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

Abstract

<jats:p>Tramadol and tapentadol are fully synthetic and extensively used analgesic opioids, presenting enhanced therapeutic and safety profiles as compared with their peers. However, reports of adverse reactions, intoxications and fatalities have been increasing. Information regarding the molecular, biochemical, and histological alterations underlying their toxicological potential is missing, particularly for tapentadol, owing to its more recent market authorization. Considering the paramount importance of liver and kidney for the metabolism and excretion of both opioids, these organs are especially susceptible to toxicological damage. In the present study, we aimed to characterize the putative hepatic and renal deleterious effects of repeated exposure to therapeutic doses of tramadol and tapentadol, using an in vivo animal model. Male Wistar rats were randomly divided into six experimental groups, composed of six animals each, which received daily single intraperitoneal injections of 10, 25 or 50 mg/kg tramadol or tapentadol (a low, standard analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively). An additional control group was injected with normal saline. Following 14 consecutive days of administration, serum, urine and liver and kidney tissue samples were processed for biochemical, metabolic and histological analysis. Repeated administration of therapeutic doses of both opioids led to: (i) increased lipid and protein oxidation in liver and kidney, as well as to decreased total liver antioxidant capacity; (ii) decreased serum albumin, urea, butyrylcholinesterase and complement C3 and C4 levels, denoting liver synthesis impairment; (iii) elevated serum activity of liver enzymes, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase, as well as lipid profile alterations, also reflecting hepatobiliary commitment; (iv) derangement of iron metabolism, as shown through increases in serum iron, ferritin, haptoglobin and heme oxygenase-1 levels. In turn, elevated serum cystatin C, decreased urine creatinine output and increased urine microalbumin levels were detected upon exposure to tapentadol only, while increased serum amylase and urine N-acetyl-β-D-glucosaminidase activities were observed for both opioids. Collectively, these results are compatible with kidney injury. Changes were also found in the expression levels of liver- and kidney-specific toxicity biomarker genes, upon exposure to tramadol and tapentadol, correlating well with alterations in lipid profile, iron metabolism and glomerular and tubular function. Histopathological analysis evidenced sinusoidal dilatation, microsteatosis, mononuclear cell infiltrates, glomerular and tubular disorganization, and increased Bowman’s spaces. Although some findings are more pronounced upon tapentadol exposure, our study shows that, when compared with acute exposure, prolonged administration of both opioids smooths the differences between their toxicological effects, and that these occur at lower doses within the therapeutic range.</jats:p>

Repeated Administration of Clinically Relevant Doses of the Prescription Opioids Tramadol and Tapentadol Causes Lung, Cardiac, and Brain Toxicity in Wistar Rats

“…Collectively, our results show that lung, heart, and brain cortex toxicological damage occurs at the biochemical, metabolic, and histological levels upon exposure to clinical doses of tramadol and tapentadol (Figure 9). As seen in our study addressing hepatorenal toxicity following consecutive opioid administration [57], lower therapeutic doses are able to induce injury if administered repeatedly. Damage accumulates along lengthier exposure periods than those we have previously assayed [55,56], but shorter than those employed in most peer studies.…”

“…Decreased brain glutathione, glutathione peroxidase, and superoxide dismutase (SOD) activities, as well as increased brain malondialdehyde (MDA), nitric oxide (NO), inducible nitric oxide synthase (iNOS), and 8-hidroxydeoxyguanosine levels, have been described in mice and rat models repeatedly administered with 20 to 168 mg/kg tramadol, through different routes [ 60 , 62 , 67 , 68 , 69 , 70 , 71 ]. Furthermore, under the conditions assayed in the present study, we have previously shown increased TBARS—a surrogate of lipid peroxidation (LPO)—and protein carbonyl groups—indicative of protein oxidation—in liver and kidney homogenates from Wistar rats exposed to both tramadol and tapentadol [ 57 ].…”

“…Comparison of tramadol and tapentadol safety profiles is justified by their structural and mechanistic similarities. However, when comparing their toxicological effects, differences in their pharmacokinetic and pharmacodynamic properties, including metabolic pathways, metabolite profiles, receptor, and transporter affinities [ 1 , 9 , 55 , 56 , 57 ], should be kept in mind. Additionally, intraperitoneally-injected drugs bypass the intestine, but are absorbed into the mesenteric vessels draining into the portal vein, thereby giving room for hepatic metabolism to occur before reaching systemic circulation [ 66 ].…”

“…Our results showed that, in acute contexts, tapentadol causes more pronounced toxic damage [ 54 , 55 , 56 ]. In a more recent study by our group, we showed that repeated administration of clinically relevant doses of tramadol and tapentadol smooths the differences between the toxicological profiles of both opioids, and that hepatorenal damage occurs at lower doses, when compared with acute exposure [ 57 ]. Several other studies with animal models were performed with high tramadol doses, in particular the median lethal dose (LD 50 ).…”

“…However, few studies were performed to understand the mechanisms associated with tapentadol toxicity, as underlined in their systematic review [ 29 ], since it is a more recent drug. In addition, there are few comparative studies on the long-term effects of clinical doses of tramadol or tapentadol [ 57 ], particularly in target tissues such as brain, heart, and lung.…”