Tramadol hydrochloride extended-release once-daily in the treatment of osteoarthritis of the knee and/or hip: a double-blind, randomized, dose-ranging trial.

This 12-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial evaluated tramadol ER (extended-release tramadol) in the management of osteoarthritis pain. Adults with knee and/or hip osteoarthritis and baseline pain intensity of ≥40 on a 100-mm visual analog scale (0 = no pain, 100 = extreme pain) received once-daily tramadol ER 100 mg (n = 201), 200 mg (n = 199), or 300 mg (n = 199), celecoxib 200 mg (n = 202; to test model sensitivity), or placebo (n = 200). Coprimary efficacy variables were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, WOMAC physical function subscale, and patient global assessment of disease activity. Tramadol ER 300 mg significantly improved patient global assessment scores compared with placebo (P ≤ 0.05), but not the other 2 coprimary efficacy variables. Tramadol ER 200 and 100 mg were not significantly different from placebo for the coprimary efficacy variables. Daily diary arthritis pain intensity scores improved significantly for tramadol ER 300 and 200 mg compared with placebo. WOMAC joint stiffness subscale, physician's global assessment, arthritis pain intensity in index and nonindex joints, and overall sleep quality scores improved significantly for tramadol ER 300 mg compared with placebo. Significant differences in efficacy between celecoxib and placebo validated the model sensitivity. Adverse events occurred more frequently with tramadol ER than placebo in the gastrointestinal (nausea, constipation, diarrhea) and central nervous (dizziness, headache) systems. In this study, tramadol ER 300 mg was effective in the management of moderate to severe painful osteoarthritis of the hip or knee. A large, increasing placebo response during the study may have contributed to the lack of statistical separation between tramadol ER 200 or 100 mg and placebo.

Production of endothelin-1 and reduced blood flow in the rat kidney during lung-injurious mechanical ventilation.

INTRODUCTION: The mechanisms by which mechanical ventilation (MV) can injure remote organs, such as the kidney, remain poorly understood. We hypothesized that upregulation of systemic inflammation, as reflected by plasma interleukin-6 (IL-6) levels, in response to a lung-injurious ventilatory strategy, ultimately results in kidney dysfunction mediated by local endothelin-1 (ET-1) production and renal vasoconstriction. METHODS: Healthy, male Wistar rats were randomized to 1 of 2 MV settings (n=9 per group) and ventilated for 4 h. One group had a lung-protective setting using peak inspiratory pressure of 14 cm H2O and a positive end-expiratory pressure of 5 cm H2O; the other had a lung-injurious strategy using a peak inspiratory pressure of 20 cm H2O and positive end-expiratory pressure of 2 cm H2O. Nine randomly assigned rats served as nonventilated controls. We measured venous and arterial blood pressure and cardiac output (thermodilution method), renal blood flow (RBF) using fluorescent microspheres, and calculated creatinine clearance, urine flow, and fractional sodium excretion. Histological lung damage was assessed using hematoxylin-eosin staining. Renal ET-1 and plasma ET-1 and IL-6 concentrations were measured using enzyme-linked immunosorbent assays. RESULTS: Lung injury scores were higher after lung-injurious MV than after lung-protective ventilation or in sham controls. Lung-injurious MV resulted in significant production of renal ET-1 compared with the lung-protective and control groups. Simultaneously, RBF in the lung-injurious MV group was approximately 40% lower (P<0.05) than in the control group and 28% lower (P<0.05) than in the lung-protective group. Plasma ET-1 and IL-6 levels did not differ among the groups and systemic hemodynamics, such as cardiac output, were comparable. There was no effect on creatinine clearance, fractional sodium excretion, urine output, or kidney histology. CONCLUSIONS: Lung-injurious MV for 4 h in healthy rats results in significant production of renal ET-1 and in decreased RBF, independent of IL-6. Decreased RBF has no observable effect on kidney function or histology.