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

Abstract

Tramadol and tapentadol, two structurally related synthetic opioid analgesics, are widely prescribed due to the enhanced therapeutic profiles resulting from the synergistic combination between μ-opioid receptor (MOR) activation and monoamine reuptake inhibition. However, the number of adverse reactions has been growing along with their increasing use and misuse. The potential toxicological mechanisms for these drugs are not completely understood, especially for tapentadol, owing to its shorter market history. Therefore, in the present study, we aimed to comparatively assess the putative lung, cardiac, and brain cortex toxicological damage elicited by the repeated exposure to therapeutic doses of both prescription opioids. To this purpose, male Wistar rats were intraperitoneally injected with single daily doses of 10, 25, and 50 mg/kg tramadol or tapentadol, corresponding to a standard analgesic dose, an intermediate dose, and the maximum recommended daily dose, respectively, for 14 consecutive days. Such treatment was found to lead mainly to lipid peroxidation and inflammation in lung and brain cortex tissues, as shown through augmented thiobarbituric acid reactive substances (TBARS), as well as to increased serum inflammation biomarkers, such as C reactive protein (CRP) and tumor necrosis factor-α (TNF-α). Cardiomyocyte integrity was also shown to be affected, since both opioids incremented serum lactate dehydrogenase (LDH) and α-hydroxybutyrate dehydrogenase (α-HBDH) activities, while tapentadol was associated with increased serum creatine kinase muscle brain (CK-MB) isoform activity. In turn, the analysis of metabolic parameters in brain cortex tissue revealed increased lactate concentration upon exposure to both drugs, as well as augmented LDH and creatine kinase (CK) activities following tapentadol treatment. In addition, pneumo- and cardiotoxicity biomarkers were quantified at the gene level, while neurotoxicity biomarkers were quantified both at the gene and protein levels; changes in their expression correlate with the oxidative stress, inflammatory, metabolic, and histopathological changes that were detected. Hematoxylin and eosin (H & E) staining revealed several histopathological alterations, including alveolar collapse and destruction in lung sections, inflammatory infiltrates, altered cardiomyocytes and loss of striation in heart sections, degenerated neurons, and accumulation of glial and microglial cells in brain cortex sections. In turn, Masson’s trichrome staining confirmed fibrous tissue deposition in cardiac tissue. Taken as a whole, these results show that the repeated administration of both prescription opioids extends the dose range for which toxicological injury is observed to lower therapeutic doses. They also reinforce previous assumptions that tramadol and tapentadol are not devoid of toxicological risk even at clinical doses.

Inflammatory Biomarkers in Addictive Disorders

“…The chronic use of opioids produces dependence, tolerance, and addiction that are mediated by immune dysregulation ( Table 7 ). Chronic opioid administration up-regulates peripheral IL-6, IL-1β, TNFα, CRP [ 131 , 134 , 135 ]. Moreover, opioid exposure in the prenatal period can impact the peripheral inflammatory profile after birth, as shown by increased serum levels of IL-1β, IL-6, TNFα, and CXCL1, with IL-1β continuing to be increased for over a month.…”

Tramadol-Induced Organ Toxicity via Oxidative Stress : A Review Study

“…Protein Carbonylation (PC) decreased in all experimental doses. No change in SOD, CAT, and caspase-3 activity was observed at all tested doses in the brain [30].…”

“…TR at a low dose has a protective effect. The activity of caspase-3 in the heart tissue decreased at all doses, and no change in lung tissue [30].…”

“…Hussein et al argued that the administration of TR in therapeutic (22.5 mg/kg) and overdoses (30,60, & 90 mg/kg) levels for 9 weeks in albino rats induced a significant increase of MDA and 8-OHdG levels, DNA fragmentation, and caspase-3 activity. Also, a significant decrease of SOD and CAT activities occurred in the brain tissue in therapeutic and overdose groups [25].…”

Therapeutic Potential of the Purinergic System in Major Depressive Disorder Associated with COVID-19

“…Specifically, tramadol can cause respiratory depression which would result in worsening the outcome of COVID-19. As for all other diseases resulting from the disease, the drug can histologically damage the lungs, heart and cerebral cortex, as it increases inflammatory modulation, increasing levels of CRP and TNF-α (Barbosa et al 2021 ).…”