Valdecoxib and its intravenous prodrug parecoxib are reported to increase thromboembolic risk after coronary artery bypass grafting. The authors conducted a randomized trial to examine their safety and analgesic efficacy in patients recovering from major noncardiac surgical procedures.
The trial was randomized and double-blind, with 10 days of treatment and 30 days of follow-up. Patients (n = 1,062) received either parenteral parecoxib for 3 days and oral valdecoxib for the rest of the treatment period or placebo medications throughout. The frequency of predefined adjudicated postrandomization adverse events, including cardiovascular thromboembolism, renal dysfunction, gastroduodenal ulceration, and wound-healing complications, was assessed in each group. Secondary efficacy endpoints included patients' pain ratings, opioid analgesic consumption (recorded as morphine equivalents), and reports of opioid-related adverse effects.
Predefined adjudicated adverse events had similar frequencies among patients who received parecoxib and valdecoxib (2.7%) and placebo patients (3.2%) (P = 0.58), including cardiovascular thromboembolic events (1.0% in each group; P = 1.0). Placebo patients consumed more morphine equivalents (66.2 +/- 92.4 mg) than did patients receiving parecoxib and valdecoxib (43.2 +/- 65.7 mg) (P < 0.001). Placebo patients had higher mean pain ratings on each of study days 2-10 (P < 0.01) and reported more opioid-related symptom distress on days 2-6 (P < 0.01).
Parecoxib and valdecoxib are useful adjuncts to opioids for the treatment of postoperative pain in noncardiac surgical patients. Further study will be required to determine the safety profile of parecoxib and valdecoxib administered to patients with known atherosclerotic disease after noncardiac surgery.
PARENTERAL administration of nonsteroidal antiinflammatory drugs is an established pharmacologic tool for reducing pain after surgery. However, the potential adverse effects of cyclooxygenase-1 inhibition, such as gastric ulceration and bleeding, have limited the use of nonspecific nonsteroidal antiinflammatory drugs in many surgical patients.1Selective cyclooxygenase-2 inhibitors are unlikely to cause these effects. However, their safety has recently been called into question because they may increase the incidence of thromboembolic cardiovascular events in nonsurgical patients receiving rofecoxib2–5or celecoxib.3,6
Also, two randomized trials of valdecoxib and its intravenous prodrug parecoxib in patients undergoing coronary artery bypass graft (CABG) surgery showed that patients taking these drugs had a higher rate of postoperative cardiovascular thromboembolic events than did patients taking placebo.7,8This difference was significant in the larger study.8In both trials, parecoxib and valdecoxib were also associated with a higher incidence of wound-healing complications.7,8However, previous short-term studies of noncardiac surgical patients receiving parecoxib and valdecoxib, e.g. , those undergoing dental, gynecologic, orthopedic, and other surgical procedures,9–12have not revealed any serious adverse effects of these drugs. Nonetheless, it is possible that the sample sizes of these studies were insufficient to detect small but clinically meaningful differences in adverse event rates between patients receiving placebo and those receiving parecoxib and valdecoxib.
To define more clearly the safety of parecoxib and valdecoxib in noncardiac surgical patients and to confirm the analgesic efficacy of these drugs, a large trial was conducted in patients recovering from a variety of major noncardiac surgical procedures.
Materials and Methods
Study Design and Procedures
The trial, conducted in 113 centers in 14 countries from September 2002 to February 2003, was a sponsor-initiated, randomized, double-blind, parallel-group, multiple-dose, placebo-controlled study with 10 days of treatment and 30 days of follow-up after study drug administration was completed. All patients had access to standard opioid medications throughout the treatment period. The institutional review board or ethics committee at each center approved the protocol, and all patients gave written informed consent.
Patients were randomly assigned to two treatment groups. The parecoxib–valdecoxib group received an initial parenteral dose of 40 mg parecoxib on the day of surgery (day 1), and then 20 mg parecoxib every 12 h for 3 days, followed by 20 mg oral valdecoxib every 12 h through the 10th day. The placebo group received matching placebo medications throughout the 10-day period. Patients who were unable to tolerate oral medications continued to receive the intravenous study drug. Other routinely administered postoperative medications, including prophylaxis against deep vein thrombosis, were permitted, except for nonsteroidal antiinflammatory drugs, sedating antihistamines, prophylactic antiemetic agents, intrathecal or epidural opioids, and local analgesics applied to the surgical incision. Although concomitant low-dose aspirin use was not required, patients already taking aspirin (325 mg/day or less) were allowed to continue.
The primary endpoint was the combined incidence of predefined postrandomization adverse events in the following four clinically relevant categories: cardiovascular events, renal events, surgical wound complications, and gastrointestinal complications. Cardiovascular events included cardiac, cerebrovascular, and peripheral vascular events. Cardiac events included myocardial infarction, severe myocardial ischemia (defined as typical ischemic chest discomfort lasting at least 10 min and associated with transient ST-segment changes of at least 1 mm on the electrocardiogram), sudden death from cardiac causes, or unexpected death without an identifiable noncardiac cause within 60 min after the onset of symptoms.
Myocardial infarction was diagnosed at autopsy or by the presence of two or more of the following: prolonged chest pain (lasting more than 20 min) that was not relieved by antianginal agents and was accompanied by new electrocardiographic ST changes of at least 1 mm, a creatine kinase (myocardial band) level greater than 2 times the upper limit of normal, or a peak troponin I level of at least 3.7 μg/l; new wall-motion abnormalities that were consistent with the occurrence of a myocardial infarction (a two-grade change) detected during catheterization, echocardiography, or radionuclide scanning; and new Q waves on serial electrocardiography that were consistent with the occurrence of myocardial infarction.13Cerebrovascular events included a new ischemic or hemorrhagic cerebrovascular accident lasting 24 h or longer or a transient ischemic attack lasting less than 24 h, diagnosed according to clinical criteria and confirmed by a diagnostic study (e.g. , computed tomography or magnetic resonance imaging).14Peripheral vascular events included deep vein thrombosis, defined as increased unilateral or bilateral leg swelling, warmth, and edema, with a confirmatory diagnostic test, and pulmonary embolism, defined as chest pain, dyspnea, or hypoxemia, with a confirmatory imaging study.
Renal events included renal failure, defined as the need for hemodialysis or peritoneal dialysis after surgery, and severe renal dysfunction, defined by a postoperative serum creatinine level of at least 2.0 mg/dl, with an increase of at least 0.7 mg/dl after randomization.15Gastroduodenal complications were defined as gastrointestinal ulcers resulting in bleeding (proven on the basis of endoscopy), perforation, or obstruction. Wound-healing complications included infection of the superficial incisional site, the deep incisional site, the organ itself, or the surgical space, or noninfectious separation or dehiscence of the wound.
The primary investigator at each site was responsible for reporting all adverse events to the sponsor, including directly observed events and those spontaneously reported by the patients. Definitions of the predefined endpoints of interest were described in detail in the study protocol and reiterated in a newsletter regularly distributed to all investigational sites. An independent, external endpoint committee (see appendix) whose members were unaware of the patients' treatment assignments used these definitions to review the data on adverse events. Adjudicated, predefined adverse events in all four categories were combined for the primary safety analysis. Secondary safety endpoints included the incidence of all adverse events, defined as any untoward medical occurrence that did not necessarily have a causal relation with study drug treatment, and serious adverse events, defined as any event that resulted in one or more of the following: death, life-threatening complication, prolongation of current hospitalization or requirement for rehospitalization, or persistent or significant disability. In addition, electrocardiograms, clinical laboratory assessments, and vital signs were analyzed at baseline, at the time of transition from intravenous to oral medication, and at the final visit (occurring between days 11 and 14). Patients were contacted by telephone 30 days after the last dose of study medication and were assessed for the occurrence of serious or clinically relevant adverse events. A data and safety monitoring board (see appendix) independently monitored safety outcomes throughout the study.
Efficacy measures, as secondary endpoints, included patients' use of any supplemental opioid analgesics, converted to morphine equivalents according to published potency ratios.16On days 1–10, using a four-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe), patients recorded their current pain level in a preprinted diary at 2, 4, 8, 12, and 24 h after the first daily dose. Also, once per day, using four-point scales, patients rated their distress from opioid-related symptoms in terms of frequency (rarely, occasionally, frequently, almost constantly), severity (slight, moderate, severe, very severe), and degree of bother (a little bit, somewhat, quite a bit, very much). Symptoms included fatigue, drowsiness, inability to concentrate, confusion, dizziness, constipation, itching, difficulty with urination, nausea, and retching/vomiting.17
Patients were men and women who were scheduled to undergo major orthopedic, abdominal, gynecologic, or noncardiac thoracic surgery requiring general or regional anesthesia and who were expected to require opioids for postoperative pain. Patients undergoing vascular surgical procedures (e.g. , carotid endarterectomy, femoral–popliteal bypass, or aortic arch or aneurysm repair), partial hepatic resection, organ transplant, or intracranial surgery were excluded. Inclusion criteria were an age of 18–80 yr, a body mass index of no more than 40 kg/m2, a weight of more than 55 kg, and an American Society of Anesthesiologists physical status classification of I–III.18
Exclusion criteria were emergency surgery, a thromboembolic event (cerebrovascular accident, transient ischemic attack, unstable angina, myocardial infarction, deep vein thrombosis, or pulmonary embolism) within 3 months before study entry, renal disease that was considered clinically significant by the investigator, or active gastrointestinal bleeding in the 60 days before surgery. Before randomization, other exclusion criteria included a surgical procedure longer than 4 h, inability to extubate the trachea within 4 h after operation, evidence of a new postoperative myocardial infarction, abnormal postoperative mental status or any new neurologic deficit, postsurgical bleeding considered significant by the investigator, a hemoglobin level of less than 8 g/dl, or a urine output of less than 30 ml/h.
The sample size of 500 patients per treatment arm provided at least 80% power to detect a doubling of the 4% estimated background incidence of all predefined adverse events combined. All eligible patients were stratified according to geographic location (North America, Europe, or another location) before randomization.
Analyses were performed on the modified intent-to-treat population, which was defined as those patients who were randomized and who received at least one dose of study medication. The primary safety analysis used the Fisher exact test to examine the proportion of patients in each group with at least one predefined adverse event. Similar analyses were performed for individual confirmed events within each of the four endpoint categories. For predefined cardiovascular events, analyses of the time to a first event were performed with the log-rank test and presented by means of Kaplan-Meier curves.
Efficacy measurements were made on each study day, i.e. , the time period between the morning dose on a given day and the morning dose on the next day. Supplemental analgesia was examined by analysis of variance of observed data only, without imputation of data after a patient withdrew from the study. Summed pain intensity scores were calculated from the five categorical pain intensity assessments recorded each day. Each rating was weighted by the number of hours between the time it was obtained and the time the previous rating was obtained, so that the summed pain intensity score = (2-h rating –x 2) + (4-h rating –x 2) + (8-h rating –x 4) + (12-h rating –x 4) + (24-h rating –x 12). The potential range of these scores was 0–72. Daily summed pain intensity scores were analyzed with general linear models. For opioid-related symptom distress, an overall composite score—the mean of the frequency, severity, and degree of bother scores for all opioid-related symptoms—was calculated for each day. These composite scores were analyzed with analyses of variance. All statistical comparisons included treatment and country as factors, were two tailed, and used an α value of 0.05. There were no prespecified stopping rules, and none of the comparisons were adjusted for interim analyses.
The sponsor collected the data. The authors had complete access to the data after unblinding. All final analyses were conducted by an independent statistician at the Texas Heart Institute in Houston.
A total of 1,062 patients from 14 countries (see appendix) were randomized: 533 to the group given parecoxib and valdecoxib and 529 to the placebo group. Enrollment and outcomes are outlined in figure 1. There were no significant differences between the two groups in preoperative characteristics, including cardiovascular risk factors (table 1), or in the proportion of patients undergoing orthopedic, gastrointestinal, gynecologic, thoracic, or other types of surgery (table 2). Duration of surgery and time from the end of surgery until administration of study medication were comparable between the two groups (table 2).
Primary Endpoint: Predefined Adjudicated Adverse Events
The patients given parecoxib and valdecoxib did not differ from the placebo patients in the incidence of predefined adjudicated adverse events in any of the four categories, or in the percentage of patients with at least one event (table 3). Cardiovascular event rates were identical in the group given parecoxib and valdecoxib and the group given placebo (1.0% vs. 1.0%; risk ratio, 1.0; 95% confidence interval, 0.29–3.5; P = 1.0; table 3). The time-to-event analysis revealed that cardiovascular events occurred throughout and after the 10-day period of drug administration in both groups (fig. 2). Likewise, surgical wound event rates were similar in the group given parecoxib and valdecoxib and the group given placebo (1.7% vs. 2.1%; risk ratio, 0.81; 95% confidence interval, 0.3–2.0; P = 0.65).
Secondary Endpoints (Safety): Adverse Events, Serious Adverse Events, Clinical Laboratory Assessments, and Vital Signs
Adverse events were reported in 285 of 525 patients taking parecoxib and valdecoxib (54.3%) and in 302 of 525 placebo patients (57.5%) over the entire study period (P = 0.29). The frequencies of three of the four most common adverse events were nearly identical between treatment groups: Nausea was reported by 96 patients taking parecoxib and valdecoxib (18.3%) and 100 placebo patients (19.0%), vomiting was reported by 54 patients taking parecoxib and valdecoxib (10.3%) and 50 placebo patients (9.5%), and constipation was reported by 64 patients taking parecoxib and valdecoxib (12.2%) and 63 placebo patients (12.0%). However, only 13 of 525 patients taking parecoxib and valdecoxib (2.5%) experienced fever, whereas 65 of 525 placebo patients (12.4%) did (P < 0.001). Sixty-nine serious adverse events occurred in 56 patients: 39 in 27 patients taking parecoxib and valdecoxib (5.1%) and 30 in 29 placebo patients (5.5%) (P = 0.77).
Seven deaths occurred during the study (table 3). Of the three deaths that occurred in patients who received parecoxib and valdecoxib, one was caused by each of the following: myocardial infarction, pulmonary embolism, and gastrointestinal hemorrhage. Four deaths occurred in patients who received only placebo; one was caused by each of the following: cardiac arrest, cardiac failure, thrombosis of a mesenteric vessel, and carcinoma. Mortality rates were not significantly different between groups (P = 0.70).
Abnormal laboratory findings were common in both treatment groups. Mean changes in laboratory values were generally small, and there were no significant differences between treatment groups in the incidence of extreme changes in any laboratory value. Vital signs were not adversely affected to a clinically meaningful extent by treatment with parecoxib and valdecoxib.
Secondary Endpoints (Efficacy): Supplemental Analgesia Requirements, Pain Ratings, Pain Interference with Function, and Opioid-related Symptom Distress
Mean cumulative morphine consumption over the entire study period was significantly greater in the placebo group (66.2 ± 92.4 mg) than in the group treated with parecoxib and valdecoxib (43.2 ± 65.7 mg) (P < 0.001). The placebo group also had significantly higher summed pain intensity scores on each of study days 2–10 (P < 0.01; fig. 3). In addition, the overall composite score for opioid-related symptom distress averaged across all symptoms showed significantly less distress among patients taking parecoxib and valdecoxib than among placebo patients on days 2–6 (P < 0.01; fig. 4).
This study of patients recovering from noncardiac surgery is the largest single randomized controlled study to evaluate the safety of any analgesic in the general surgery setting. We did not find a higher incidence of cardiovascular thromboembolic or other adverse events among patients who received parecoxib and valdecoxib for 10 days for postoperative pain control than among patients who received placebo. In contrast, our recent study found that CABG patients who received parecoxib and valdecoxib for 10 days after surgery had a significantly higher incidence of thromboembolism than did patients who received placebo.8We previously speculated that the increased risk of thromboembolic events among CABG patients receiving parecoxib and valdecoxib may be due to preexisting generalized atherosclerotic disease, exposure to the additional risks of cardiopulmonary bypass, or both.8Data from the current study tend to confirm these speculations, because most patients were not at high risk for underlying atherosclerotic disease–t(fewer than 3% had a previous myocardial infarction, fewer than 7% had a history of coronary artery atherosclerosis, and fewer than 5% had a history of angina), and none of the procedures required a period of cardiopulmonary bypass. Nevertheless, one third of the patients in the current study were hypertensive, and one third had hyperlipidemia.
In a previous study of CABG patients,7patients receiving 80 mg parecoxib or valdecoxib daily for 14 days had a significantly higher incidence of sternal wound infections and healing complications than did patients receiving placebo. Similarly, in a more recent study of CABG patients,8patients receiving 40 mg parecoxib or valdecoxib daily for 10 days had a numerically higher incidence of sternal wound infections and healing complications than did patients receiving placebo. We speculated that inhibition of the cyclooxygenase-2 enzyme impedes reparative inflammatory responses and increases susceptibility to wound infections or, alternatively, that the analgesic and antipyretic effects of parecoxib and valdecoxib may delay detection of incipient infection. However, in the current noncardiac surgical study, wound infections and healing complications were not more frequent in patients receiving 40 mg parecoxib and valdecoxib daily for 10 days, confirming similar findings in all previous noncardiac surgical studies of which we are aware. Possibly, in CABG surgery, the sternum is particularly susceptible to healing complications that might be affected by a selective cyclooxygenase-2 inhibitor. Other clinically relevant adverse events, including renal dysfunction and upper gastrointestinal events, were not associated with parecoxib and valdecoxib in the current study or in any previous studies.
A limitation of this study is the pooled endpoint of predefined adjudicated adverse events in four unrelated diagnostic categories (arterial or venous thromboembolic events, renal insufficiency or failure, gastroduodenal ulceration, and wound infections or healing complications). Another limitation of the study is the sample size. Although this was the largest trial of any nonsteroidal antiinflammatory drug in patients undergoing noncardiac surgery, the number of adverse events was relatively small and possibly inadequate to detect a particular safety signal. This is especially true for cardiovascular thromboembolic events, given the low level of risk in this population compared with CABG surgery patients. Nevertheless, this population was representative of the majority of patients who undergo major surgery.
The current study showed that parecoxib and valdecoxib provide effective analgesia at a dose of 40 mg/day. Other investigators have also reported reduced opioid consumption and improved pain scores with postoperative administration of 40 mg parecoxib per day.8–12Reduction in opioid use was accompanied by significant improvement in patients' ability to perform daily activities and a reduction in both the frequency and the severity of symptoms of opioid intolerance. In fact, efficacy may be optimal if initial administration occurs earlier, in the preoperative or intraoperative period.19Use of two analgesic agents that act by different mechanisms (i.e. , multimodal analgesia) is recommended for acute pain management because it provides superior efficacy while minimizing the adverse effects of opioids.20Although highly effective, opioids are associated with respiratory depression, alterations in mental status, nausea and vomiting, constipation, prolongation of paralytic ileus, pruritus, and urinary retention.21
Improving postoperative analgesic management has become a major initiative in American health care.22This trial showed that parecoxib and valdecoxib are useful adjuncts to opioids in noncardiac surgical patients if administered at recommended doses (a 40-mg loading dose followed by 20 mg every 12 h) over a short term (no more than 10 days). However, until parecoxib and valdecoxib are studied further in noncardiac surgical patients with known atherosclerotic disease, these drugs should be reserved for patients at low risk for thromboembolic events.
The authors thank Stephen N. Palmer, Ph.D., E.L.S. (Scientific Medical Writer, section of Scientific Publications, The Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas), for editorial assistance and William K. Vaughn, Ph.D. (Vice President of Biostatistics and Epidemiology, The Texas Heart Institute at St. Luke's Episcopal Hospital), for statistical support.
The following investigators participated in the study: Argentina: Hospital Aleman, Buenos Aires—Alejandro Gabriel Haidbauer, M.D.; Hospital Interzonal General de Agudos Presidente Peron, Buenos Aires—Eduardo Pataro, M.D.; Hospital Municipal Bernadino Rivadavia, Buenos Aires—Carlos Gaeta, M.D.; University of Buenos Aires—Eduardo Huertas, M.D., Alejandro Oria, M.D. Australia: Northern Hospital, Epping—Juris Briedis, M.D.; Austin and Repatriation Medical Centre, Heidelberg—Jane Trinca, M.D.; Royal Brisbane Hospital, Herston—Michael Fanshawe, M.D.; Alfred Hospital, Melbourne—Paul Myles, M.D.; Royal Melbourne Hospital, Parkville—Kate Leslie, M.D.; Prince of Wales Hospital, Randwick—Stephen Gatt, M.D. Bulgaria: Pirogov Emergency Medicine Institute, Pirogov—Alexander Tcherveniakov, M.D.; Multifunctional Hospital for Active Treatment, Plovdiv—Borislav Ninov, M.D., Georgi Deenichin, M.D.; Alexandrovska University Hospital, Sofia—Dore Dorev, M.D.; Specialized Hospital for Active Treatment for Gynecology and Obstetrics, Sofia—Ilko Assenov, M.D. Canada: University of Alberta, Edmonton—Michael Jacka, M.D.; Capital District Health Authority, Halifax—Benjamin L. Schelew; London Health Science Center, London—Richard Tilsworth, M.D.; University Health Network Toronto Western Hospital, Toronto—Vincent W. Chan, M.D.; Centre Hospitalier Universitaire de Sherbrooke–Fleurimont, Fleurimont—Marie-Jose Colas, M.D.; Saskatoon City Hospital, Saskatoon—Joan Stevenson, M.D. Chile: Clinica Santa Maria, Santiago—Agustin Espejo, M.D.; Hospital Clinico De La Pontificia, Santiago—Mario Guerrero, M.D.; Hospital Clinico Universidad de Chile, Santiago—Fernando Maluenda, M.D.; Hospital Dipreca, Santiago—Victor Ortuvia; Hospital Mutual de Seguridad, Santiago—Juan Pablo Ilic, M.D. Czech Republic: Mulac Hospital, Pilsen—Vladislav Fruhauf, M.D.; Charles University Hospital (Pilsen), Pilsen—Karel Koudela, M.D., Ph.D.; University Hospital of Pilsen, Pilsen—Vladislav Treska, M.D., Ph.D.; Bulovka University Hospital, Prague—Ivo Kofranek, M.D.; Charles University Hospital (Prague), Prague—Jaroslav Faltyn, M.D., Robert Gurlich, M.D., Jiri Svoboda, M.D.; Faculty Hospital Motol, Prague—Jan Neumann, M.D., Ph.D.; Masarykova Hospital, Ústí nad Labem—Jan Schraml, M.D. Finland: Keski-Suomen Keskussairaala, Jyvaskyla—Maija Pesola, M.D.; Satakunnan Keskussairaala, Pori—Sari Sjovall, M.D.; Turku University Hospital, Turku—Jouko Jalonen, M.D. Israel: Sapir Medical Center, Kfar Saba—Mordechai Gutman, M.D.; Rabin Medical Center, Petah Tikva—Uzi Eshkenazi, M.D., Franklin Greif, M.D.; Kaplan Medical Center, Rehovot—Zeev Sthoeger, M.D., Chanan Tauber, M.D.; Sourasky Medical Center, Tel Aviv—Itzhak Otremski, M.D., David Zeltser, M.D. New Zealand: Canterbury Urology Research Trust, Christchurch—Stephen Mark, M.D.; Middlemore Hospital, M.D., Otahuhu, Auckland—Stuart Walker, M.D.; Timaru Hospital, Timaru—Anne Phillips, M.D. Poland: Akademii Medycznej w Poznaniu, Krakow—Artur Hartwich, M.D.; Katedra i Klinika Chirurgi Ogolinej Gastroenterologicznej i Endokrynologicnej, Poznan—Michal Drews, M.D.; Medical University of Warsaw, Warsaw—Wojciech Rowinski; Samodzielny Publiczny Centralny Szpital Kliniczny, Warsaw—Ireneusz Wojciech Krasnodebski, M.D. Romania: County Hospital Brasov, Brasov—Cucu Alin, M.D.; Ellas Hospital Bucharest, Bucharest—Adrian Miron, M.D.; Floreasca Emergency Hospital Bucharest, Bucharest—Mircea Beuran, M.D.; Oncology Institute Bucharest, Bucharest—Alexandru Blidaru, M.D.; Cantacuzino Hospital Bucharest, Bucharest—Dan Ioan Secara, M.D.; Coltea Hospital Bucharest, Bucharest—Traean Burcos, M.D.; County Clinical Hospital Cluj Napoca, Cluj Napoca—Marian Vasile Todoran, M.D.; County Clinical Hospital Craiova, Craiova—Ioan Gugila, M.D. South Africa: Jan S. Marais Hospital, Bellville, Cape Town—J. T. Perry, M.D.; Rosepark Hospital, Bloemfontein—Athony Travers, M.D.; Parklands Hospital, Durban—Nicholas Nathan Armstrong, M.D.; Westville Hospital, Durban—Robert Llewellyn Graham, M.D.; Panorama Medi Clinic, Parow—E. Vermaak, M.D. Ukraine: Kiev City Clinical Hospital 12, Kiev—Peter D. Fomin, M.D.; Kiev Regional Clinical Hospital, Kiev—Vladimir I. Mamchich, M.D.; National A. A. Bogomoltetz Medical University, Kiev—Mykhaylo P. Zakharash, M.D.; Sumy Regional Oncology Center, Sumy—Igor O. Vynnychenko, M.D. United States: Alabama Clinical Therapeutics, Department of Orthopaedic Surgery, Department of Clinical Investigation, Birmingham—P. Lauren Savage, Jr., M.D.; Helen Keller Hospital, Department of Anesthesiology, Sheffield, Alabama—Timothy Ivan Melson, M.D.; Maricopa Medical Center, Department of Surgery, Phoenix—Marco V. Canulla, M.D., F.A.C.S.; Old Pueblo Anesthesia, Department of Anesthesiology, Tucson—Casey D. Blitt, M.D.; Hot Springs Mercy Pain Clinic, Department of Pain Management, Hot Springs, Arkansas—Donald Lewis Boos, Jr., M.D.; The Surgical Clinic of Central Arkansas, Department of General Surgery, Little Rock—W. Everett Tucker, M.D.; Biomedical Research Institute of America, Partner, Bakersfield, California—Blas Deleon Hernandez, M.D.; Saddleback Memorial Medical Center, Department of Anesthesiology, Laguna Hills, California—R. Kevin Jones, M.D.; Kerlan-Jobe Orthopaedic Clinic, Department of Orthopaedic Surgery, Los Angeles—Andrew Ira Spitzer, M.D.; UCLA, Department of Anesthesiology, Los Angeles—Michael Ferrante, M.D., F.A.B.P.M.; Huntington Memorial Hospital, Department of Anesthesia, Pasadena, California—Neil Kumar Singla, M.D.; University of California-Davis, Division of Pain Medicine-Ambulatory Care Center, Sacramento, California—Barth Lance Wilsey, M.D.; Yale University School of Medicine, Department of Anesthesiology, New Haven, Connecticut—Raymond S. Sinatra, M.D., Ph.D.; Washington Hospital Center, Colon Rectal Department, Washington, D.C.—Lee Elton Smith, M.D.; Christiana Care Health Services, Department of Surgery, Newark, Delaware—Gerard James Fulda, M.D., F.A.C.S., F.C.C.M., F.C.C.P.; Southeastern Clinical Research Consultants, Department of Anesthesiology, Orlando, Florida—Walter Jerry Merrell, M.D.; Sacred Heart Hospital, Department of Surgery, Pensacola, Florida—Kurt T. Stockamp, M.D.; DeKalb Medical Center, Owner, Decatur, Georgia—Maurice Jove, M.D.; Rush-Presbyterian St. Luke's Medical Center, Department of Anesthesiology, Chicago—Asokumar Buvanendran, M.D.; Galesburg Cottage Hospital, President, Galesburg, Illinois—Myron Basil Stachniw, M.D.; University of Kansas Medical Center, Department of Anesthesiology, Kansas City—Anthony L. Kovac, M.D.; University of Kentucky Chandler Medical Center, Department of Anesthesiology, Lexington—Joseph Robert Holtman, Jr., M.D., Ph.D.; University of Louisville, Outcomes Research Institute, Louisville, Kentucky—Rainer C. Lenhardt, M.D.; Boston University Medical Center, Department of Anesthesiology, Boston—Eric Thompson Pierce, M.D., Ph.D.; Rx Trials, Silver Spring, Maryland—Kurt R. Larson, M.D.; Ridgeview Research, Investigator, Chaska, Minnesota—Mark Ellis Friedland, M.D.; University of Missouri-Columbia, Department of Pain Management, Columbia, Missouri—Robert B. Fisher, D.O.; St. John's Medical Research Group, Department of Orthopedics, Springfield, Missouri—Richard A. Seagrave, Jr., M.D., F.A.C.P.; Cooper Hospital/University Medical Center, Department of Anesthesiology, Camden, New Jersey—Irwin Gratz, D.O.; University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Department of Anesthesia, New Brunswick, New Jersey—Geza Kalman Kiss, M.D.; Montefiore Medical Center, Department of Surgery, Bronx, New York—Thanjavur S. Ravikumar, M.D.; Drs. Stulberg & Wilde, Inc., Cleveland—Bernard N. Stulberg, M.D.; LeHigh Valley Hospital, Department of Surgery, Allentown, Pennsylvania—Richard Charles Boorse, M.D.; Magee-Womens Hospital of the University of Pittsburgh Medical Center, Department of Anesthesiology, Pittsburgh—Derek Jean Davis, M.D.; Charleston Surgical Associates, General Surgery, Charleston, South Carolina—Paul Lawrence Baron, M.D.; University of Texas Southwestern Medical Center, Department of Anesthesiology and Pain Management, Dallas—Girish P. Joshi, M.D., B.S., M.B., F.F.A.R.C.S.I.; University of North Texas Health Science Center at Fort Worth, Department of Surgery, Fort Worth, Texas—Albert H. Olivencia-Yurvati, F.A.C.O.S., F.I.C.S., F.A.H.A., D.O.; Memorial Hermann Healthcare System-Memorial City Hospital, Department of Anesthesiology, Houston—Harold S. Minkowitz, M.D.; The University of Texas Health Science Center at Houston, Department of Anesthesiology, Houston—Ralf Gebhard, M.D.; Baylor Medical Center at Irving, Department of Clinical Research, Irving, Texas—William Thomas Dickey, M.D.; Mid-Atlantic Cardiothoracic Surgeons, Department of Cardiac and Thoracic Surgery, Norfolk, Virginia—Joseph Newton, M.D.; University of Wisconsin, Department of Surgery, Madison—Michael J. Schurr, M.D.; Southeast Surgical, Department of General Surgery, Milwaukee—Nicholas Nathan Armstrong, M.D. Endpoint Committee: Andrew Whelton (Chair), Paul Barash, Jeffrey Brinker, Gary Gerstenblith, Jay Goldstein, Phil Gorelick, Michael Kelly, Paul Waymack. Data and Safety Monitoring Board: Gerald A. Faich (Chair), Donald Berry, Ping Hsu, Mark F. Newman, William B. White.