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The purpose of this trial was to compare the efficacy, safety and side effects of post-operative pain therapy using oral controlled release formulations of tramadol and oxycodone.In a prospective, randomized, double-blind investigation, we observed the post-operative course of 57 patients scheduled for orthopedic surgery. We assessed pain at rest and during exercise, vital signs and side effects using direct measuring and Numerical Rating Scales over a period of three post-operative days. We used chi-squared or Fisher's exact test for categorical variables and the Mann–Whitney U-test for numerical variables (p < 0.05).Demographic medical data and pain levels did not differ between the two treatments. Parameters for vital signs remained stable. Nausea and emesis occurred significantly more frequently with tramadol (p = 0.011, p = 0.013). Despite insignificance, central effects such as sedation, insomnia, myoclonus or nightmares were more frequent with tramadol. During the post-operative period, dizziness and sedation were attenuated significantly in the tramadol group (p = 0.031, p = 0.015) as was dry mouth in the oxycodone group (p = 0.041).Our findings underline the efficacy of oral controlled release formulations of tramadol and oxycodone for post-operative pain therapy. Controlled release oxycodone was shown to cause less nausea and emesis than controlled release tramadol. Further investigation is needed in order to confirm these results.