| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
PHARMACOKINETICS AND PHARMACODYNAMICS |
From Endo Pharmaceuticals Inc., Chadds Ford, Pennsylvania (Dr. Ahdieh, Dr. Ma, Dr. Lee) and TheraQuest Biosciences, Blue Bell, Pennsylvania (Dr. Babul). Funding was provided by Endo Pharmaceuticals Inc. (Chadds Ford, PA) and Penwest Pharmaceuticals Co. (Danbury, CT).
Address for reprints: Harry Ahdieh, PhD, Director, Clinical Operations, Endo Pharmaceuticals Inc., Chadds Ford, PA 19317.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
12 hours after administration. Comparisons with other oral opioids are warranted, especially in the setting of outpatient and day surgery.
Key Words: Analgesia • arthroplasty • oxymorphone • pain • opioid
Oxymorphone (14-hydroxydihydromorphinone) is a semisynthetic opioid agonist that modulates pain by acting with significant specificity at the µ-opioid receptor,9 has several times the analgesic potency of its parent compound morphine,10 and is efficacious and well tolerated for the relief of a variety of painful conditions, including presurgical administration,11 post-surgical use,12,13 following labor and delivery,14 and use as PCA.15
Until recently, oxymorphone has only been formulated for parenteral or rectal administration. A new extended-release (ER) oral formulation of oxymorphone is linked to a TIMERx® delivery system16 and has pharmacokinetic characteristics consistent with a 12-hour dosing frequency.17 The ER matrix of the TIMERx® system alters and delays drug dissolution and absorption from the gastrointestinal tract, thereby changing the pharmacokinetic profile relative to immediate-release drug formulations. Drug release from the ER matrix is controlled by the rate of penetration of water into the hydrophilic matrix and the subsequent expansion of the gel coating. The low fluctuation in plasma oxymorphone concentration over the 12-hour dosing period suggests maintenance of analgesic efficacy and a lower potential for causing concentration-dependent adverse effects.17 Although the efficacy of parenteral oxymorphone is well established, differences in pharmacokinetics between parenteral and oral oxymorphone, especially ER oral oxymorphone, necessitate rigorous evaluation of the analgesic efficacy of the new oral formulation.
In this double-blind, placebo-controlled study, the analgesic effects of oxymorphone ER were assessed in patients with moderate or severe postsurgical knee pain using both conventional evaluation of analgesic response and an opioid dose-sparing evaluation over the course of 24 hours (two dose cycles).
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Pretreatment Period
In the period preceding treatment with study medication (day 0), patients who had undergone knee arthroplasty received intermittent bolus doses of opioids (hydromorphone, morphine, meperidine, or fentanyl) to maintain adequate analgesia until beginning PCA with the same opioid. A standardized equianalgesic dose range18 of open-label IV opioid was administered by PCA until the morning of the day after knee surgery (day 1).
Treatment Period
PCA was to be discontinued between 5:00 and 8:00 a.m. on day 1. Patients who developed at least moderate pain intensity (on a categorical scale) and a visual analog scale (VAS) score 45 mm within 6 hours of PCA discontinuation received study medication (oxymorphone 20 mg or placebo) between 5:00 and 11:00 a.m. on day 1, followed by a second dose in 12 hours.
This study incorporated two measures of analgesic efficacy: (1) a 12-hour standard analgesic evaluation following a single dose of study drug and (2) an opioid PCA dose-sparing evaluation during a 24-hour assessment period associated with two doses of study drug. Assessments for the standard analgesic evaluation phase included pain intensity (VAS and categorical), pain relief (categorical), whether pain was half gone, and a global evaluation of study medication at 12 hours. Times to onset of perceptible and meaningful pain relief were recorded. Assessments for the opioid PCA dose-sparing phase included average (usual) pain intensity (VAS) since the previous assessment, average (usual) pain intensity since the first dose of study medication (pain recall), and a second global evaluation at 24 hours. Safety was assessed by adverse events, routine laboratory analyses, physical examination, and vital signs. The use of any concomitant medication was recorded. The protocol and informed consent form were reviewed and approved by the institutional review board for each study center (see the appendix).
|
Patients
To participate in the trial, patients had to have undergone unilateral knee arthroplasty. Additional procedures were permitted in the target knee, provided that the concurrent surgical procedure was not expected to produce a greater degree of surgical trauma than the orthopedic procedure. In all cases, patients had to experience moderate or severe pain at baseline to be randomized. Men and nonpregnant, nonlactating women ages 18 to 80 years who were classified as 1 to 3 (based on the American Society of Anesthesiologists Physical Status classification system),19 developed moderate or severe pain intensity (categorical scale and VAS) within 6 hours of PCA discontinuation, and were able to tolerate oral analgesics were eligible for enrollment.
Exclusion criteria included other painful physical conditions or the presence of any psychiatric or medical condition that could have resulted in noncompliance with study procedures or compromised the interpretation of study results. Patients with intolerance or hypersensitivity to study medication, liver function impairment (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] > 2 times the upper limit of normal), chronic respiratory insufficiency, active neoplastic disease, increased intracranial pressure or history of seizure disorder, ileostomy, colonostomy, or paralytic ileus were excluded. Prohibited medications included intraoperative epidural or intrathecal long-duration opioids within 24 hours or short-duration opioids within 16 hours of study medication administration, opioids or corticosteroids injected into the surgical field, other opioid or nonopioid analgesics from 16 hours before study medication to the completion of the final efficacy assessment, and local anesthetics following surgery. Other medications with the potential to confound analgesia or interact with opioids were also prohibited: antidepressant initiation or dose change or monoamine oxidase inhibitor use within 2 weeks or systemic corticosteroid use within 7 days. Aspirin for cardiovascular disease prophylaxis, aceta-minophen for fever treatment 6 hours before study drug dosing, and ibuprofen for headache treatment 12 hours before study drug dosing were permissible.
Dosing Schedule for Pretreatment and Treatment Periods
Pretreatment
Following surgery, epidural or intrathecal opioids or local anesthetics were not permitted. Intermittent doses of opioids such as hydromorphone, morphine, meperidine, or fentanyl were permitted until opioid treatment by IV PCA could be established. Postoperative IV PCA hydromorphone, morphine, meperidine, or fentanyl treatment was established as soon as possible after surgery (day 0). The PCA device was programmed to provide standard equianalgesic doses of either morphine (1-2 mg) or meperidine (10-20 mg) with a lockout period of 6 to 10 minutes, hydromorphone (0.05-0.25 mg) with a lockout of 5 to 10 minutes, or fentanyl (50-100 mcg) with a lockout period of 3 to 8 minutes.18 In case of inadequate pain control, an additional rescue bolus of morphine (1-2 mg), meperidine (10-20 mg), hydromorphone (0.10-0.25 mg), or fentanyl (100-200 mcg) could be given via the pump, using a manual override. Patients were to receive treatment with only one of the opioids. Transfer to one of the other three opioid treatments was to take place only when necessary.
Treatment
PCA was discontinued preferably between 5:00 and 8:00 a.m. on the morning of the day following surgery (day 1). Details of all postoperative analgesia medications (dose and timing) were recorded. Patients developing at least moderate pain received a single dose of oxymorphone ER 20 mg or matching placebo. A second dose was administered approximately 12 hours after the first dose. Rescue analgesia (oxymorphone 0.2 mg IV) was available at any time.
The first dose of rescue medication was administered by study personnel after pain assessments and the patient's global assessment of therapy had been completed. Thereafter, the patient could self-administer doses of PCA oxymorphone 0.2 mg as needed, with a 10-minute lockout between doses. If pain relief was inadequate, the PCA oxymorphone dose was increased to 0.3 mg or 0.4 mg. Continuous inadequate pain relief could be treated with additional rescue bolus doses of oxymorphone 0.2 mg through the pump using manual override. In the event of dose-related side effects, the PCA oxymorphone demand dose could be reduced to 0.1 mg. Use of PCA oxymorphone did not preclude patients from receiving the second 12-hour dose of study medication.
Efficacy Assessments
Standard Acute Pain Analgesic Evaluation
All pain assessments were completed under the supervision of a study coordinator. Categorical scales assessed pain intensity (measured from 0 [none] to 3 [severe]) and pain relief (measured from 0 [none] to 4 [complete]) to quantify current pain intensity and pain relief. Pain intensity was also assessed by a 100-mm VAS, with 0 mm designated as no pain and 100 mm as extreme pain. Patients self-assessed their pain before the first dose of study medication (baseline) and serially (15, 30, and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 h) thereafter, recording each assessment in a diary without referring to previously recorded assessments. Patients used stopwatches to simply and reliably record the times to perceptible and meaningful pain relief.
At 12 and 24 hours, patients also recorded their current pain intensity (by using the VAS and categorical scales to complete the statement, "My pain at this time is..."), pain intensity recall (serially) on average since the last assessment time (by using a VAS to complete the statement, "My average [usual] pain since the last pain recording has been..."), and pain intensity recall since the last dose of study medication at 12 and 24 hours (by using a VAS to complete the statement, "My average [usual] pain since I first took my study medication has been..."). At 12 and 24 hours, patients completed a global evaluation of pain relief, with scores ranging from 5 (poor) to 1 (excellent).
PCA Opioid Dose-Sparing Evaluation
The time to the first rescue analgesic dose and the quantity of rescue oxymorphone received by PCA over the 24-hour study period were recorded.
Safety Assessments
Adverse events and their severity and relation to study medication were recorded. Routine laboratory analyses and physical examinations were performed before treatment and at the end of the study or at early termination. Vital signs were recorded before the first dose of study medication, hourly for the first 8 hours after initial dosing, and at 10, 12, and 24 hours or at early termination.
Statistical Methodology
Computed Parameters
All measures of efficacy were those typically used in acute pain models and derived from patient pain assessments and from consumption of rescue oxymorphone by PCA.
Time-weighted methods were used to compute total pain relief (TOTPAR). Specifically, TOTPAR = 
(T[i] - T[i -1]) x pain relief (i), where T (0) = 0, T (i) was the scheduled time for pain assessment, and pain relief (i) was the time-specific pain relief. A higher score indicates more pain relief over the summed time period. Additional end points during the conventional single-dose 12-hour evaluation included the following: pain relief (categorical scale) and peak pain relief; time-specific pain intensity difference from baseline (PID), calculated from categorical and VAS scales as the pain intensity at baseline minus the pain intensity at the postdose time points; VAS and categorical sum of pain intensity differences (SPID) at 0 to 12 hours postdose, computed with the time-weighted method used to compute TOTPAR; sum of pain relief and PID on the categorical scale (PRID) at postdose time points; and summed PRID scores (SPRID) at 0 to 12 hours postdose. Time-weighted methods similar to those used to compute TOTPAR were used to compute SPRID. Higher values indicate greater combined pain relief and a decrease in pain intensity at the specified assessment time (PRID) and over the summed time period (SPRID). Additional assessments included time to meaningful pain relief (measured with stopwatches) and patient global evaluation.
Total PCA oxymorphone rescue consumption at 0- to 12- and 0- to 24-hour intervals were used to assess the opioid dose-sparing effects of oxymorphone ER.
TOTPAR, SPRID, SPID, PRID, PID, peak pain relief, and pain intensity recall since the previous assessment were analyzed by analysis of covariance (ANCOVA), with treatment and center as factors and baseline pain intensity as covariate. A Kaplan-Meier analysis was used to analyze time variables (time to meaningful pain relief, time to rescue medication), and patient global evaluations were analyzed by ANCOVA.
Baseline and demographic variables were analyzed by descriptive statistics (continuous variables) or by the Cochrane-Mantel-Haenszel test adjusted for center (categorical variables). Adverse events were compared between groups using the Fisher exact test. Changes in weight and vital signs were analyzed within groups (paired t-test) and between groups (ANCOVA with screening values as covariate). Changes from baseline in laboratory data were analyzed within groups (Wilcoxon signed rank test) and between groups (Cochrane-Mantel-Haenszel test adjusted for center and Kruskal-Wallis test adjusted for comparison of mean change from baseline).
All statistical tests were performed as two-tailed tests, and all effects were considered to be statistically significant if p 
0.05.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
|
Fifty-eight patients in each group completed the 12-hour efficacy assessment and were included in the intent-to-treat population (defined as all patients who were randomized to treatment, took at least the first dose of study medication, and completed the 12-h efficacy evaluation for the 24-hour assessment period) associated with two doses of study drug.
Efficacy
Standard Acute Pain Analgesic Evaluation
For nearly all efficacy parameters, a single 20-mg dose of oxymorphone ER provided significantly greater analgesia compared with placebo, as demonstrated by the 12-hour postdose analgesic data presented in Table III. In addition, the onset of analgesic action, as measured by median time to "meaningful pain relief," was 3.05 hours in the oxymorphone ER group compared with > 12 hours for the placebo group.
|
At 12 hours postdose, pain relief scores were 1.30 ± 1.14 for oxymorphone versus 0.94 ± 0.95 for placebo (p = 0.0322; Figure 1), with corresponding PRID scores of 1.51 ± 1.85 and 0.86 ± 1.43, respectively (p = 0.0247). Oxymorphone ER was associated with a significantly higher mean PID based on VAS scores from 1.5 to 12 hours (Figure 2A); comparable results were observed at most time points 3 hours using the PID categorical scale (Figure 2B).
|
|
Multiple-Dose Analgesic Evaluation
Oxymorphone ER was associated with significantly less PCA oxymorphone consumption and improved pain intensity recall (average pain since previous assessment at the 0- to 6-, 6- to 12-, and 0- to 12-h time intervals) and patient global assessment scores for the 0- to 12-hour and 0- to 24-hour multiple-dose analgesic evaluations (Table IV).
|
Safety
The safety population included all 126 patients who were randomized to treatment and received at least one dose of study medication. Forty-nine adverse events were reported by 31 of 126 (24.6%) patients, including 27 events reported by 17 of 65 (26.2%) patients in the oxymorphone ER group and 22 events reported by 14 of 61 (23.0%) patients in the placebo group. A single severe adverse event (drowsiness) was reported for a patient receiving oxymorphone. All other adverse events were mild to moderate in severity. The most commonly reported events were those typically associated with opioid therapy (Table V). Three oxymorphone-treated patients experienced serious adverse events that were deemed probably related to the study medication and prompted early withdrawal (respiratory acidosis, central nervous system depression, and sedation in a 65-year-old man; lethargy, hypotension, supraventricular tachycardia, and ST wave abnormality in a 71-year-old man; and confusion, agitation, and combativeness in a 72-year-old woman). There were no clinically significant differences between the two treatment groups for mean change in vital signs, laboratory test results, or physical examination findings.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
We conducted this study of oxymorphone ER in patients undergoing knee arthroplasty because the degree of trauma and pain is significant, and the surgical procedure is generally accepted as a sensitive and robust model for the evaluation of putative analgesics. The oral bioavailability of oxymorphone ER is approximately 10% (Endo Pharmaceuticals Inc., data on file, 2003). In the current study, the mean administration of oxymorphone through IV PCA over a 12-hour period was approximately 4 mg/patient in the placebo group (Table IV). Thus, a 12-hour equianalgesic dosage of oxymorphone ER is predicted to be 40 mg. In the present study, half the equianalgesic dosage (20 mg every 12 h) significantly improved pain relief and reduced PCA use while providing an appropriate safety margin for a first assessment of oxymorphone ER in this patient population.
Oxymorphone ER 20 mg demonstrated an overall incidence of adverse events similar to that of placebo. Some patients experienced opioid-related adverse events that included somnolence (3.1%), nausea (10.8%), lethargy (3.1%), dizziness (3.1%), constipation (1.5%), and pruritus (4.6%). The mean age of patients in this study was 65 years, with 54% of oxymorphone-treated patients 65 years old. Although oxymorphone ER was effective and generally well tolerated in this predominantly older patient population, additional dose titration studies are needed to further assess the optimal dose required to provide a balance between adverse events and analgesic relief.
Patients who underwent either general or regional anesthesia were included in the study to accurately reflect the variability in standards of care across institutions, but several precautions were taken to reduce analgesic confounders. Injections of opioids or corticosteroids were not permitted within the surgical field. Epidural or intrathecal opioids or local anesthetics were not permitted following surgery, and investigators excluded any patients who may have received a medication that might compromise analgesic evaluations. Patients were restricted to PCA opioids such as hydromorphone, morphine, meperidine, or fentanyl, according to standard postoperative procedures, and an appropriate washout period was instituted to establish baseline pain scores before administration of the first dose of oxymorphone ER or placebo.
Assessing analgesic efficacy over the course of many hours can be difficult because of the confounding effect of rescue analgesia.20 For this reason, most clinical trials of analgesics conducted as part of a drug development program have tended to either terminate pain assessments at the time of first rescue analgesic use or assess reductions of rescue analgesic use rather than the reduction in pain as the primary end point. Because oxymorphone ER is administered on a fixed 12-hour dosing schedule, breakthrough pain, particularly in this type of postsurgical setting, may occur during the 12-hour dosing interval. For this purpose and consistent with the standard of care, we allowed patients to use PCA rescue, and total consumption was calculated. The sustained analgesic efficacy of oxymorphone ER was evident by significantly less PCA consumption during the single-dose (0-12 h) and multiple-dose (0-24 h) evaluations. As indicated by several time-dependent measures in the standard analgesic evaluation (pain relief, PID, and PRID), analgesia began approximately 2 hours after administration of a single dose and lasted at least 12 hours.
The time to meaningful pain relief of approximately 3 hours further confirms the time to onset of action and underscores the importance of immediate-release or short-acting opioid formulations to provide rapid analgesia, particularly in the immediate postoperative period. But sustained-release opioid formulations are useful for providing and maintaining analgesia beyond the immediate postoperative period. A single dose of oxymorphone ER 20 mg, in conjunction with reduced supplemental PCA, alleviates postsurgical pain for at least 12 hours after administration. This is analogous to receiving a background opioid analgesic infusion to help manage postsurgical pain.
In conclusion, this randomized controlled trial demonstrated that oxymorphone ER 20 mg provides effective analgesia for at least 12 hours with an acceptable tolerability profile and reduced rescue analgesic requirements during the postsurgical period.
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
FOOTNOTES |
|---|
Submitted for publication October 8, 2003; Revised version accepted April 5, 2004.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
1. Owen H, McMillan V, Rogowski D: Postoperative pain therapy: a survey of patients' expectations and their experiences. Pain 1990;41: 303-307.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. Kuhn S, Cooke K, Collins M, Jones JM, Mucklow JC: Perceptions of pain relief after surgery. Br Med J 1990;300: 1687-1690.
3. Dolin SJ, Cashman JN, Bland JM: Effectiveness of acute postoperative pain management: I. Evidence from published data. Br J Anaesth 2002;89: 409-423.
4. Jacox A, Carr DB, Mahrenholz DM, Ferrell BM: Cost considerations in patient-controlled analgesia. Pharmacoeconomics 1997;12: 109-120.[Web of Science][Medline] [Order article via Infotrieve]
5. Choiniere M, Rittenhouse BE, Perreault S, Chartrand D, Rousseau P, Smith B, et al: Efficacy and costs of patient-controlled analgesia versus regularly administered intramuscular opioid therapy. Anesthesiology 1998;89: 1377-1388.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Rittenhouse BE, Choiniere M: An economic evaluation of pain therapy after hysterectomy: patient-controlled analgesia versus regular intramuscular opioid therapy. Int J Technol Assess Health Care 1999;15: 548-562.[Web of Science][Medline] [Order article via Infotrieve]
7. McDonald DD: Postoperative pain after hospital discharge. Clin Nurs Res 1999;8: 355-367.
8. Rawal N, Hylander J, Nydahl PA, Olofsson I, Gupta A: Survey of postoperative analgesia following ambulatory surgery. Acta Anaesthesiol Scand 1997;41: 1017-1022.[Web of Science][Medline] [Order article via Infotrieve]
9. Sinatra RS, Hyde NH, Harrison DM: Oxymorphone revisited. Semin Anesth 1988;7: 209-215.
10. Eddy NB, Lee LEJ: The analgesic equivalence to morphine and relative side action liability of oxymorphone (4-hydroxydihydromorphinone). J Pharmacol Exp Ther 1959;125: 116-121.
11. Sinatra RS, Harrison DM: A comparison of oxymorphone and fentanyl as narcotic supplements in general anesthesia. J Clin Anesth 1989;1: 253-258.[CrossRef][Medline] [Order article via Infotrieve]
12. Beaver WT, Feise GA: A comparison of the analgesic effect of oxymorphone by rectal suppository and intramuscular injection in patients with postoperative pain. J Clin Pharmacol 1977;17: 276-291.[Abstract]
13. Swerdlow M, Murray A, Daw RH: A study of postoperative pain. Acta Anaesthesiol Scand 1963;7: 1-19.[Web of Science][Medline] [Order article via Infotrieve]
14. Ransom S: Oxymorphone as an obstetric analgesic: a clinical trial. Anaesthesia 1966;21: 464-471.[Web of Science][Medline] [Order article via Infotrieve]
15. Lampert BA, Sundstrom FD, Merrill J, Meinhardt D, Boyd-Long L: Oxymorphone in patient-controlled analgesia. Anesthesiol Rev 1988;15: 35-39.
16. Penwest Pharmaceuticals: TIMERx control release delivery systems. Accessed June 30, 2003, from http://www.penwest.com/timerx.php?section=drugdeltech&page=timerx&page2=timerx
17. Adams MP, Ahdieh H: Pharmacokinetics and dose-proportionality of oxymorphone extended release and its metabolites: results of a randomized crossover study. Pharmacotherapy; 2004;24: 468-478.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
18. McCaffrey M: Pain management: problems and progress, in: McCaffrey M, Pasero C (eds.), Pain: Clinical Manual. St. Louis, MO: Mosby; 241-243.
19. American Society of Anesthesiologists: A report by the American Society of Anesthesiologists Task Force on Pain Management, Cancer Pain Section. Anesthesiology 1996;84: 1243-1257.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Silverman DG, O'Connor TZ, Brull SJ: Integrated assessment of pain scores and rescue morphine use during studies of analgesic efficacy. Anesth Analg 1993;77: 168-170.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  K. W Chamberlin, M. Cottle, R. Neville, and J. Tan Oral Oxymorphone for Pain Management Ann. Pharmacother., July 1, 2007; 41(7): 1144 - 1152. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Oxymorphone ER 20 mg significantly better than placebo (p < 0.01). ER, extended release.
