Vitamin E supplementation ameliorates the hepatotoxicity induced by Tramadol: toxicological, histological and immunohistochemical study

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

“…Signs of cellular degeneration, including nuclei fragmentation and poor definition, were increasingly apparent along with tramadol dose, while they were observed at all tapentadol doses, on whose slides hypopigmented areas could also be seen ( Figure 7 and Figure 8 ). Indeed, related cellular and tissue alterations, comprising necrosis, apoptosis, hydropic degeneration, karyolitic and pyknotic nuclei, cytolysis, tissue disorganization and loss of architecture, were reported in analogous studies using mainly tramadol, but also heroin, nalbuphine and morphine [ 71 , 73 , 76 , 77 , 78 , 79 , 81 , 84 , 85 , 87 , 88 , 90 , 92 , 93 , 94 , 95 ]. In turn, vascular congestion, with erythrocyte extravasation, was unique to tapentadol exposure ( Figure 7 ), as seen in our previous acute exposure assays [ 98 ].…”

“…Multiple studies report increased MDA levels in liver, kidney and serum upon opioid repeated administration, such as those from Awadalla, El-Gaafarawi, Elkhateeb, Ibrahim and their respective colleagues, who orally administered rats with 30 to 150 mg/kg tramadol, for 20 to 30 days [ 75 , 76 , 84 , 88 , 89 ], as well as similar studies with morphine [ 80 , 82 ] and heroin [ 90 ]. These studies have also associated tramadol exposure with decreased levels of antioxidant defenses, such as reduced glutathione, glutathione peroxidase, superoxide dismutase and catalase in liver and kidney tissues [ 76 , 84 , 88 ], as well as in serum [ 89 ]. Studies concerning repeated administration of morphine in mice have also led to similar results in liver [ 82 , 91 ].…”

“…In an attempt to further characterize the hepatic effects of tramadol exposure, several studies have also reported increased serum ALT, AST, ALP and GGT activities following repeated administration of rodents with doses ranging from 3 to 200 mg/kg, through different routes [ 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 81 , 84 ]. Analogous assays with morphine have led to similar results [ 80 , 82 , 87 ].…”

“…), intramuscular, subcutaneous), exposure periods ranging from acute to chronic, and doses ranging from therapeutic ones to overdoses. All have shown liver and kidney commitment, evidenced through increased liver enzyme activities, blood urea nitrogen (BUN), creatinine [ 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ], tissue oxidative markers (e.g., increased liver and kidney malondialdehyde (MDA) levels) [ 75 , 76 , 80 , 82 , 84 , 88 , 89 , 90 ], as well as through decreased antioxidant activity (e.g., decreased catalase, superoxide dismutase and glutathione peroxidase activities, decreased glutathione levels) [ 76 , 80 , 82 , 83 , 84 , 88 , 89 , 90 , 91 ]. Hepato- and nephrotoxicity were also observed at the histological level.…”

“…Hepato- and nephrotoxicity were also observed at the histological level. Liver histological findings include centrilobular congestion, cytolysis and sinusoidal dilatation [ 71 , 73 , 74 , 76 , 77 , 78 , 79 , 81 , 84 , 85 , 87 , 88 , 92 , 93 , 94 , 95 , 96 ], while kidney histopathology comprises endothelial cell swelling, atrophied glomeruli with collapsed tufts, wide Bowman’s spaces and interstitial nephritis; in turn, inflammatory cell infiltration, vacuolization, degeneration, focal necrosis, hemorrhage and fibrosis have been reported for both organs [ 71 , 74 , 76 , 77 , 78 , 81 , 84 , 85 , 88 , 95 ].…”