Tramadol-Induced Organ Toxicity via Oxidative Stress : A Review Study
International Journal of Medical Toxicology and Forensic Medicine,
Vol. 12 No. 1 (2022),
13 January 2022
,
Page 35430
https://doi.org/10.32598/ijmtfm.v12i1.35430
Abstract
Background: Tramadol (TR) is a synthetic opioid-like centrally acting analgesic used for moderate to severe pain management in various diseases. Numerous investigations have supported the association between tramadol use and increased levels of oxygen-free radicals. Mass production of reactive oxygen species produces secondary toxic compounds. This could damage the internal components of the cell and ultimately causes organ damage. There exists a growing trend of tramadol abuse and the increasing reports of poisoning, abuse, and mortality due to this drug. Thus, the present study aimed to review the animals and human studies on the effects of acute and chronic exposure of tramadol in inducing organ toxicities through oxidative stress.
Methods: Pubmed, Google Scholar, and Scopus bibliographic databases were searched for studies that investigated oxidative stress as a mechanism of toxicity by tramadol. A manual search of reference lists of the retrieved articles was conducted. Data were collected from 2000 to 2021 (up to June 2021).
Results: From 28 articles concerning experimental and human studies of TR-induced oxidative stress organ damage, which included in this review, the occurrence of lipid peroxidation, alteration in the levels of total antioxidant capacity, and other oxidative stress biomarkers in many organs such as the brain, liver, kidney, adrenal and lung in the experimental studies of tramadol exposure have been observed.
Conclusion: Oxidative stress could be considered the most critical toxic mechanism in TR-induced tissue damage.
- Tramadol
- Reactive oxygen species
- Oxidative stress
- Toxicity
How to Cite
References
Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clincal Pharmacokinetics. 2004; 43(13):879-923. [DOI:10.2165/00003088-200443130-00004]
Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R. Trends in tramadol: Pharmacology, metabolism, and misuse. Anesthesia and Analgesia. 2017;124(1):44-51.[DOI: 10.1213/ANE.0000000000001683]
Faria J, Barbosa J, Moreira R, Queirós O, Carvalho F, Dinis-Oliveira RJ. Comparative pharmacology and toxicology of tramadol and tapentadol. European Journal of Pain. 2018 ;22(5):827-844. [DOI: 10.1002/ejp.1196]
Shalaby AM, Aboregela AM, Alabiad MA, El Shaer DF. Tramadol promotes oxidative stress, fibrosis, apoptosis, ultrastructural and biochemical alterations in the adrenal cortex of adult male rat with possible reversibility after withdrawal. Microscopy and Microanalysis. 2020; 26(3):509-523. [DOI:10.1017/S1431927620001397]
Vazzana M, Andreani T, Fangueiro J, Faggio C, Silva C, Santini A, et al. Tramadol hydrochloride: Pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomedicine and Pharmacotherapy. 2015; 70:234-238. [DOI:10.1016/j.biopha.2015.01.022]
Abdel-Hamid IA, Andersson KE, Waldinger MD, Anis TH. Tramadol Abuse and Sexual Function. Sexual Medicine Reviews. 2016;4(3):235-246. [DOI: 10.1016/j.sxmr.2015.10.014]
Shadnia S, Soltaninejad K, Heydari K, Sasanian G, Abdollahi M. Tramadol intoxication: A review of 114 cases. Human and Experimaental Toxicology. 2008; 27(3):201-205. [DOI:10.1177/0960327108090270] [PMID]
Daubin C, Quentin C, Goullé JP, Guillotin D, Lehoux P, Lepage O, Charbonneau P. Refractory shock and asystole related to tramadol overdose. Clinical Toxicology (Phila). 2007;45(8):961-4. [DOI: 10.1080/15563650701438847]
Clarkson JE, Lacy JM, Fligner CL, Thiersch N, Howard J, Harruff RC, et al. Tramadol (Ultram) concentrations in death investigation and impaired driving cases and their significance. Journal of Forensic Science. 2004; 49(5):1101-1105. [PMID]
Clarot F, Goullé JP, Vaz E, Proust B. Fatal overdoses of tramadol: Is benzodiazepine a risk factor of lethality? Forensic Science International. 2003;134(1):57-61. [DOI: 10.1016/s0379-0738(03)00100-2]
Awadalla EA, Salah-Eldin A-E. Histopathological and molecular studies on tramadol mediated hepato-renal toxicity in rats. IOSR Journal of Pharmacy and Biological Sciences. 2015;10(6):90-102. [DOI:10.9790/3008-10639010]
Nazifi S, Tabrizi AS, Mohammadi S, Erjaee H, Mirzaie A. The effect of tramadol and meloxicam, alone and in combination on oxidative stress status in dogs. Comparative Clinical Pathology. 2019; 28:1055–1060. [DOI.org/10.1007/s00580-019-02927-w]
Ali HA, Afifi M, Saber TM, Makki AA, Keshta AT, Baeshen M, et al. Neurotoxic, hepatotoxic and nephrotoxic effects of tramadol administration in rats. Journal of Molecular Neuroscience. 2020; 70(12):1934-1942. [DOI:10.1007/s12031-020-01592-x]
Baghishani F, Mohammadipour A, Hosseinzadeh H, Hosseini M, Ebrahimzadeh-Bideskan A. The effects of tramadol administration on hippocampal cell apoptosis, learning and memory in adult rats and neuroprotective effects of crocin. Metabolic Brain Disease. 2018; 33(3):907-916. [DOI:10.1007/s11011-018-0194-6]
Simeon GG, Abbey ST. Some marker enzymes and histological alteration on the administration of tramadol hydrochloride on rat liver. Modern Research in Inflammation. 2014; 3(2):48-58. [DOI:10.4236/mri.2018.71002]
Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, et al. Oxidative stress: harms and benefits for human health. Oxidative Medicine and Cellular Longevity. 2017; 2017:8416763. [DOI:10.1155/2017/8416763] [PMID]
Sajja RK, Rahman S, Cucullo L. Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress. Journal of Cerebral Blood Flow and Metabolism. 2016;36(3):539-54. [DOI: 10.1177/0271678X15616978]
Soltaninejad K, Abdollahi M. Current opinion on the science of organophosphate pesticides and toxic stress: a systematic review. Medical Science Monitor. 2009;15(3):RA75-90. [PMID]
Dandekar A, Mendez R, Zhang K. Cross talk between ER stress, oxidative stress, and inflammation in health and disease. Methods in Molecular Biology. 2015;1292:205-14.[DOI: 10.1007/978-1-4939-2522-3_15]
Mohamed HM, Mahmoud AM. Chronic exposure to the opioid tramadol induces oxidative damage, inflammation and apoptosis, and alters cerebral monoamine neurotransmitters in rats. Biomedicine and Pharmacotherapy. 2019; 110:239-247. [DOI:10.1016/j.biopha.2018.11.141]
Bameri B, Shaki F, Ahangar N, Ataee R, Samadi M, Mohammadi H. Evidence for the involvement of the dopaminergic system in seizure and oxidative damage induced by tramadol. International Journal of Toxicology. 2018; 37(2):164-170. [DOI:10.1177/1091581817753607]
Carrillo-Munguía N, González-Trujano ME, Huerta M, Trujillo X, Díaz-Reval MI. Tramadol and tramadol+ caffeine synergism in the rat formalin test are mediated by central opioid and serotonergic mechanisms. BioMed Research International. 2015; 2015:686424. [DOI:10.1155/2015/686424] [PMID]
Mohamed TM, Ghaffar HMA, El Husseiny RM. Effects of tramadol, clonazepam, and their combination on brain mitochondrial complexes. Toxicology and Industrial Health. 2015; 31(12):1325-1333. [DOI:10.1177/0748233713491814] [PMID]
Bloms-Funke P, Dremencov E, Cremers T, Tzschentke T. Tramadol increases extracellular levels of serotonin and noradrenaline as measured by in vivo microdialysis in the ventral hippocampus of freely-moving rats. Neurosci Letters. 2011; 490(3):191-195. [DOI:10.1016/j.neulet.2010.12.049] [PMID]
Hussein SA, Abdel Aal SAL. Neurodegeneration and oxidative stress induced by tramadol administration in male rats: The effect of its withdrawal. Benha Veterinary Medical Journal. 2017; 33(2):149-159. [DOI:10.21608/bvmj.2017.30017]
Zhuo HQ, Huang L, Huang HQ, Cai Z. Effects of chronic tramadol exposure on the zebrafish brain: a proteomic study. Journal of Proteomics. 2012;75(11):3351-64. [DOI: 10.1016/j.jprot.2012.03.038]
Raj K, Gupta GD, Singh S. l-Theanine ameliorates motor deficit, mitochondrial dysfunction, and neurodegeneration against chronic tramadol induced rats model of Parkinson's disease. Drug and Chemical Toxicology. 2021;1-12. [DOI: 10.1080/01480545.2021.1907909]
Sarhan NR, Taalab YM. Oxidative stress/PERK/apoptotic pathways interaction contribute to tramadol neurotoxicity in rat cerebral and cerebellar cortex and thyme enhances the antioxidant defense system: Histological, immunohistochemical and ultrastructural study. International Journal of Scientific Reports. 2018; 4(6):124. [DOI:10.18203/issn.2454-2156.IntJSciRep20182083]
Ghoneim FM, Khalaf HA, Elsamanoudy AZ, Helaly AN. Effect of chronic usage of tramadol on motor cerebral cortex and testicular tissues of adult male albino rats and the effect of its withdrawal: Histological, immunohistochemical and biochemical study. International Journal of Clinical and Experimental Pathology. 2014; 7(11):7323-7341. [PMID: 25550769]
Faria J, Barbosa J, Leal S, Afonso LP, Lobo J, Moreira R, et al. Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats. Toxicology. 2017; 385:38-47. [DOI:10.1016/j.tox.2017.05.003]
Barbosa J, Faria J, Garcez F, Leal S, Afonso LP, Nascimento AV, et al. Repeated administration of clinically relevant doses of the prescription opioids tramadol and tapentadol causes lung, cardiac, and brain toxicity in wistar rats. Pharmaceuticals. 2021; 14(2):97. [DOI:10.3390/ph14020097]
Albrakati A. Neuroprotective effect of physical exercise on neuronal apoptosis induced by tramadol in cerebral cortex of rats. Biointerface Research in Applied Chemistry. 2020; 10:7209-7222. [DOI:10.33263/BRIAC106.72097222]
Samadi M, Shaki F, Bameri B, Fallah M, Ahangar N, Mohammadi H. Caffeine attenuates seizure and brain mitochondrial disruption induced by Tramadol: the role of adenosinergic pathway. Drug and Chemical Toxicology. 2019; 1-7. [DOI:10.1080/01480545.2019.1643874]
Mohammadipour A, Hosseini M, Fazel A, Haghir H, Rafatpanah H, Pourganji M, et al. The effects of exposure to titanium dioxide nanoparticles during lactation period on learning and memory of rat offspring. Toxicology and Industrial Health. 2016; 32(2):221-228. [DOI:10.1177/0748233713498440]
Daulatzai MA. Neurotoxic saboteurs: straws that break the hippo's (hippocampus) back drive cognitive impairment and Alzheimer's disease. Neurotoxicology Reseach. 2013; 24(3):407-459. [DOI: 10.1007/s12640-013-9407-2 ]
Cui K, Luo X, Xu K, Ven Murthy MR. Role of oxidative stress in neurodegeneration: recent developments in assay methods for oxidative stress and nutraceutical antioxidants. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2004; 28(5):771-799. [DOI:10.1016/j.pnpbp.2004.05.023]
Abdel-Zaher AO, Abdel-Rahman MS, Elwasei FM. Protective effect of Nigella sativa oil against tramadol-induced tolerance and dependence in mice: Role of nitric oxide and oxidative stress. Neurotoxicology. 2011; 32(6):725-733. [DOI:10.1016/j.neuro.2011.08.001]
Sadek KM, Lebda MA, Abouzed TK, Nasr SM, El-Sayed Y. The molecular and biochemical insight view of lycopene in ameliorating tramadol-induced liver toxicity in a rat model: Implication of oxidative stress, apoptosis, and MAPK signaling pathways. Environmental Science and Pollution Research (international). 2018; 25(33):33119-130. [DOI:10.1007/s11356-018-3265-7]
Owoade A, Adetutu A, Olorunnisola O. Hematological and biochemical changes in blood, liver and kidney tissues under the effect of tramadol treatment. Journal of Alcohol and Drug Dependence. 2019; 7(327):2. [DOI:10.4172/2329-6488.1000326]
Barbosa J, Faria J, Garcez F, Leal S, Afonso LP, Nascimento AV, et al. Repeated administration of clinical doses of tramadol and tapentadol causes hepato-and nephrotoxic effects in wistar rats. Pharmaceuticals (Basel). 2020; 13(7):149. [DOI:10.3390/ph13070149]
Abdel-Aal FS, Al-Shahed FZ, F Al-Saeed H. Effects of camel's milk supplementation on adult male albino rats subjected to tramadol-induced nephrotoxicity. Al-Azhar Medical Journal. 2016; 45(2):345-364. [DOI:10.12816/0029134]
Salah H, Eldamaty E, Eldamaty H. Protective effects of barley and wheat grasses on nephrotoxicity in rats and some biochemical parameters induced by tramadol. Egypt Journal of Nutrition and Health. 2020; 15(1):67-83. [DOI:10.21608/ejnh.2020.117339]
Arafa MH, Atteia HH. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6) are associated with long term tramadol treatment-induced oxidative damage and hepatotoxicity. Toxicology and Applied Pharmacology. 2018; 346:37-44. [DOI:10.1016/j.taap.2018.03.019]
Abdelaleem SA, Hassan OA, Ahmed RF, Zenhom NM, Rifaai RA, El-Tahawy NF. Tramadol induced adrenal insufficiency: Histological, immunohistochemical, ultrastructural, and biochemical genetic experimental study. Journal of Toxicology. 2017; 2017:9815853. [DOI:10.1155/2017/9815853]
Ahmed MA, Kurkar A. Effects of opioid (tramadol) treatment on testicular functions in adult male rats: The role of nitric oxide and oxidative stress. Clinical and Experimental Pharmacology and Physiology. 2014; 41(4):317-323. [DOI:10.1111/1440-1681.12213]
Agarwal A, Prabakaran SA. Mechanism, measurement, and prevention of oxidative stress in male reproductive physiology. Indian Journal of Experimental Biology. 2005; 43(11):963-974. [PMID: 16315393]
Nna VU, Osim EE. Testicular toxicity following separate and combined administration of PDE5 inhibitors and opioid: Assessment of recovery following their withdrawal. Andrologia. 2017; 49(6). [DOI:10.1111/and.12669]
Koohsari M, Ahangar N, Mohammadi E, Shaki F. Ameliorative effect of melatonin against reproductive toxicity of tramadol in rats via the regulation of oxidative stress, mitochondrial dysfunction, and apoptosis-related gene expression signaling pathway. Addiction and Health. 2020; 12(2):118-129. [DOI:10.22122/ahj.v12i2.265]
Ibrahim MA, Salah-Eldin AE. Chronic addiction to tramadol and withdrawal effect on the spermatogenesis and testicular tissues in adult male albino rats. Pharmacology. 2019; 103(3-4):202-211. [DOI:10.1159/000496424]
Abd HH, Ahmed HA, Mutar TF. Moringa oleifera leaves extract modulates toxicity, sperms alterations, oxidative stress, and testicular damage induced by tramadol in male rats. Toxicology Research (Camb). 2020; 24;9(2):101-106. [DOI:10.1093/toxres/tfaa009]
Bilir A, Erkasap N, Koken T, Gulec S, Kaygisiz Z, Tanriverdi B, et al. Effects of tramadol on myocardial ischemia-reperfusion injury. Scandinavian Cardiovascular Journal. 2007; 41(4):242-247. [DOI:10.1080/14017430701227747]
Takhtfooladi HA, Takhtfooladi MA, Karimi P, Asl HA, Mobarakeh SZ. Influence of tramadol on ischemia-reperfusion injury of rats' skeletal muscle. International Journal of Surgery. 2014;12(9):963-8. [DOI: 10.1016/j.ijsu.2014.07.015]
Mahmoud MF, Gamal S, Shaheen MA, El-Fayoumi HM. The effects of tramadol on hepatic ischemia/reperfusion injury in rats. Indian Journal of Pharmacology. 2016;48(3):275-80. [DOI: 10.4103/0253-7613.182882]
- Abstract Viewed: 797 times
- PDF Downloaded: 734 times