Background DN (diabetic neuropathy) is a common disorder and two thirds of diabetic patients have clinical or subclinical neuropathy. Pain in DN can be spontaneous or stimulus induced and aggravate in nights. µ-opioid receptor make weak-reply to an antinociceptive effect of opioid agonist but κ-opioid receptors create antinociceptive response appropriately. Methods Diabetic animals were treated intraperitoneally for 3weeks in 9 groups including different doses of oxycodone and codeine with constant dose of metformin (200mg/kg). The normal saline group was considered as a negative control group and diabetic group as positive control. After 3 weeks Hot plate and tail flic test were done and fasting blood glucose was measured. After that Animals were sacrificed and oxidative stress biomarkers including lipid peroxidation, protein carbonyl content, and glutathione content were measured in brain and liver isolated mitochondria. Conclusion In this study finding demonstrated that Oxycodone (high dose 8mg/kg) with effect on both µ-opioid receptor and κ-opioid receptor significantly enhances the effects of metformin therapy in mices with painful diabetic neuropathy. In addition, opioid drugs induced stress oxidative and MDA formation in brain and liver.As well as, in diabetic mices, glucose level in all drug groups significantly decreased in compared to positive diabetic group.