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Celecoxib-tramadol co-crystal (CTC) is a first-in-class analgesic co-crystal of celecoxib and racemic tramadol with an improved pharmacologic profile, conferred by the co-crystal structure, compared with its active constituents administered alone/concomitantly.We evaluated CTC in moderate-to-severe acute postoperative pain.This randomized, double-blind, factorial, active- and placebo-controlled phase 3 trial (NCT03108482) was conducted at 6 US clinical research centers. Adults with moderate-to-severe acute pain following bunionectomy with osteotomy were randomized to oral CTC (200 mg [112 mg celecoxib/88 mg rac-tramadol hydrochloride] every 12 h), tramadol (50 mg every 6 h), celecoxib (100 mg every 12 h), or placebo for 48 h. Patients, investigators, and personnel were blinded to assignment. The primary endpoint was the 0-48 h sum of pain intensity differences (SPID0-48) in all randomized patients. Pain intensity was assessed on a 0-10 numerical rating scale (NRS). Safety was analyzed in patients who received study medication. Funded by ESTEVE Pharmaceuticals.In 2017 (March to November), 1323 patients were screened and 637 randomized to CTC (n = 184), tramadol (n = 183), celecoxib (n = 181), or placebo (n = 89). Mean baseline NRS was 6.7 in all active groups. CTC had a significantly greater effect on SPID0-48 (least-squares mean: -139.1 [95% confidence interval: -151.8, -126.5]) than tramadol (-109.1 [-121.7, -96.4]; p 0.001), celecoxib (-103.7 [-116.4, -91.0]; p 0.001), or placebo (-74.6 [-92.5, -56.6]; p 0.001). Total treatment-emergent adverse events (TEAEs) were 358 for CTC and 394 for tramadol. Drug-related TEAEs occurred in 37.7% patients in the CTC group, compared with 48.6% in the tramadol group. There were no serious TEAEs/deaths.CTC provided greater analgesia than comparable daily doses of tramadol and celecoxib, with similar tolerability to tramadol. CTC is approved in the United States.

Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p

The undertreatment of acute and chronic pain continues to be a significant health concern in the U.S. Opioids are recommended for the treatment of acute or chronic pain of moderate to severe intensity that is not responsive to other pharmacologic agents, such as nonsteroidal antiinflammatory drugs. A high level of interindividual responses to the analgesic effects and side effects of opioids necessitates the availability of multiple treatment options. Extended-release and immediate-release oral formulations of oxymorphone hydrochloride were recently approved by the U.S. Food and Drug Administration and may provide new options for patients who have not achieved adequate and well-tolerated analgesia with their current opioid. This review provides an overview of the basic pharmacology (including pharmacokinetic and pharmacodynamic profiles), clinical efficacy and tolerability of both oral oxymorphone formulations.

Background and objective: Opioid treatment has played a limited role in the management of diabetic neuropathy, in part because of concerns about the responsiveness of neuropathic pain to opioid treatment. This controlled study evaluated the efficacy and safety of controlled-release (CR) oxycodone in subjects with moderate to severe pain due to diabetic neuropathy. Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study included 159 subjects with moderate to severe pain due to diabetic neuropathy. Treatment began with either one 10-mg tablet of CR oxycodone (n = 82) or identical placebo (n = 77) every 12 hours. Doses could be increased every 3 days to a maximum of 6 tablets (60 mg CR oxycodone) every 12 hours. Treatment lasted up to 6 weeks. The primary efficacy variable was overall average daily pain intensity during study days 28 to 42. Results: At an average (SD) dose of 37 (21) mg per day (range 10 to 99 mg/d), CR oxycodone provided more analgesia than placebo ( p = 0.002) in the intent-to-treat cohort. From days 28 to 42, overall average daily pain intensity (least squares mean ±SE), rated in subject diaries on a numeric scale of 0 (no pain) to 10 (pain as bad as you can imagine), was 4.1 ± 0.3 in subjects given CR oxycodone and 5.3 ± 0.3 in placebo-treated subjects. Overall, 80 (96%) of 82 subjects given CR oxycodone and 52 (68%) of 77 subjects who received placebo reported adverse events. The most common adverse events in the CR oxycodone group were opioid related. Conclusions: In this 6-week trial, CR oxycodone was effective for the treatment of moderate to severe pain due to diabetic neuropathy. Adverse events were typical of opioid-related side effects.

This is a report on a University of Illinois Hospital series of cases of extracapsular base of the neck osteotomy for slipped capital femoral epiphyses. The osteotomy was performed on 20 hips in 16 patients, with a 71/2 year average follow-up. The results of this procedure are encouraging and illustrate the advantages of technical simplicity and minimal risk of avascular necrosis. The method does not create any additional deformity. The only disadvantage is that the correction could be limited. The maximum correction of posterior tilt was 55 degrees and the maximum correction of varus deformity was 50 degrees.