**11. Carcinogenic effects**

In long-term studies on rats and mice, no tramadol-attributed carcinogenic changes were detected. Histopathologic evaluations showed increased risk of hepatic adenoma in the males and non dose-related pulmonary adenoma in females. No specific mutations or chromosomal impairments were detected in rats, mice, or hamsters due to tramadol use. In skin and eye tests, tramadol had weak corrosive effects on the white rabbits' eyes but no irritating changes on their skin [2]. Oral administration of tramadol was reported to have no carcinogenic effects on the mice and rats. No mutations or increased risk of gene toxicity were detected in humanbeings, either [17].

Tramadol can cause urinary retention because of opioid agonistic effects that can increase the tonicity of the bladder sphincter [68]. Also, it was shown to have hazardous effects on the growth, survival, and reproduction system of Daphnia Magna with the most effects on the latter. Long-term exposures decreased expression of the *vtg* gene which is an important biomarker in the reproduction of the oviparous animals [64,95].

In a study by Matthiesen et al, low dose of tramadol had no effect on the fertility, giving birth, and lactation of the rats and had no teratogenic effects on the fetus [17]. These results are however in contrast to the results withdrawn by Bornas who mentioned that laboratory studies had confirmed the teratogenic effects of tramadol on the animals. Tramadol and M1 metabolite can cross the placenta easily because of their low molecular weights [55].
