Tramadol and tapentadol are synthetic opioid analgesics widely used in the treatment of moderate to severe pain, both in acute and chronic settings. Their mechanism of action combines mu-opioid receptor agonism and neurotransmitter reuptake inhibition, acting synergistically to optimize analgesia and minimize side effects. However, adverse reactions, including serotonin syndrome and respiratory depression, have been reported, and their abuse potential has not been fully established. Since they are frequently used in a chronic context, often concomitantly with other drugs, the evaluation of their abuse, genotoxic and carcinogenic potential becomes relevant. The present study aims to evaluate the abuse potential of therapeutic doses of both opioids, sub-chronically administered to Wistar rats. Abuse- and anxiety-oriented behavioral studies, including conditioned place preference studies, will be performed upon intraperitoneal injection with tramadol, tapentadol, in single or combined administrations with naloxone, fluoxetine and MDMA. In addition, the putative genotoxic and carcinogenic effect of both opioids will be assessed by quantifying 8-OHdG levels in the same animals.