{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T17:28:54Z","timestamp":1770226134027,"version":"3.49.0"},"reference-count":187,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T00:00:00Z","timestamp":1611705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Tramadol and tapentadol, two structurally related synthetic opioid analgesics, are widely prescribed due to the enhanced therapeutic profiles resulting from the synergistic combination between \u03bc-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-\u03b1 (TNF-\u03b1). Cardiomyocyte integrity was also shown to be affected, since both opioids incremented serum lactate dehydrogenase (LDH) and \u03b1-hydroxybutyrate dehydrogenase (\u03b1-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 &amp; 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/ph14020097","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T12:20:26Z","timestamp":1611750026000},"page":"97","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Repeated Administration of Clinically Relevant Doses of the Prescription Opioids Tramadol and Tapentadol Causes Lung, Cardiac, and Brain Toxicity in Wistar Rats"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2236-1029","authenticated-orcid":false,"given":"Joana","family":"Barbosa","sequence":"first","affiliation":[{"name":"IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal"},{"name":"UCIBIO, REQUI<i>M<\/i>TE\u2014Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7753-0219","authenticated-orcid":false,"given":"Juliana","family":"Faria","sequence":"additional","affiliation":[{"name":"IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal"},{"name":"UCIBIO, REQUI<i>M<\/i>TE\u2014Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Fernanda","family":"Garcez","sequence":"additional","affiliation":[{"name":"IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal"}]},{"given":"Sandra","family":"Leal","sequence":"additional","affiliation":[{"name":"IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal"},{"name":"Department of Biomedicine, Unit of Anatomy, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"CINTESIS\u2014Center for Health Technology and Services Research, Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal"}]},{"given":"Lu\u00eds Pedro","family":"Afonso","sequence":"additional","affiliation":[{"name":"Department of Pathology, Portuguese Institute of Oncology of Porto, 4200-072 Porto, Portugal"}]},{"given":"Ana Vanessa","family":"Nascimento","sequence":"additional","affiliation":[{"name":"IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal"}]},{"given":"Roxana","family":"Moreira","sequence":"additional","affiliation":[{"name":"IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal"}]},{"given":"Frederico C.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Experimental Therapeutics\/iCBR, Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal"}]},{"given":"Od\u00edlia","family":"Queir\u00f3s","sequence":"additional","affiliation":[{"name":"IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3858-3494","authenticated-orcid":false,"given":"F\u00e9lix","family":"Carvalho","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUI<i>M<\/i>TE\u2014Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7430-6297","authenticated-orcid":false,"given":"Ricardo Jorge","family":"Dinis-Oliveira","sequence":"additional","affiliation":[{"name":"IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal"},{"name":"UCIBIO, REQUI<i>M<\/i>TE\u2014Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/ejp.1196","article-title":"Comparative pharmacology and toxicology of tramadol and tapentadol","volume":"22","author":"Faria","year":"2018","journal-title":"Eur. 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