Background: Estimate the expenditure of computer-related worktime resulting from the use of clinical decision support systems (CDSS) to prevent adverse drug reactions (ADR) among patients undergoing chronic pain therapy and compare the employed check systems with respect to performance and practicability. Methods: Data were collected retrospectively from 113 medical records of patients under chronic pain therapy during 2012/2013. Patient-specific medications were checked for potential drug-drug interactions (DDI) using two publicly available CDSS, Apotheken Umschau (AU) and Medscape (MS), and a commercially available CDSS AiDKlinik (R) (AID). The time needed to analyze patient pharmacotherapy for DDIs was taken with a stopwatch. Measurements included the time needed for running the analysis and printing the results. CDSS were compared with respect to the expenditure of time and usability. Only patient pharmacotherapies with at least two prescribed drugs and fitting the criteria of the corresponding CDSS were analyzed. Additionally, a qualitative evaluation of the used check systems was performed, employing a questionnaire asking five pain physicians to compare and rate the performance and practicability of the three CDSSs. Results: The AU tool took a total of 3:55:45 h with an average of 0:02:32 h for 93 analyzed patient regimens and led to the discovery of 261 DDIs. Using the Medscape interaction checker required a total of 1:28:35 h for 38 patients with an average of 0:01:58 h and a yield of 178 interactions. The CDSS AID required a total of 3:12:27 h for 97 patients with an average time of analysis of 0:01:59 h and the discovery of 170 DDIs. According to the pain physicians the CDSS AID was chosen as the preferred tool. Conclusions: Applying a CDSS to examine a patients drug regimen for potential DDIs causes an average extra expenditure of work time of 2:09 min, which extends patient treatment time by 25 % on average. Nevertheless, the authors believe that the extra expenditure of time employing a CDSS is outweighed by their benefits, including reduced ADR risks and safer clinical drug management.