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Role of BeNzodiazepiNeS iN CaRdiaC SafeTy of low MeThadoNe doSeS iN paTieNTS duRiNg MeThadoNe MaiNTeNaNCe TReaTMeNT S. Petkovic ; V. Mijatovic ; I. Samojlik; S. Vukmirovic ; A. Dickov; and T. Popov Faculty of Medicine, University of Novi Sad, Vojvodina, Serbia; and Institute of Cardiovascular Diseases Vojvodina, Sremska Kamenica, Serbia Introduction: Despite the fact that most of health care professionals are aware of possible respiratory depressant effect of methadone and benzodiazepines coadministration, recently published data reveal that ventricular arrhythmia and cardiac arrest are currently the most frequent adverse event attributed to methadone and benzodiazepine comedication. The aim of this study is to assess cardiac safety of low methadone doses used concomitantely with benzodiazepines in opiate addicts in methadone maintenance treatment (MMT). Material and Methods: A clinical trial in which participated 30 opiate addicts at the start of MMT was performed. ECG (to calculate corrected QT (QTc) interval) and blood sampling (to determine methadone and diazepam concentrations ) were performed in all study participants at 3 time points (before the introduction of MMT, after 1 and 6 mo of MMT). Methadone and diazepam concentrations in serum were determined by using liquid chromatography-mass spectrometry (LC-MS). Results: The length of QTc interval before the introduction of MMT was 411.87 ± 27.22 ms, after 1 month of MMT 425.20 ± 17.71 ms and after 6 months of MMT 423.50 ± 14.72 ms. The mean methadone concentration at observed time points was 176.77 ± 118.56 ng/ mL and 342.86 ± 181.54 ng/mL, respectively, while the mean diazepam concentration was 560.74 ± 436.72 ng/mL and 1045.32 ± 932.72 ng/mL, respectively. There was a statistically significant increase in the length of QTc interval after 1 and 6 months of MMT in comparison to the value before the application of MMT. A statistically significant correlation between the concentration of methadone and QTc interval length after 1 and 6 months of MMT was observed and it remained statistically significant if concentration of diazepam was included. Conclusions: Further studies could clarify the possible role of benzodiazepines in the increasing cardiotoxicity of methadone in opiate addicts in MMT. Acknowledgement: The Ministry of Education and Science of the Republic of Serbia (grant numbered 41012) supported this research work.

e30 Volume 35 Number 8S Conclusion: LHA tends to accept EU requirements as much as it could match local regulation, but local regulation differs significantly from EU. As a consequence, LSU makes additional efforts and communications with LHA and Company, to fulfill each requirement in its own way. The differences could be overcome with harmonization of local regulation with EU and if LHA receive access to EudraVigilance database. Disclosure of Interest: None declared.