Effects of Tramadol Addiction on Brain of Adult Male Albino Rats and Role of lofexidine during Withdrawal Period: A Biochemical, Histopathological and Immunohistochemical Study

Document Type : Original Article


1 Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

2 Department of pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt.


Background: Tramadol is a synthetic opioid analgesic commonly prescribed for moderate to severe pain, becoming abused more popular among teens in most countries. In addition to the euphoric and mood-enhancing effects sought by tramadol abusers, taking this drug for nonmedical purposes, abusing tramadol can lead to tolerance and dependence. Abusers who continue to take tramadol long enough and at high enough doses will eventually develop a physical dependence on the drug and experience unpleasant, or even dangerous, symptoms of withdrawal if they stop taking the medication. Objective: To study the biochemical, histopathological and immunohistochemical changes of repeated administration of tramadol on the brain cells of male albino rats and role of duration of addiction in the damaging effects produced, and to prove if there is a role for lofexidine in the treatment of tramadol addiction in withdrawal period and detect the changes after recovery period and withdrawal of tramadol .Materials and methods: 100 adult male albino rats were randomly divided into equal 5groups: Group I: (20 rats) Control group: including those given normal feeding. Group II: (20 rats) Tramadol treated group for one month. Group III: (20 rats) Tramadol treated group for 2 months. Group IV: (20 rats) Tramadol treated for one month then given lofexidine for another month during withdrawal. Group V: (20 rats) Tramadol treated for one month and left for another month for recovery. Animals were observed for any behavioral changes throughout the research and recorded. At the end of the experiment animals were scarified by cervical dislocation under inhalation anesthesia, autopsy was done and the brain specimens were obtained, prepared for biochemical study for dopamine level and others preserved for histopathological and immunohistochemical study with their specific procedures. Results: Repeated Tramadol administration resulted in rats behavioral changes( restlessness, irritability defensive aggressive reactions) and produced decreased dopamine levels and significant brain damage in the histopathological and immunohistochemical study that increased with increased period of intake (The maximum damage was recorded in group III with two months tramadol administration, varying degrees of recovery after stoppage of intake were noted in Group V and more improvement by Lofexidine treatment in Group IV). Conclusions: Repeated Tramadol administration causes degenerative changes on the rat brain which increased with increasing the period of this administration. Some improvement was detected after stoppage and more improvement with Lofexidine treatment in withdrawal period.