Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain.

OBJECTIVE: To evaluate whether subjects with knee or hip osteoarthritis (OA) pain on non-steroidal anti-inflammatory drugs (NSAIDs) received greater benefit when tanezumab monotherapy replaced or was coadministered with NSAIDs. METHODS: Subjects (N=2700) received intravenous tanezumab (5 or 10 mg) or placebo every 8 weeks with or without oral naproxen 500 mg twice daily or celecoxib 100 mg twice daily. Efficacy was assessed as change from baseline to week 16 in three co-primary endpoints: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function and Patient's Global Assessment (PGA) of OA. Safety assessments included adverse events, physical and neurological examinations, laboratory tests and vital signs. RESULTS: Although all tanezumab treatments provided significant improvements in WOMAC Pain and Physical Function over either NSAID alone, only tanezumab+NSAIDs were significant versus NSAIDs with PGA and met the prespecified definition of superiority. Combination treatment did not substantially improve pain or function over tanezumab monotherapy. Adverse event frequency was higher with tanezumab than with NSAIDs and highest with combination therapy. Higher incidence of all-cause total joint replacements occurred with tanezumab+NSAID versus tanezumab monotherapy or NSAIDs. Rapidly progressive OA incidence was significantly greater versus NSAID in all tanezumab groups except tanezumab 5 mg monotherapy. CONCLUSIONS: Subjects receiving partial symptomatic relief of OA pain with NSAIDs may receive greater benefit with tanezumab monotherapy. While only coadministration of tanezumab with NSAIDs met the definition of superiority, combination treatment did not provide important benefits over tanezumab monotherapy; small differences in efficacy were negated by treatment-limiting or irreversible safety outcomes. TRIAL REGISTRATION NUMBER: NCT00809354.

The role of the orthopaedic surgeon in minimizing mortality and morbidity associated with fragility fractures.

Osteoporosis is an underrecognized and undertreated condition associated with fracture. More than 2 million fragility fractures occur each year, almost 300,000 of them hip fractures associated with a threefold risk for future fractures, as well as a 15% to 33% mortality rate within the first year of fracture. Orthopaedic surgeons can facilitate osteoporosis treatment by coordinating care for patients with fragility fractures by managing the current fracture, evaluating risk factors for osteoporosis, and, for hospitalized patients, developing a follow-up plan that notes whether the patient should be further evaluated or treated for osteoporosis. For the patient seen in the office, evaluation for osteoporosis should be performed and, if indicated, treatment should be undertaken. When osteoporosis treatment is warranted, diphosphonates are the standard of care, and administration of zoledronic acid once yearly has been proven to reduce the risk of subsequent fractures after low-energy hip fracture. By following these steps, orthopaedic surgeons can help ensure that patients with fragility fractures receive appropriate osteoporotic treatment, thereby reducing the risk of subsequent fractures.

The effect of initiating a preventive multimodal analgesic regimen on long-term patient outcomes for outpatient anterior cruciate ligament reconstruction surgery.

BACKGROUND: Unrelieved postoperative pain may impair rehabilitation, delay recovery, and result in poor outcomes. Preventive multimodal analgesic techniques may improve long-term outcome after surgery. METHODS: We randomized 200 consecutive patients to receive acetaminophen 1000 mg and either celecoxib 400 mg or placebo 1-2 h before anterior cruciate ligament surgery. All patients received intraarticular analgesics and had an external cooling system applied to the operative knee. After discharge patients were instructed to take acetaminophen 1000 mg every 6 h and either celecoxib 200 mg every 12 h or matching placebo for the first 14 days postoperatively. All patients were enrolled in an accelerated rehabilitation program. Six months postoperatively, the level of activity was assessed, as was the presence of patellofemoral complications including: anterior knee pain, flexion contracture, quadriceps weakness, and complex regional pain syndrome. RESULTS: More patients in the control group developed patellofemoral complications compared to the celecoxib group (P = 0.001) including anterior knee pain (14/96; 15%) vs (4/95; 1%), complex regional pain syndrome (7/96; 7%) vs (1/95; 1%), flexion contractures (9/96; 9%) vs (2/95; 2%), and scar tissue requiring re-arthroscopy (8/96; 8%) vs (2/95; 2%) respectively. More patients in the celecoxib group returned to a higher activity level (84% vs 65%) (P < 0.01), were able to participate at a more intense level (P < 0.02), and return to full sports activity (P < 0.05). CONCLUSIONS: The administration of celecoxib as a component of a preventive multimodal analgesic technique for anterior cruciate ligament reconstruction reduces long-term patellofemoral complications and increases the likelihood of returning to a preinjury level of activity.

Evaluating the analgesic efficacy of administering celecoxib as a component of multimodal analgesia for outpatient anterior cruciate ligament reconstruction surgery.

BACKGROUND: Cyclooxygenase-2 inhibitors may play an important role in multimodal management of pain after orthopedic surgery. We examined the analgesic efficacy of administering celecoxib as a component of a multimodal analgesic regimen for outpatient anterior cruciate ligament (ACL) surgery. METHODS: Two-hundred consecutive patients were randomized to receive acetaminophen 1000 mg and either celecoxib 400 mg or placebo 1-2 h before ACL surgery. All patients received intraarticular analgesics (bupivacaine, clonidine, and morphine) and had an external cooling system applied to the operative knee. After discharge, patients were instructed to take acetaminophen 1000 mg every 6 h and either celecoxib 200 mg every 12 h or matching placebo for the first 14 days postoperatively. Oxycodone 5-10 mg was available for rescue analgesia. RESULTS: Patients in the celecoxib group were more likely to experience less pain in the recovery room (P < 0.01) and require less opioids (P < 0.001) for postoperative analgesia. These patients reported a lower incidence of postoperative nausea and vomiting (P < 0.05) and were discharged home earlier (P < 0.05). While at home, patients in the celecoxib group reported lower pain scores both at rest (P < 0.05) and with movement (P < 0.01), and used less oxycodone at all postoperative time intervals. CONCLUSIONS: The perioperative administration of celecoxib decreases postoperative pain, opioid use, postoperative nausea and vomiting, and recovery room length of stay. These results support the use of celecoxib as a component of a preventive multimodal analgesic technique for ACL surgery.

The COX-2 specific inhibitor Valdecoxib versus tramadol in acute ankle sprain: a multicenter randomized, controlled trial.

BACKGROUND: The cyclooxygenase-2 specific inhibitor valdecoxib has not been approved in the United States for treatment of acute pain. HYPOTHESIS: Valdecoxib 20 mg twice daily or once daily (both with a 40-mg loading dose) is not clinically inferior to tramadol for treating the signs and symptoms of acute ankle pain. STUDY DESIGN: Randomized, controlled clinical trial; Level of evidence, 1. METHODS: Patients (N = 829) with acute first- or second-degree ankle sprain received 7 days' treatment with valdecoxib 20 mg either twice daily or once daily (both with 40-mg loading dose), tramadol 50 mg 4 times daily, or placebo. The primary end point was Patient's Assessment of Ankle Pain visual analog scale on day 4; a test of noninferiority compared valdecoxib with tramadol. RESULTS: On day 4, both valdecoxib doses were significantly better versus placebo and were comparable with tramadol in relieving ankle pain. On day 7, valdecoxib, but not tramadol, significantly reduced pain versus placebo. On days 4 and 7, more patients resumed normal walking with valdecoxib (45%-47% and 73%-79%, respectively) than with placebo (35% and 64%, respectively) or tramadol (38% and 67%, respectively). In contrast to valdecoxib, the number of withdrawals due to adverse events was significantly higher in the tramadol group (12.2% vs 3.4%; P = .0005). CONCLUSIONS: Valdecoxib was comparable with tramadol and was significantly better than placebo in treating acute ankle sprain, and it enabled more patients to resume normal walking on days 4 and 7. Both valdecoxib and tramadol were well tolerated.

The effect of cyclooxygenase-2 inhibition on acute and chronic donor-site pain after spinal-fusion surgery.

BACKGROUND AND OBJECTIVES: The development of chronic pain after spinal-fusion surgery represents a significant source of morbidity. One of the predictive factors for the development of chronic postsurgical pain is inadequate acute postoperative pain management. Further, the up-regulation of cyclooxygenase-2 (COX-2) after surgery may result in neuro-plastic changes that may contribute to a progression from acute to chronic pain. The goal of this prospective, randomized, double-blind study was to examine the effect of perioperative COX-2 inhibition on acute and chronic donor-site pain in patients undergoing spinal-fusion surgery. METHODS: Eighty patients scheduled to undergo instrumented posterior spinal fusion were randomized to either receive celecoxib 400 mg 1 hour before surgery, and then 200 mg every 12 hours after surgery for the first 5 days or receive matching placebo at similar time intervals. Patients were administered morphine via patient-controlled analgesia pump for the first 24 hours, and then acetaminophen and oxycodone tablets. Patients were asked to quantify their average pain on postoperative days 1 to 5. At 1 year after surgery, patients were questioned about the presence and subjective characteristics of any residual donor-site pain. RESULTS: Patients administered celecoxib reported lower pain scores and less opioid use during the first 5 postoperative days. Chronic donor-site pain was significantly higher (P<.01) in the placebo group (12 of 40, or 30%) compared with the celecoxib group (4 of 40, or 10%) at 1 year after surgery. CONCLUSIONS: The administration of celecoxib for the first 5 days after spinal-fusion surgery resulted in improved analgesia and a reduction in chronic donor-site pain at 1 year after surgery.

Analgesic efficacy of perioperative celecoxib in ambulatory arthroscopic knee surgery: a double-blind, placebo-controlled study.

PURPOSE: To examine whether celecoxib, administered perioperatively, reduces opioid consumption and opioid-related adverse effects, and provides effective analgesia, in patients undergoing ambulatory arthroscopic knee meniscectomy. METHODS: Patients (> or = 18 years) with diagnosed knee meniscus disease were given celecoxib (400 mg; n = 99) or placebo (n = 101) 1 hour before they underwent arthroscopic knee surgery; this was followed by celecoxib (200 mg) or placebo given postoperatively at their first request for pain medication. Surgery was performed with patients under general anesthesia (fentanyl, 1 to 3 microg/kg plus 0.25% intra-articular bupivacaine, 10 to 20 mL) administered at the index joint. Every 4 to 6 hours, patients were allowed 1 to 2 tablets of hydrocodone bitartrate 5 mg/acetaminophen 500 mg (and optional opioids as needed). All efficacy analyses were conducted in the modified intent-to-treat population. RESULTS: In the 24 hours following surgery, total opioid consumption was significantly reduced in the celecoxib group (3.6 tablets) compared with the placebo group (4.6 tablets; P = .009). Celecoxib was associated with significant reductions in opioid consumption compared with placebo at 10 to 12 hours (P = .005) and at 12 to 24 hours (P = .012). The percentage of placebo-treated patients (41%) who required opioid analgesics was significantly greater than the percentage of celecoxib-treated patients who required opioids (22%; P = .008) at 10 to 12 hours. Adverse events (AEs) were experienced by more patients in the placebo group (37%) than in the celecoxib group (18%). Incidences of opioid-related events, such as central nervous system disorders (12% v 3%, respectively) and constipation (5% v 1%, respectively), were higher in placebo-treated patients than in those given celecoxib. CONCLUSIONS: Perioperative administration of celecoxib plus optional opioids reduces the use of opioids and the occurrence of opioid-related AEs compared with treatment with placebo plus optional opioids given to patients undergoing arthroscopic knee meniscectomy. LEVEL OF EVIDENCE: Level I, randomized, double-blind, placebo-controlled, parallel-group study.

The effect of cyclooxygenase-2 inhibition on analgesia and spinal fusion.

BACKGROUND: Cyclooxygenase (COX)-2-specific inhibitors demonstrate analgesic efficacy comparable with that of conventional nonsteroidal anti-inflammatory drugs but are associated with reduced gastrointestinal side effects and an absence of antiplatelet activity. Thus, they can be administered to patients undergoing spinal fusion surgery without an added risk of bleeding. However, concerns regarding a possible deleterious effect on bone-healing have limited their routine use. Celecoxib, a COX-2 inhibitor, recently was approved for the treatment of acute pain. The goals of the present study were to examine the analgesic efficacy of celecoxib and to determine the incidence of nonunion at one year following spinal fusion surgery. METHODS: Eighty patients who were scheduled to undergo spinal fusion received either celecoxib or placebo one hour before the induction of anesthesia and every twelve hours after surgery for the first five postoperative days. Pain scores and morphine use were recorded one hour after arrival in the post-anesthesia care unit and at four, eight, twelve, sixteen, twenty, and twenty-four hours later. Intraoperative blood loss was recorded. The status of the fusion was determined radiographically at the time of the one-year follow-up. RESULTS: There were no differences in demographic data or blood loss between the two groups. Pain scores were lower in the celecoxib group at one, four, eight, sixteen, and twenty hours postoperatively. There were no differences between the two groups with regard to the pain scores at twelve and twenty-four hours postoperatively. Morphine use was lower in the celecoxib group at all postoperative time-intervals. There was no difference between the celecoxib group and the placebo group with regard to the incidence of nonunion at the time of the one-year follow-up (7.5% [three of forty] compared with 10% [four of forty]). CONCLUSIONS: The perioperative administration of celecoxib resulted in a significant reduction in postoperative pain and opioid use following spinal fusion surgery. In addition, the short-term administration of this COX-2-specific non-steroidal anti-inflammatory drug had no apparent effect on the rate of nonunion at the time of the one-year follow-up.

Acute pain following musculoskeletal injuries and orthopaedic surgery: mechanisms and management.

The undertreatment of acute pain associated with musculoskeletal conditions and surgical procedures is a focus of growing concern to orthopaedic surgeons. Fortunately, the armamentarium now includes recent advances in the understanding of how undertreated acute pain can lead to chronic pain, the development of new therapeutic agents, and new approaches to pain management. The concept of neuronal plasticity (the ability of neurons to profoundly alter their structure, function, or biochemical profile in response to repeated afferent sensory input) is now central to the understanding of the development of chronic pain from acute pain. Local inflammation in injured tissue increases the sensitization of specialized peripheral sensory neurons (nociceptors), leading to repeated afferent input into the central nervous system. Resolving inflammation before these events occur may prevent modifications in the central nervous system that lead to chronic pain. Therefore, it is important to reduce pain and inflammation at both the central and peripheral level. In addition to traditional agents (aspirin, nonspecific nonsteroidal anti-inflammatory drugs, opioids, local anesthetics, and regional blocks), more recently developed agents, such as cyclooxygenase-2 specific inhibitors, are now available. Combinations of these agents, as well as combinations of pharmacologic and nonpharmacologic approaches, are being used as multimodal therapy to treat the multiple sources of acute pain. Clinical practice guidelines for the management of acute pain now emphasize the incorporation of new knowledge into solid, evidence-based practice. This knowledge, combined with further understanding of the anatomic, physiologic, cellular, and molecular basis of pain, will provide the basis forfuture approaches to the management of acute pain in orthopaedic practice.

Complex regional pain syndrome.

Abnormal posttraumatic pain may delay recovery and severely impact health-related quality of life. The term complex regional pain syndrome describes abnormally intense and prolonged pain that is not related to tissue damage and is sometimes a sequela of injury. Various treatment strategies, including therapy, parental interventions, and peripheral surgery, are used to manage the condition.

Efficacy of celecoxib versus ibuprofen in the treatment of acute pain: a multicenter, double-blind, randomized controlled trial in acute ankle sprain.

Ankle sprain is a common acute soft-tissue injury that often results in pain, inflammation, and ecchymosis. In this multicenter, double-blind, randomized parallel-group study, 445 adult patients received celecoxib 400 mg/day, ibuprofen 2,400 mg/day, or placebo for 10 days. Patients had experienced grade 1 or 2 ankle sprains within 48 hours and had moderate to severe ankle pain. Patient's Global Assessment of Ankle Injury responses, given on days 4 and 8, showed that the celecoxib group improved significantly more than the placebo group did, with 67% of the celecoxib group versus 55% of the placebo group improving at day 4 (P < .05). Patient's Assessment of Ankle Pain Visual Analog Scale on Weight Bearing responses, also given on days 4 and 8, showed that celecoxib was as efficacious in the treatment of ankle sprain as the maximum therapeutic dosage of ibuprofen and that, compared with placebo, it reduced pain significantly more (P < .05). The celecoxib group recovered and returned to function earlier (after 5 days) than did either the placebo group (8 days) or the ibuprofen group (6 days); the celecoxib-placebo difference was significant. Celecoxib, a cyclo-oxygenase-2-specific inhibitor with platelet-function-sparing properties, may be useful as a multimodal adjuvant in the treatment of ankle sprain.

Efficacy and safety of intravenous tanezumab for the symptomatic treatment of osteoarthritis: 2 randomized controlled trials versus naproxen.

OBJECTIVE: Two studies evaluated efficacy and safety of tanezumab versus naproxen for treatment of knee or hip osteoarthritis (OA). METHODS: Randomized controlled studies [NCT00830063 (Study 1015, n=828) and NCT00863304 (Study 1018, n=840)] of subjects with hip or knee OA compared intravenous tanezumab (5 mg or 10 mg) to placebo and naproxen (500 mg twice daily). Coprimary outcomes were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function (0-10 numerical rating scale), and patient's global assessment of OA at Week 16. RESULTS: In both studies, tanezumab reduced pain versus placebo [least squares mean differences, 95% CI, tanezumab 5 mg: -1.21 (-1.72, -0.70); -1.13 (-1.65, -0.62); tanezumab 10 mg: -0.91 (-1.42, -0.40); -0.80 (-1.32, -0.29)], and improved function and global scores. Tanezumab 5 mg produced greater pain reduction [-0.76 (-1.28, -0.25); -0.69 (-1.21, -0.17)], and favorable functional and global outcomes versus naproxen. Pain reductions with tanezumab 10 mg versus naproxen did not reach significance, unlike functional (both studies) and global (1 study) outcomes; thus, tanezumab 10 mg was not superior to naproxen, and predefined statistical testing procedures were not met, allowing for conclusion of superiority of tanezumab 5 mg over naproxen despite replicated favorable coprimary outcomes. Tanezumab was associated with greater incidence of peripheral sensory adverse events (paresthesia, hyperesthesia, hypoesthesia, burning sensation), pain in extremity, peripheral edema, and arthralgia. Overall frequency and discontinuations as a result of adverse events were similar to placebo and naproxen. CONCLUSION: Tanezumab provides efficacious treatment of knee or hip OA and may have therapeutic utility in patients with OA who experience inadequate analgesia with nonsteroidal antiinflammatory drugs.

Safety evaluation of fospropofol for sedation during minor surgical procedures.

STUDY OBJECTIVE: To evaluate the safety of intravenous (IV) fospropofol when used to provide minimal to moderate sedation in patients undergoing minor surgical procedures. DESIGN: Phase 3, open-label, single-arm study. SETTING: Multi-center. PATIENTS: 123 ASA physical status I, II, III, and IV patients, aged>or=18 years. INTERVENTIONS: Patients were pretreated with fentanyl 50 microg before receiving an initial dose of IV fospropofol 6.5 mg/kg. Patients could receive up to 5 supplemental doses of fospropofol 1.63 mg/kg to reach a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score

Efficacy of celecoxib, a COX-2-specific inhibitor, and naproxen in the management of acute ankle sprain: results of a double-blind, randomized controlled trial.

OBJECTIVE: To assess the efficacy and safety of celecoxib and naproxen in the treatment of acute ankle sprain. DESIGN: Double-blind, parallel-group, randomized trial. SETTING: Multicenter outpatient. PATIENTS: Adult patients (n = 397) with acute first-degree or second-degree ankle sprain. INTERVENTIONS: Patients randomized to celecoxib 200 mg b.i.d. (n = 198) or naproxen 500 mg b.i.d. (n = 198) for 7 days. MAIN OUTCOME MEASURES: Primary measures of efficacy were Patient's Assessment of Ankle Pain Visual Analogue Scale (VAS) and Patient's Global Assessment of Ankle Injury. Secondary efficacy measures included Physician's Global Assessment of Ankle Injury, Patient's Return to Normal Function/Activity, and Patients' and Physicians' Satisfaction Assessments. Adverse events (AEs) were reported by investigators during the study. RESULTS: For the primary endpoints at day 4, the mean pain VAS scores were 31.9 mm +/- 1.96 for celecoxib and 29.0 mm +/- 1.91 for naproxen, and the responder rate for Patient's Global Assessment of Ankle Injury was 71% in the celecoxib group and 72% in the naproxen group, differences that were not statistically significant. In addition, noninferiority analysis demonstrated treatment differences that were within prespecified minimal clinical important differences. Gastrointestinal AEs were the most common AE, accounting for 14% in the celecoxib group and 21% in the naproxen group. The incidence of dyspepsia was 3% for celecoxib compared with 12% for naproxen (P = 0.032). CONCLUSIONS: Celecoxib is as effective as naproxen in treating acute first-degree or second-degree ankle sprains but causes significantly less dyspepsia.