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ANALGESIA

A Multiple-Day Regimen of Parecoxib Sodium 20 mg Twice Daily Provides Pain Relief After Total Hip Arthroplasty

Eugene R. Viscusi, MD^*, Joseph S. Gimbel, MD, Andreas M. Halder, MD, PhD, Michael Snabes, MD, PhD, Mark T. Brown, MD^||, and Kenneth M. Verburg, PhD^||

From the *Department of Anesthesiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; Arizona Research Center, Phoenix, Arizona; Klinik für Endoprothetik, Waldhausstrasse, Sommerfeld, Germany; Pfizer Global Research and Development, Skokie, Illinois; and ||Pfizer Global Research and Development, New London, Connecticut.

Address correspondence and reprint requests to Eugene R. Viscusi, MD, Department of Anesthesiology, Acute Pain Management, Jefferson Medical College of Thomas Jefferson University, 111 S. 11th St., Suite G-8490, Philadelphia, PA 19107. Address e-mail to Eugene.viscusi{at}jefferson.edu.

Abstract

BACKGROUND: This multicenter, multiple-dose, randomized, double-blind, parallel-group study compared the analgesic efficacy and safety of two dosing regimens of parecoxib sodium (parecoxib) versus placebo after total hip arthroplasty.

METHODS: On study Day 1, 490 patients received a postoperative initial loading dose of IV parecoxib 40 mg, followed by a re-dose of parecoxib 20 mg in 484 of 490 patients. Subsequently, 479 randomized patients received double-blind treatment with parecoxib 20 mg bid (n = 159), parecoxib 20 mg qd (n = 159) followed by placebo, or placebo (n = 161) on Day 2.

RESULTS: Patients treated with parecoxib 20 mg bid reported significantly lower summed pain intensity over 24 h (SPI-24) scores and improved patients’ global evaluation of study medication (PGESM) ratings compared with placebo-treated patients on Days 2 to 5 (P < 0.05). For patients treated with parecoxib 20 mg qd, SPI-24 scores were significantly lower on Days 3 and 4 (P < 0.05), and PGESM ratings significantly improved on Day 5 compared with placebo. The incidence of adverse events was similar in all treatment groups with the exception of fever, vomiting and impaired concentration, which were significantly more common in the placebo group compared with one or other of the parecoxib treatment groups (P < 0.05).

CONCLUSION: Multiple-day administration of parecoxib 20 mg once or twice daily is effective and generally well tolerated after total hip arthroplasty.

Parecoxib sodium (parecoxib), an injectable cyclooxygenase-2 (COX-2) selective inhibitor, is the prodrug of valdecoxib. Parecoxib has been shown to provide rapid and prolonged analgesia after surgery.1–3 Following hip or knee arthroplasty, a single dose of parecoxib 40 mg produced onset of analgesia within 11 min.3,4 In addition, the median duration of analgesia (based on the need for rescue medication) was approximately 6 to 8 h. The elimination half-life of valdecoxib, the active moiety of parecoxib, is approximately 5 to 10 h.

The majority of patients undergoing major orthopedic surgery have pain requiring treatment with analgesics for several days after surgery. Two previous trials showed that parecoxib administered for a relatively short duration (20 or 40 mg twice daily over 2 days) combined with patient-controlled analgesia (PCA) or IV bolus morphine resulted in significantly improved postoperative analgesic management, with significantly greater pain relief, greater patient satisfaction, and less morphine consumption compared with morphine alone.5,6

To further characterize the optimal dosing regimen of parecoxib, the primary objective of our study was to assess the analgesic efficacy of two dosing regimens of parecoxib compared with placebo when administered to patients for 3 to 5 days after total hip arthroplasty (THA). Previous studies showed that an initial 40-mg parecoxib dose was consistently the most effective single or initial dose, and that parecoxib 20 mg bid was the optimum daily dose.3,4,7 The secondary objectives of the trial were to evaluate general safety, effect on health outcome measures and effect on opioid-related symptoms.

METHODS

The study was approved by an institutional review board or ethics committee and conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki. All patients gave written, informed consent.

Patients aged 18 to 80 yr and undergoing elective primary THA or revision were eligible for enrollment. Women of childbearing potential had to be surgically sterile or using adequate contraception. All eligible patients were required to be in a stable postoperative condition. Patients were excluded if they were receiving inotropic drugs, had evidence of cardiac ischemia, had active wounds or other bleeding, had not been tracheally extubated, had abnormal postoperative mental status or verified new-onset neurologic deficit, or had a urine output <30 mL/h postoperatively. Patients with a history of an esophageal, gastric, pyloric channel, or duodenal ulcer within 1 mo of surgery were excluded from the study as were patients with a history of clinically significant gastrointestinal (GI) disease (defined as active bleeding), renal disease, cerebrovascular (CV) accident, transient ischemic attack, myocardial infarction, unstable myocardial ischemia (angina), deep vein thrombosis (DVT) or pulmonary embolism (PE) within 3 mo of surgery. Patients were also excluded if they were receiving concomitant treatments likely to confound analgesic responses.

Among the permitted medications, patients receiving 325 mg/d of aspirin at a stable dose for at least 1 mo before the first dose of study were allowed to continue their aspirin regimen for the duration of the study. Selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors, at stable doses from 4 wk prior to surgery through the duration of the study, were allowed. Medications specifically excluded were tricyclic antidepressants, tranquilizers, neuroleptics, neuroleptic antiemetics, COX-2 selective inhibitors, nonsteroidal antiinflammatory drugs, and corticosteroids. Long-acting or topical analgesics or anesthetic applied to the surgical incision were not permitted. Patients requiring an emergency THA or emergency revision procedure were excluded. Patients received general anesthesia and intraoperative opioids as part of their anesthetic regimen, or they received epidural anesthesia or spinal anesthesia. Epidural or intrathecal opioids of any kind were prohibited.

This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, multiple-dose study conducted in 53 study centers in six countries (Appendix available at www.anesthesia-analgesia.org). The analgesic efficacy of two parecoxib-dosing regimens, administered for up to 5 days in patients after THA, was compared with placebo treatment. The study consisted of a single-blind phase (patients but not investigators were blinded to treatment) on Day 1 (day of surgery), followed by a double-blind phase on Days 2 to 5.

On Day 1, all patients received a standard analgesic regimen that consisted of an initial loading dose of parecoxib 40 mg IV within 2 h after the end of anesthesia, followed by parecoxib 20 mg IV administered upon request between 1 and 12 h after the first dose, or it was administered at 12 h or at midnight, whichever came first, after the first dose if not requested sooner. In addition, supplemental analgesia (morphine) was available by PCA pump or IV bolus on request and was made available within 1 h after the end of anesthesia.

Patients were randomized into the double-blind phase to receive parecoxib 20 mg IV bid, parecoxib 20 mg IV followed by placebo, or placebo bid in a 1:1:1 ratio. Patients received their first dose of study medication on Days 2 to 5 at approximately 8 am. The second dose of study medication (parecoxib 20 mg IV or placebo) was given upon request, but no earlier than 1 h, after the first dose of study medication and within 12 h after the first dose, if not requested prior to that time. Patients in need of additional pain relief after taking both doses of study medication were given parenteral morphine by bolus injection (2–4 mg every 2–4 h, as needed). Alternatively, for patients who could tolerate oral medication on Days 3 to 5, rescue medication consisted of one tablet of either oral codeine 30 mg/acetaminophen (paracetamol) 500 mg or hydrocodone 5 mg/acetaminophen 500 mg (both every 4–6 h, as needed), which was to be discontinued 2 to 3 h before study medication was administered. The discontinuation of supplemental analgesia from approximately 6 am to 8 am (±1 h) was intended to ensure that all patients had a similar baseline level of pain prior to administration of study drug.

Patients were provided with a randomization number at enrollment and randomized on Day 2 to a 1:1:1 ratio of treatment. The patients were stratified into two groups before randomization based on whether or not they were to receive anticoagulants for prophylaxis of DVT to ensure that the three randomized treatment groups were balanced for the safety assessment of thromboembolic events, including DVT.

During the study, thromboembolic events were monitored and assessed by the clinical judgment of the investigator. Adjudication of thromboembolic events was made by a blinded events/end-point committee to assess evidence of clinical symptoms, and a positive diagnostic test (venous ultrasonography, angiography, magnetic resonance imaging, radionuclide scan or impedance plethysmography) was required. In the absence of a positive diagnostic test, a suspicion of a thromboembolic event must have been sufficiently compelling to require full dose anticoagulant treatment.

The primary analyses of the trial were a priori identified to be performed on treatment Day 2 and Day 3, with supplemental analyses to be performed on treatment Day 4 and Day 5. Patients were considered to have completed the study after receiving six doses (3 days) of study medication (i.e., completed Day 3 of the study). For safety analyses, patients were considered to have completed the study if they did not withdraw from the study over the entire duration (5 days) due to adverse events, lack of efficacy, protocol violation, consent withdrawn, sponsor decision, or lost to follow-up, regardless of whether they required analgesic medication for all 5 days.

The primary efficacy measures were SPI-24 (categorical scale) on Days 2 and 3 and the PGESM on Days 2 and 3. SPI-24 is patterned after the summed pain intensity difference scores over a given time interval; however, the difference from baseline was not used in our study because all patients had received single-blind study medication and their baseline scores were no longer randomly distributed. PGESM was validated in an earlier parecoxib trial and showed moderate correlations (r = 0.42–0.55) with multiple factors, including pain intensity (PI), pain interference, opioid-related symptoms, and high correlations (r = 0.70–0.80) with patient ratings of pain treatment satisfaction at Day 1 and Day 7.8 A systematic review of PGESM results indicated sensitivity to treatment effects in a systematic review of previous parecoxib trials.9

PI was assessed at rest just before the first dose of study medication, at 2, 4, 8, 12, and 16 h after the first dose, and just before taking the second dose of study medication and the first dose of rescue medication each day. For PI assessments, patients rated their pain on a categorical scale ranging from none (0) to mild (1), moderate, (2) or severe (3). The SPI-24 score was calculated by weighting the PI scores by the time interval between successive scheduled assessments, and summing over the total time period assessed; therefore, the range of possible values was 0 to 72 (larger numbers indicate more pain). Participants completed a PGESM each morning before taking the first dose of study medication, and again just before the first dose of rescue medication each day (rating the study medication for pain as: 1 = poor, 2 = fair, 3 = good, 4 = excellent).

Secondary efficacy measures included the SPI-24 (categorical scale) and PGESM on Days 4 and 5, time-specific PI [categorical and 100 mm visual analog scale (VAS)] on Days 2 to 5, percentage of patients who took rescue medication, and the amount of rescue medication taken on Days 2 to 5. Extensive evidence indicates that single-item PI ratings are reliable and valid in VAS and four-category Likert response formats.10 Pain interference with function scores derived from the modified Brief Pain Inventory-short form (mBPI-sf) were measured over 24 h on Days 2 to 5 and rated using an 11-point numeric scale ranging from 0 = does not interfere to 10 = completely interferes. The BPI is validated in 25 different languages by examining the consistency of its two-factor structure (i.e., severity of pain and impact of pain). Health Outcome Measures were individual and composite pain interference with function scores derived from the mBPI-sf.

Opioid-Related Symptom Distress Scale (OR-SDS) scores were collected on Days 2 to 5. The OR-SDS questionnaire collected information on the occurrence and degree of bother associated with opioid-related adverse effects, including fatigue, drowsiness, inability to concentrate, nausea, dizziness, constipation, itching, difficulty with urination, and retching/vomiting.11 Patients recorded their symptoms before taking the first dose of study medication each day. Postsurgical recovery measures were collected throughout the trial.

Safety was assessed by routine clinical laboratory analyses, physical examination, and by monitoring adverse events throughout the study. Prespecified safety end-points were also analyzed and adjudicated by an external independent events committee, who were blinded to treatment assignment. The end-points included cardiovascular (CV) thromboembolic events, or cardiac ischemia or arrest, cerebrovascular events such as ischemic or hemorrhagic stroke or infarct, DVT, or PE), renal failure or dysfunction, upper GI ulcer complications (perforation, obstruction, or bleeding), and wound-healing complications [superficial surgical site infection (SSI), deep incisional SSI, organ space SSI, noninfectious wound separation, or dehiscence].

The study was designed to test the null hypothesis that treatment with parecoxib would offer analgesia no better on average than use of PCA and rescue analgesic medication alone. Assuming a reduction of approximately 60% in effect sizes due to the natural history of acute pain over Days 2 to 5, a sample size of 150 randomized patients per arm who began the double-blind phase of the study on Day 2 would have at least 80% joint power to detect effect sizes of –0.45 and 0.45 in SPI-24 and PGESM, respectively. The primary efficacy measured at an level of 0.05 and assumed a correlation of –0.6. Homogeneity of treatment groups at baseline was ascertained by analysis of variance. We used the SAS statistical analysis software (version 6.12, SAS Institute Inc, Cary, NC). Analyses of efficacy and health outcomes measures were performed on the modified intent-to-treat cohort, defined as all randomized patients who took at least one dose of study medication on Day 2. The SPI-24 results were analyzed using a general linear model with treatment and center as factors and baseline PI as a covariate. Prior to unblinding, an interaction analysis was performed for primary efficacy and health outcomes measures using country rather than center, given that a number of centers recruited few patients. The interaction analysis showed that SPI-24 was significant on Day 2, but not Day 3, for parecoxib 20-mg bid compared with placebo. SPI-24 mean scores were similar between parecoxib 20 mg bid and placebo for Canada only. No obvious cause was determined for this interaction.

PI scores within a particular day were inputted on a patient-by-patient basis using linear interpolation among observed scores, unless no further pain scores were obtained on that day. In such cases, the missing scores were inputted using the last observation carried forward (LOCF) technique. Prospectively, LOCF was permitted for a missing value in a 24-h period but not allowed if all assessments of pain were missing in a 24-h period. The requirement for SPI as a primary efficacy measure, and this method of censoring LOCF data minimizes the potential for bias associated with inputted values.

Scores from assessments obtained after rescue medication on a particular day were treated as missing in the efficacy analyses and were inputted as described above. Assessments completed before the second dose of study medication and before rescue medication on each day were incorporated. The PGESM scores were analyzed using the Cochran-Mantel-Haenszel method, controlling for center.

Time-specific PI, components of the mBPI-sf, and the total amount of rescue medication data were analyzed using a general linear model with treatment and center as factors and baseline PI as a covariate. OR-SDS questionnaire scores were analyzed using a general linear model with treatment and center as factors. Safety analyses included all randomized patients who received at least one dose of study medication. Comparisons between treatment groups were performed using Fisher’s exact test.

RESULTS

Of the 501 patients enrolled into the study, 11 were withdrawn before receiving any study medication; 490 received at least one dose of study medication on Day 1 in the postoperative anesthetic care unit (PACU) and were evaluated for safety (Fig. 1). Eleven additional patients dosed on Day 1 were withdrawn prior to randomization into the double-blind phase on Day 2; thus, 479 patients who received double-blind treatment on Day 2 were included in the analysis of efficacy and, of these, 95% (455/479) of patients completed the study (i.e., received at least six doses of study medication on Days 1–3). There were no statistically significant differences among the treatment groups with respect to patient demographic and baseline characteristics (Table 1). The anesthetic techniques during surgery were evenly distributed among the treatment groups in the double-blind phase (Table 2).

View larger version (10K): [in this window] [in a new window]   Figure 1. Patient disposition.

Mean SPI-24 scores were significantly lower in patients treated with parecoxib 20 mg bid compared with those receiving placebo on Days 2 to 5 (P < 0.05; Fig. 2). In addition, the mean SPI-24 score was significantly lower on Days 3 and 4 in patients receiving parecoxib 20 mg qd versus those receiving placebo (P < 0.05).

View larger version (17K): [in this window] [in a new window]   Figure 2. Summed pain intensity over 24 h scores on Days 2 to 5. aP < 0.05 versus placebo. The scale ranged from 0 to 72, where larger numbers indicate more pain.

More patients in the parecoxib treatment groups rated their medication as "good" or "excellent" on the PGESM than placebo-treated patients on Days 2 to 5 (Fig. 3). The difference in rating distributions was significant between the parecoxib 20 mg bid and placebo treatment group on Days 2 to 5 (P 0.007) and between the parecoxib 20 mg qd and the placebo treatment group on Day 5 (P = 0.028). The PGESM rating distributions were significantly different in favor of parecoxib 20 mg bid treatment compared with parecoxib 20-mg qd treatment on Days 3, 4 and 5 (P 0.048).

View larger version (14K): [in this window] [in a new window]   Figure 3. Patients’ global evaluation of study medication scores on Days 2 to 5. aSignificantly different from placebo. bSignificantly different from parecoxib 20 mg qd. The numbers on top of the bars are the numbers of patients in each group.

Baseline PI on Day 2 was not statistically significantly different across the treatment groups for either categorical (P = 0.982) or VAS (P = 0.996) measurements. A time-specific analysis of PI (categorical) scores was performed during the 24-h period from Day 2 through Day 5 (Fig. 4). On Day 2, the mean PI score for the parecoxib 20-mg bid group was significantly (P 0.05) lower than for placebo at the 4-h to 24-h assessments and at the 12-h assessment in the 20-mg qd parecoxib group compared with placebo. On Day 3, the mean PI score was significantly (P 0.05) lower than placebo group at 2 h in the 20-mg bid parecoxib group and in both parecoxib groups from the 8-h through 24-h assessments. On Day 4, a significant difference between parecoxib 20 mg bid and placebo occurred at 8 h though 24 h, and at 4 h through 16 h in the parecoxib 20-mg qd group. On Day 5, significant (P 0.05) differences between parecoxib 20 mg bid and placebo occurred at hours 4, 8, 16, and 24. The mean time-specific PI scores for the parecoxib 20-mg bid treatment group were generally lower than for the parecoxib 20-mg qd treatment group, but the differences were not statistically significant at any time point. Similar results were reported for mean time-specific PI (VAS) scores (data not shown).

View larger version (11K): [in this window] [in a new window]   Figure 4. Pain intensity (categorical) at each time point on Days 2 to 5. Pain intensity on a 4-point rating scale: no pain (0) to severe pain (3). aP 0.05 for parecoxib 20 mg qd versus placebo. bP 0.05 for parecoxib 20 mg bid versus placebo.

There were no significant differences among groups in the consumption of rescue analgesia on Days 2, 4, or 5 (Table 3). On Day 3, patients in the parecoxib 20-mg bid treatment group consumed significantly less rescue medication compared with patients in the placebo treatment group (P 0.05). There was no significant difference in mean amount of rescue medication consumed by patients in the parecoxib 20-mg qd and placebo treatment groups on any assessment day. Fewer patients in the parecoxib treatment groups took rescue medication than in the placebo treatment group (data not shown).

On Days 2 to 4, there were no statistically significant differences among the treatment groups in mean mBPI-sf pain interference with function composite scores. All three groups showed lower mBPI-sf pain interference scores from Day 2 to Day 3, and there was a trend toward greater improvement in the parecoxib 20 mg bid group (parecoxib 20 mg bid, 0.56 ± 1.14; parecoxib 20 mg qd, 0.66 ± 1.28; placebo, 0.73 ± 1.55). On Day 5, the mean mBPI-sf pain interference with function composite score was significantly lower in the parecoxib 20-mg bid treatment group (0.47 ± 1.05) than in the placebo treatment group (0.78 ± 1.60; P < 0.05). There were no significant differences between the two parecoxib treatment groups on Days 2 to 5.

The Symptom Distress Questionnaire showed significant benefit in the parecoxib sodium 20 mg bid group compared with placebo with respect to the bothersome opioid-related symptoms for fatigue (Days 2 and 3, parecoxib sodium 20 mg bid); drowsiness (Day 3, parecoxib sodium 20 mg bid); inability to concentrate (Day 2, parecoxib sodium 20 mg bid); and for nausea (Day 3, parecoxib sodium 20 mg bid; Day 4, both parecoxib sodium treatments; and Day 5, parecoxib sodium 20 mg qd). There was a significant overall reduction in the combined-dimension, average composite score, a summary of the overall multiple-day patient-reported experiences of opioid symptoms, in the parecoxib 20-mg bid group compared with placebo for Days 2 through 5 (P < 0.05).

The postsurgical recovery measures included time to first oral fluid and solid food intake, unassisted ambulation, unassisted bathroom use, time to return of bowel function, last morphine dose, and total length of hospital stay. The only significant differences (P < 0.05) among groups was time to first unassisted bathroom use, which was significantly lower in the parecoxib 20 mg qd group compared with the parecoxib 20 mg bid group, and time to first oral fluid intake, which was shorter in the placebo and parecoxib 20-mg bid group compared with the parecoxib 20-mg qd group.

A post hoc responder analysis was performed to determine the percentage of patients who responded to treatment at a clinically meaningful level on Days 2 to 5. A responder to treatment was defined as a patient meeting any two of the following three criteria on a daily basis: 1) 30% reduction in baseline PI prior to the administration of study medication in PACU (Day 1) using a VAS from 0 to 100 mm, where 0 = no pain, and 100 = worst pain, 2) no use of rescue medication, and/or 3) a PGESM rating of "excellent." The percentage of patients who responded to treatment at a clinically meaningful level on Days 2 to 5 was significantly higher in the parecoxib 20-mg bid and 20-mg qd treatment groups than in the placebo group, with the exception of parecoxib 20-mg qd treatment on Day 2 (Table 4).

During the single-blind phase of the study, in which all patients received a standard analgesic regimen, 46.5% (288/490) of patients experienced at least one adverse event, the majority of which were mild or moderate in severity. Nausea was the most frequently reported adverse event. In addition, one serious adverse event, hypotension, was reported. During the double-blind phase, the incidence of any adverse event was not significantly different among the treatment groups with the exception of vomiting, fever, and impaired concentration, which occurred in significantly more patients in the placebo group than in the parecoxib 20 mg qd (vomiting) or parecoxib 20 mg bid (fever and impaired concentration) groups (Table 5). The majority of adverse events were mild or moderate in severity. Three patients experienced a total of four serious adverse events: one placebo-treated patient had a headache and a cerebrovascular disorder; one patient treated with parecoxib 20 mg qd experienced arthrosis and another in the same group had a cerebrovascular disorder. No deaths occurred during the study. No significant treatment differences were observed in the incidence of the prespecified adjudicated adverse events of CV thromboembolic events, renal dysfunction, upper GI ulcers, or wound-healing complications. Two confirmed events, TIAs, occurred in one patient during the single-blind phase and in one patient in the parecoxib 20-mg qd treatment group during the double-blind phase.

View this table: [in this window] [in a new window]   Table 5. Incidence of Adverse Events Occurring in 2% of Patients During the Double-Blind Phase

DISCUSSION

The primary measures of efficacy, the SPI-24 categorical scale and PGESM on Days 2 and 3, showed that parecoxib was effective and well tolerated in the postsurgical treatment of THA. Patients receiving parecoxib 20 mg bid reported significantly less pain compared with the placebo group at a majority of time points on Days 2 and 3 and parecoxib 20 mg qd was associated with similar results on Day 3. These results, together with the improvements in PGESM scores, indicate that parecoxib 20 mg bid was more effective than placebo and somewhat more effective than parecoxib 20 mg qd. The results of this study also indicate that multiple-day treatment with the parenteral COX-2 selective inhibitor parecoxib can reduce postoperative acute pain to a clinically meaningful extent in patients undergoing THA. Treatment with parecoxib 20 mg bid, and to a somewhat lesser extent parecoxib 20 mg qd, significantly reduced pain over 4 days of treatment compared with placebo, as well as modestly reducing the need for rescue medication. The improved management of pain in these patients was achieved without increasing the occurrence or postoperative burden of adverse events. Thus, on balance, the bid parecoxib 20-mg regimen provided a more consistent level of efficacy than 20 mg once daily. Neither parecoxib regimen provided consistently measurable effects on health outcome measures or on opioid-related symptoms in our study; however, modest benefits that were evident occurred largely in patients treated with parecoxib 20 mg bid. Taken together, the results of our study support the use of parecoxib as part of a multimodal analgesic plan in managing acute postsurgical pain over several days.12,13

Based on our experience across a number of postsurgical settings, the total amount of supplemental and rescue opioid medication taken by PCA, injection, or oral administration and converted to morphine equivalents was low across all treatment groups. This may have contributed to the inability to detect reductions in opioid requirements and accompanying improvement in tolerability. As a result of low opioid use, there were no significant differences between the parecoxib and placebo groups, which contrasts with other trials designed to examine the opioid-sparing effect of parecoxib in the THA and total knee arthroplasty surgical setting.5,6 On Days 4 and 5, the consumption of rescue analgesia increased compared with Day 3 within each group. However, this is explained by the fact that the mean amount of rescue medication was determined only for those patients who actually took study medication on any given day and only patients with poor control of postsurgical pain remained in the study on Days 4 and 5.

Parecoxib was well tolerated with no evidence of increasing patient burden for adverse effects above standard of care alone. Recently, concerns about the CV safety of nonselective nonsteroidal antiinflammatory drugs and COX-2 selective inhibitors have been raised. The number of confirmed CV adverse events in our study was small (two events, both TIAs; one in the single-blind phase and one in the parecoxib 20-mg qd group in the double-blind phase). As the safety assessments were not a primary objective of the study and the number of patients was too small to make any valid conclusion, our study is admittedly limited in excluding any potential safety concern. Furthermore, it should be noted that high-risk patients, such as those with a history of clinically significant GI disease, renal disease, cerebrovascular accident, transient ischemic attack, myocardial infarction, angina, DVT, or PE within 3 mo of surgery, were excluded from the study. This is not unlike clinical practice where therapies may be selected using a risk versus benefit analysis. Furthermore, not all therapies are appropriate for all patients.

The safety results in this study are consistent with those in another large general noncardiac surgery study, which showed no significant safety difference between the parecoxib and placebo treatment groups.14 In contrast, two studies in patients undergoing coronary artery bypass graft surgery showed that parecoxib was associated with an increased incidence of thrombotic CV events compared with placebo treatment.15,16

All patients received the same analgesic regimen of parecoxib in the PACU along with supplemental analgesia to ensure that each patient had adequate pain control and to establish a common baseline for pain evaluation going forward in the double-blind phase. In addition, this 24-h prerandomization phase helped to minimize the potential effect of residual intraoperative analgesia. However, we recognize some possible limitations in this trial in that medications administered during surgery were not standardized due to the number and diversity of centers involved. Although all intraoperative medications were recorded, we did not evaluate differences among treatment groups, and we did not tabulate and compare intraoperative opioid use or assess potential differences in opioid-related adverse experiences for patients in each group who had intraoperative opioids such as those who had general anesthesia. In addition, nearly all patients received parecoxib 60 mg in the PACU on Day 1; this might have reduced the sensitivity to detect differences in analgesia among groups in the double-blind phase and might have contributed to the lower than expected opioid consumption. The categorical difference in PI between the parecoxib and placebo groups was less than we expected based on the anticipated size effect used as a basis to power this trial.

In conclusion, multiple-day administration of parecoxib 20 mg once or twice daily is effective and generally well tolerated after THA.

ACKNOWLEDGMENTS

We are grateful to Harry Cui, PhD, for providing statistical support. Editorial support was provided by R. Passmore, PhD, at Parexel, and was funded by Pfizer Inc.

Footnotes

Accepted for publication April 16, 2008.

This study was sponsored by Pfizer Global Research and Development. Drs Viscusi, Gimbel and Halder received research support to perform this study and have no other financial interest in the sponsor.

Drs Brown and Verburg are full-time employees of Pfizer Inc.

Michael Snabes is currently at MCS Medical Consulting, Winnetka, Illinois.

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