Abstract Opioids such as tramadol, are powerful analgesics and used extensively in the clinical management of severe and chronic pain but also are drugs of abuse. This study was designed to evaluate the histologic changes in rat brain cortex due to chronic use of tramadol at different doses. Forty male albino rats weighing (175–225 g) were included and divided equally into 4 groups. Control group (1st group) was given distilled water orally. The treated groups (2nd, 3rd and 4th groups) received tramadol orally at doses of 10, 20, and 40 mg/kg/day respectively. All rats were sacrificed on the 30th day and the brains were removed. Sections of each brain block were examined by light and electron microscopes. The presence and the number of apoptotic neurons were investigated in the cerebral cortex as well as in the hippocampal region by using AnalySIS LS Report 2005, Soft Imaging System GmbH software. The total number of apoptotic neurons in low dose of tramadol group (3% of total nerve cells) was not significantly different as compared with the control group. The number of apoptotic neurons was significantly higher in both moderate (12 %) and high doses (17 %) of tramadol groups as compared with the control (p< 0.05). In conclusion, these results suggest that, chronic use of tramadol of moderate and high doses was found to cause neuronal degeneration in the rat brain, which probably contributes to cerebral dysfunction. These findings should be taken into consideration when long-term use of tramadol is indicated. Keywords: tramadol, opioid, apoptosis, neurotoxicity