extended release and placebo in adults with pain associated with osteoarthritis of the hip or knee.

BACKGROUND: Oxymorphone extended release (ER) is a tablet formulation of the mu-opioid agonist oxymorphone designed to achieve a low peak-to-trough fluctuation in plasma concentrations over a 12-hour dosing period. OBJECTIVE: This study compared the analgesic efficacy, dose response, and tolerability of 3 doses of oxymorphone ER given every 12 hours with those of placebo in patients with pain related to osteoarthritis (OA) of the hip or knee. METHODS: This was a 2-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, Phase III trial. Patients with OA of the hip or knee who were receiving an opioid medication for chronic, moderate to severe pain or who were judged by the investigator to have received suboptimal analgesia with nonopioid analgesics entered a 2- to 7-day washout of analgesic medication. When pain in the index joint was >40 mm on a 100-mm visual analog scale (VAS), patients were randomized to receive 1 of 4 regimens: oxymorphone ER 10 mg q12h during weeks 1 and 2; oxymorphone ER 20 mg q12h in week 1 and 40 mg q12h in week 2; oxymorphone ER 20 mg q12h in week 1 and 50 mg q12h in week 2; or placebo q12h during weeks 1 and 2. The primary end point was the change in VAS score for arthritis pain intensity. Other assessments included the Western Ontario and McMaster Universities (WOMAC) OA Index subscales for pain, stiffness, and physical function and the composite index; the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) physical health component summary (PCS) score; the Chronic Pain Sleep Inventory (CPSI) score; vital signs; clinical laboratory parameters; and adverse events (AEs). AEs were recorded at each clinic visit. RESULTS: Three hundred seventy patients were randomized to treatment (95 oxymorphone ER 10 mg, 93 oxymorphone ER 40 mg, 91 oxymorphone ER 50 mg, and 91 placebo), and 198 completed the study. Least squares mean changes from baseline in the VAS arthritis pain intensity score were -21, -28, -29, and -17 mm in the oxymorphone ER 10, 40, and 50 mg and placebo groups, respectively (P = 0.002, modified Tukey linear trend test). Oxymorphone ER 40 and 50 mg produced significant improvements from baseline compared with placebo in the WOMAC subscale scores for pain (least squares mean change: -85.1, -108.0, and -42.5, respectively; P < or = 0.025 for 40 mg, P < or = 0.001 for 50 mg), stiffness (-40.5, -48.1, and -17.0; both, P < or = 0.001), and physical function (-256.8, -310.8, and -116.5; P < or = 0.01 and P < or = 0.001, respectively); the SF-36 PCS score (4.6, 3.6, and -0.1; P < 0.001); and the CPSI score (-21.2, -22.2, and -10.7; P < 0.05). The 10-mg dose also was associated with significant improvements compared with placebo in the WOMAC pain (-83.6; P < or = 0.025) and physical function subscales (-232.9; P < or = 0.025) and the SF-36 PCS score (3.9; P < 0.001). The most frequently reported AEs (> or =5% of patients) in the oxymorphone ER groups were nausea (39.4%), vomiting (23.7%), dizziness (22.6%), constipation (22.2%), somnolence (17.6%), pruritus (16.5%), and headache (15.0%). The majority of AEs with oxymorphone ER were mild or moderate in intensity. Three serious AEs (urinary retention, central nervous system depression, and pancreatitis) were considered possibly or probably related to study medication. CONCLUSION: In these patients with chronic, moderate to severe pain related to OA of the hip or knee, oxymorphone ER administered twice daily for 2 weeks produced dose-related reductions in arthritis pain intensity and improvements in physical function.

Efficacy and safety of oxymorphone immediate release for the treatment of mild to moderate pain after ambulatory orthopedic surgery: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the analgesic efficacy and safety of 5 mg of oxymorphone immediate release (IR) for mild to moderate pain. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: Ambulatory surgical centers. PARTICIPANTS: Outpatients (age, > or = 18 y) undergoing knee arthroscopy. INTERVENTION: Randomization to 5 mg of oxymorphone IR or placebo hourly as needed for up to 8 hours. MAIN OUTCOME MEASURE: Sum of pain intensity difference (SPID) from baseline to 8 hours. RESULTS: Among 122 patients randomized, 70.5% and 28.7% had moderate or mild postsurgical pain at baseline, respectively. The mean SPID score was significantly greater in the oxymorphone IR group, showing greater pain relief, compared with the placebo group (least squares mean difference +/- standard error, 76.9+/-28.09; 95% confidence interval, 21.26-132.59; P=.007). More placebo patients (48.4%) required rescue medication than oxymorphone IR patients (16.7%), with median times to use of rescue medication of 6 hours 54 minutes and more than 8 hours, respectively (P<.001). More patients (47.4%) rated oxymorphone IR "very good" or "excellent" for pain relief versus placebo (25.0%). No oxymorphone IR-treated patients discontinued because of adverse events (AEs) or experienced serious AEs. CONCLUSIONS: Five milligrams of oxymorphone IR was well tolerated and effective at relieving mild or moderate postsurgical pain after outpatient knee surgery.

Oxymorphone extended-release tablets relieve moderate to severe pain and improve physical function in osteoarthritis: results of a randomized, double-blind, placebo- and active-controlled phase III trial.

OBJECTIVE: To compare oxymorphone extended release (ER) and placebo on indices of pain, function, and safety in patients with chronic osteoarthritis (OA) pain. DESIGN: In this multicenter, double-blind, placebo- and active-controlled, parallel-group, dose-ranging study, patients were randomized to oxymorphone ER 20 mg (N = 121), oxymorphone ER 40 mg (N = 121), oxycodone controlled release 20 mg (N = 125), or placebo (N = 124) every 12 hours. The primary efficacy end point was change in arthritis pain intensity (visual analog scale, 0-100) from baseline to week 3 for the oxymorphone ER 40 mg group versus placebo. RESULTS: The primary end point was achieved: the week 3 oxymorphone ER least squares mean difference (LSMD) from placebo was -9.0 (95% confidence interval [CI]: -16.2 to -1.8; P = 0.015). Secondary efficacy analysis showed similar improvements at week 4 (LSMD from placebo, -10.3 [95% CI: -17.7 to -2.8]; P = 0.007) and with oxymorphone ER 20 mg at week 3 (LSMD from placebo, -7.7 [95% CI: -15.0 to -0.4]; P = 0.039) and week 4 (LSMD from placebo, -7.5 [95% CI: -15.0 to 0.0]; P = 0.050). Weeks 3 and 4 pain intensity decreased by approximately 30-40%. Oxymorphone ER 20 and 40 mg improved from baseline on the Western Ontario and McMaster Universities Osteoarthritis Composite Index and pain and physical function subscales at week 4. Adverse events in all opioid groups included mild to moderate nausea, constipation, and somnolence. CONCLUSIONS: In this short-term study, oxymorphone ER was superior to placebo for relieving pain and improving function in patients with moderate to severe chronic OA pain, and is an alternative to other sustained-release opioids.

Single- and multiple-dose pharmacokinetic and dose-proportionality study of oxymorphone immediate-release tablets.

INTRODUCTION: Oxymorphone hydrochloride (referred to as oxymorphone), a semisynthetic mu-opioid agonist, is known to produce a more rapid onset of action and greater analgesic potency compared with its parent compound, morphine. Until recently, oxymorphone has been available only in suppository and intravenous formulations. This study examined the pharmacokinetics and dose proportionality of a new immediate-release (IR) tablet formulation of oxymorphone and its metabolites (6-OH-oxymorphone and oxymorphone-3-glucuronide) following single- and multiple-dose administration in healthy volunteers. STUDY DESIGN: A randomised, three-way crossover design was employed, with a target sample size of 24 healthy men and women. METHODS: A single dose of oxymorphone IR (5, 10 and 20mg) was administered on day 1. After drug washout on day 2, study participants then received the same dose every 6 hours (22 total doses) on days 3 to 8. Treatment periods were separated by a 7-day washout. Naltrexone hydrochloride was coadministered to prevent opioid-related adverse events. Blood was collected up to 48 hours after day 1 to determine single-dose pharmacokinetics and up to 6 hours after the last dose for determination of pharmacokinetics at steady state. RESULTS: Twenty-three of 24 enrolled subjects (12 men, 11 women) completed the study. Following a single dose of 5, 10 or 20mg, the oxymorphone IR mean area under the plasma concentration versus time curve from time zero to infinity ([AUC(infinity)] 4.5, 9.1 and 20.1 microg . h/L, respectively) and maximum plasma concentration ([C(max)] 1.1, 1.9 and 4.4 microg/L, respectively) confirmed dose proportionality. 6-OH-oxymorphone and oxymorphone-3-glucuronide also increased in an approximate 2-fold fashion. Similar results were observed for AUC and C(max) of oxymorphone and its metabolites at steady state. Steady state was achieved within 3 days of 6-hourly administration. The median t(max) (time to reach C(max)) was 0.5 hours for all single doses of oxymorphone and at steady state, and the terminal elimination half-life (t(1/2)) was approximately 7.3-9.4 hours. Adverse events were generally mild, and no clinically significant changes in laboratory or other safety variables were noted. DISCUSSION: Because successful pain management often requires careful drug titration across a wide therapeutic dose range, it is important that opioid formulations provide predictable increases in drug concentration with increasing dose. The single-dose and steady-state pharmacokinetic profiles of oxymorphone IR tablets were linear and dose proportional across the dose range from 5 to 20mg.

Safety, tolerability, and effectiveness of oxymorphone extended release for moderate to severe osteoarthritis pain: a one-year study.

A 52-week, multicenter, open-label extension study was performed to evaluate the safety, tolerability, and effectiveness of oxymorphone extended release (ER), a novel tablet formulation of oxymorphone hydrochloride, in 153 patients with moderate to severe chronic osteoarthritis-related pain. Sixty-one patients (39.9%) completed the study. Common opioid-related nonserious adverse events (AEs) caused most withdrawals. However, approximately one-half of withdrawals due to AEs were among opioid-naive patients who received placebo in a previous trial and were started on a dose of 20 mg every 12 hours, suggesting that tolerability can be improved by titrating from a lower initial dose. Mean pain scores initially decreased as previously opioid-naive patients achieved adequate pain relief, reached stable levels after the first 6 weeks, and remained stable at mild levels throughout the remainder of the study (average pain, 20-25 mm on 100-mm Visual Analog Scale). Average daily dosing remained stable throughout the study (median, 40 mg/d). At each assessment, at least 80% of patients rated their global satisfaction with oxymorphone ER as "excellent," "very good," or "good." Oxymorphone ER provides a new 12-hour analgesic for the treatment of moderate to severe chronic osteoarthritis-related pain in patients who may require long-term opioid therapy.

Oxymorphone extended release does not affect CYP2C9 or CYP3A4 metabolic pathways.

Two 14-day, randomized, open-label, parallel-group studies examined the effects of extended-release (ER) oxymorphone on CYP2C9 or CYP3A4 metabolic activities in healthy subjects. On days -1, 7, and 14, subjects received either a CYP2C9 probe (tolbutamide 500 mg) or CYP3A4 probes (midazolam and [14C N-methyl]-erythromycin for the erythromycin breath test). Subjects were randomized to 5 groups: high-dose oxymorphone ER (3 x 20 mg q12h) + naltrexone (50 mg q24h); low-dose oxymorphone ER (10-20 mg q12h); rifampin (2 x 300 mg q24h), an inducer of CYP2C9 and CYP3A4 activities; naltrexone (50 mg q24h); or CYP probes alone (controls). Probe metabolism was significantly altered by rifampin on days 7 and 14 (P < .05), whereas probe metabolism was not significantly affected by low-dose oxymorphone ER or by high-dose oxymorphone ER plus naltrexone. Oxymorphone ER exhibits a minimal potential for causing metabolic drug-drug interactions mediated by CYP2C9 or CYP3A4.

Effectiveness and safety of oral extended-release oxymorphone for the treatment of cancer pain: a pilot study.

GOALS OF WORK: Inadequate analgesia and/or unmanageable adverse events frequently result in the need to rotate patients with cancer pain to a different opioid. The availability of a novel oral extended-release (ER) formulation of oxymorphone provides clinicians with another treatment option. In this study, we assessed the analgesic effectiveness and safety of the new oral ER formulation of oxymorphone following treatment with controlled-release (CR) morphine sulfate or oxycodone. PATIENTS AND METHODS: Adults with moderate to severe cancer pain were stabilized for > or =3 days on morphine CR or oxycodone CR, and then treated for 7 days at their stabilized dose. Drug selection was based upon patients' previous use or investigator preference. Patients were then crossed over for 7 days of treatment at an estimated equianalgesic dosage of oxymorphone ER. Pain was assessed using a visual analog scale, and adverse events were recorded. MAIN RESULTS: A total of 86 patients entered open-label treatment. Of 34 patients assigned to morphine CR and 52 assigned to oxycodone CR, 21 (61.8%) and 42 (80.8%) completed stabilization and began treatment with oxymorphone ER, respectively; 59 of 63 (93.7%) completed treatment with oxymorphone. There were no significant differences in daily pain intensity scores between oxymorphone ER and comparators (paired t -test). Rescue medication use, expressed as the percent of the daily dose of scheduled opioid, was greater during morphine CR treatment than after crossover to oxymorphone ER (25.2% vs 13.3%; P <0.05, Wilcoxon's test). The tolerability/safety profiles (e.g., nausea, drowsiness, somnolence) were similar for all opioids. CONCLUSIONS: Cancer patients stabilized on morphine CR or oxycodone CR were safely and rapidly converted to a lower milligram dose of oxymorphone ER that provided adequate pain relief with comparable tolerability. These results justify additional trials with oxymorphone ER.

The efficacy and safety of oral immediate-release oxymorphone for postsurgical pain.

In this double-blind, parallel-group study, we compared 3 oxymorphone immediate-release (IR) doses with placebo for efficacy and with oxycodone IR and placebo for safety in patients with acute moderate-to-severe postsurgical pain. During the single-dose phase (n = 300), patients received oxymorphone IR 10, 20, or 30 mg; oxycodone IR 10 mg; or placebo. All oxymorphone IR doses were superior for providing pain relief for 8 h (P < 0.05), with a significant analgesic dose response (P < 0.001). Significant pain intensity differences occurred by 45 min (20- and 30-mg doses; P < 0.05). Discontinuations for lack of efficacy totaled 42% among placebo-treated patients and 27% among those treated with oxymorphone IR. Patients requiring rescue medication after 3 h were allowed to receive additional study drug every 4 to 6 h as needed for the multiple-dose phase (n = 164). All oxymorphone groups maintained analgesia for 48 h. The median dosing interval was >9.5 h for oxymorphone IR 30 mg and > or =7 h for the other groups. Opioid-related adverse events, similar among groups, were generally mild or moderate. Oxymorphone IR 10, 20, or 30 mg provided significant dose-related pain relief compared with placebo, and this relief was maintained over several days with a safety profile comparable to that of oxycodone IR.

Establishing the dosage equivalency of oxymorphone extended release and oxycodone controlled release in patients with cancer pain: a randomized controlled study.

OBJECTIVE: To compare the analgesic efficacy and safety of oxymorphone extended release (ER) and oxycodone controlled release (CR) in patients with moderate to severe cancer pain. RESEARCH DESIGN AND METHODS: This randomized, multicenter, double-blind, 2-period crossover study included adult outpatients (>or= 18 years of age) with moderate or severe cancer pain who were first titrated for 3-10 days with open-label oxymorphone or oxycodone to achieve a stable dose that provided and other efficacy parameters were comparable for adequate analgesia with tolerable adverse events and no requirement for more than 2 doses of rescue medication per day. The subsequent double-blind treatment phase was a 7- to 10-day period of oxycodone CR or oxymorphone ER treatment followed by crossing over to the alternate medication for another 7-10 days. During the treatment phase, up to 2 doses per day of morphine sulfate 15-mg tablets were allowed as rescue. MAIN OUTCOMES AND MEASURES: Assessments included the Brief Pain Inventory, global evaluations, Karnofsky performance status, and clinical laboratory evaluations (serum chemistry profile, complete blood count, urinalysis). Efficacy variables were analyzed using a mixed-effects model with treatment, sequence, and period as fixed effects and subject as a random effect. RESULTS: Forty-seven patients entered the titration/stabilization phase, 44 received at least 1 dose of study drug, 42 completed the first double-blind phase, and 40 completed the second double-blind phase. Mean pain intensity scores the 2 groups. The mean daily dosage of oxycodone CR (91.9 mg) was twice that of oxymorphone ER (45.9 mg), an equianalgesic dose ratio of 2:1. Rescue medication use was low in both groups (approximately 1 tablet of morphine sulfate 15 mg/day). No significant differences in opioid adverse events were observed between the groups. CONCLUSIONS: Adult patients with cancer who were taking oxycodone CR were readily converted to oxymorphone ER and required half the milligram dose to stabilize their pain. Within 72 h, most patients achieved a stable dose that provided adequate relief with similar opioid adverse events.

Efficacy of oxymorphone extended release in postsurgical pain: a randomized clinical trial in knee arthroplasty.

Patients with moderate or severe pain following knee arthroplasty and washout from standard patient-controlled analgesia (PCA) were randomized to receive 20 mg of an extended-release (ER) oxymorphone formulation (n = 65) or placebo (n = 61) q12h for 1 day. Oxymorphone PCA was used as rescue analgesic. Oxymorphone ER provided significant improvements over placebo for most standard single-dose analgesic parameters, including mean total pain relief (TOTPAR) over 0 to 12 hours (19.30 vs. 13.72; p = 0.0056), as well as for all multiple-dose (24-h) efficacy assessments. Oxymorphone-treated patients used significantly less rescue PCA than those who received placebo (p < 0.02). Adverse events such as nausea and constipation were typical of opioids, and laboratory and physical findings were similar between groups. Oxymorphone ER was effective and generally well tolerated. A single dose was active from 2 hours until > or = 12 hours after administration. Comparisons with other oral opioids are warranted, especially in the setting of outpatient and day surgery.

Pharmacokinetics and dose-proportionality of oxymorphone extended release and its metabolites: results of a randomized crossover study.

STUDY OBJECTIVE: To evaluate the pharmacokinetics and dose-proportionality of four dose strengths (5, 10, 20, and 40 mg) of oxymorphone extended release (ER) under both single-dose and steady-state conditions. DESIGN: Randomized, three-period, four-sequence, crossover study. SETTING: Bioavailability clinic. SUBJECTS: Twenty-four healthy adult volunteers. INTERVENTION: Each subject received three of the four possible doses. The three 8-day administration periods were separated by a 7-day washout. Plasma was collected for up to 48 hours after a single dose on day 1 and during a 12-hour dosage interval at steady state. Naltrexone was administered to reduce opioid-related adverse effects. MEASUREMENTS AND MAIN RESULTS: Twenty-three subjects completed at least one study period. Dose-proportionality and linearity were confirmed after single doses (mean oxymorphone ER area under the concentration versus time curve [AUC] 4.54, 8.94, 17.80, and 37.90 ng x hr/ml for 5-, 10-, 20-, and 40-mg doses, respectively) and at steady state (mean oxymorphone ER AUC 5.60, 9.77, 19.3, and 37.0 ng x hr/ml for 5-, 10-, 20-, and 40-mg doses every 12 hrs, respectively). Similar results were found for maximum plasma concentration. Metabolite (6-hydroxyoxymorphone and oxymorphone-3-glucuronide) plasma levels also increased in a linear fashion after single-dose administration and at steady state. CONCLUSION: The pharmacokinetic profile of oxymorphone ER demonstrates linearity and dose-proportionality under single-dose and steady-state conditions for the parent compound and its metabolites for doses of 5-40 mg.