Purpose: Poorly controlled pain is linked to several other undesirable outcomes. These outcomes are upsetting to patients, their families, and society as a whole. Although opioids and non-steroidal anti-inflammatory drugs are the cornerstone of the nociceptive pain treatment, the use of these drugs is restricted due to their side effects. Therefore, it is essential to develop new treatment alternatives for pain. Our study aimed to examine the pain relief effectiveness of Venlafaxine, Atomoxetine and Trazodone at 3 different doses alone, and in combination with each other in an acute pain model. Material and Methods: The analgesic effectiveness of Venlafaxine, Atomoxetine, and Trazodone at three different doses alone and in combination in an acute pain model in rats was examined using the hot plate and tail flick methods. Results: Venlafaxine and Trazodone, Venlafaxine showed dose-dependent analgesic effect when compared to the control. When Venlafaxine at dose of 2 mg/kg were combined with Atomoxetine at doses of 1, 3 and 6 mg/kg, the analgesic effects were significantly increased compared to these drugs alone. When Venlafaxine at dose of 2 mg/kg were combined with trazodone at doses of 4, 12 and 24 mg/kg, the analgesic effects were significantly increased compared to these drugs alone. Conclusion: All in all, our data suggest these combinations may offer a beneficial treatment option for acute pain in future.