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Hematological and Biochemical Changes in Blood Liver and Kidney Tissues under the Effect of Tramadol Treatment Abiodun Olusoji Owoade Adewale Adetutu and Olubukola Sinbad Olorunnisola Department of Biochemistry Ladoke Akintola University of Technology Ogbomosho Nigeria Corresponding author: Abiodun Olusoji Owoade Department of Biochemistry Ladoke Akintola University of Technology Ogbomosho Nigeria Tel: +2348068013304 E-mail: aoowoadelautech.edu.ng Received date: March 21 2019 Accepted date: April 15 2019 Published date: April 20 2019 Copyright: ©2019 Owoade AO et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use distribution and reproduction in any medium provided the original author and source are credited. Abstract This study aimed to investigate the effects of tramadol administration on some haematological and biochemical indices in rats. Tramadol was administered orally to rats for 28 days at a dose of 10 mg/kg body weight/day 50 mg/kg body weight/day and 100 mg/kg body weight/day. Twenty-four hours after the last tramadol blood liver and kidney were removed from the animals after an overnight fast and analysed for their haematological and biochemical parameters. Results obtained revealed that tramadol administration significantly reduced the levels of white blood cells WBC red blood cell RBC haemoglobin and platelet count PLT while its resulted in non-significant changes in other haematological parameters examined when compared with control rats. Tramadol intake significantly increased plasma levels of alkaline phosphatase ALP aspartate aminotransferase AST creatinine and urea while its reduced total protein levels. Hepatic and renal thiobarbituric acid reactive substances TBARS levels were significantly increased by tramadol administration while levels of endogenous antioxidant enzymes superoxide dismutase SOD catalase CAT and reduced glutathione GSH were reduced. This study confirmed the risk of increased oxidative stress hepatotoxicity and nephrotoxicity due to tramadol administration. Although tramadol is reported to be effective in pain management its toxicity should be kept in mind. Keywords: Tramadol Haematological Oxidative stress Hepatotoxicity Nephrotoxicity Introduction Tramadol is a synthetic centrally acting analgesic with efects similar to those of codeine and 10 times less than morphine 1. Tramadol has a wide range of applications mostly in the treatment of moderate to severe acute or chronic pain 2. It is an efective analgesic in acute ureteric spasm postoperative musculoskeletal and cancer pain 34. Te analgesic efect of tramadol is mediated by three mechanisms: mu opioid binding nor-epinephrine and serotonin reuptake inhibition 56. Tramadol is metabolized mainly in the liver by cytochrome P450 CYP2D6 cytochrome P4503A CYP3A4 and cytochrome P450 isozyme CYP2B6 being O-and N-demethylated to fve diferent metabolites followed by conjugation with glucuronic acid and sulphate 7. Tramadol is responsible for life-threatening poisonings resulting in consciousness impairment seizures agitation and respiratory depression 8. Like other opioids central apnea has been attributed to the ingestion of elevated doses of tramadol 9. Terefore tramadol toxic efects should be kept in mind during long term therapy especially in large doses 10. Although opioids are efective in the treatment of pain but activation of μ-opioid receptors MOR by opioids are known to cause side efects such as central nervous system CNS depression nausea dependence and addiction 1112. Presently addicts abuse tramadol every day by using the drug without doctor prescriptions. In the USA and Europe there have been an upsurge in tramadol use following withdrawal of dextropropoxyphene from the market thus raising the risk of increased poisonings and deaths attributed to this drug 13. Similarly in Nigeria the rate of tramadol abuse has been on the increase among Nigerian youths in recent time 14. Te main factor responsible for this could be link to of-label use of tramadol as on- demand treatment for premature ejaculation PE 1516. However wide-spread use of tramadol is associated with toxicity and a recent study showed that tramadol cause brain heart and lung toxicity 17. Terefore there is need to conduct a study that would examine the toxicity of tramadol in the liver where tramadol is metabolized and in the kidney where tramadol metabolites are excreted thus making liver and kidney the primary toxicity targets for tramadol. Terefore in the present work we performed an in vivo study using male W istar rats to analyse oxidative stress biochemical and haematological alterations at the liver and kidney levels deriving from exposure to a broad range of tramadol. Materials and Methods Reagents Tiobarbituric acid TBA nicotinamide adenine dinucleotide reduced NADH and tramadol hydrochloride were obtained from Sigma–Aldrich Chemical Co. Ltd. England. Nitrobluetetrazolium NBT 55 ′-Dithiobis 2-nitrobenzoic acid DTNB are product of Fluka Buchs Switzerland. All other chemicals used were analytical grade. Experimental design Twenty 20 male wistar strain albino rats were divided into four groups of fve rats each according to their weight. Group I labelled control received saline solution orally for 28 days. Group II received tramadol dose at 10 mg/kg/day body weight of rat. Group III received Journal of Alcoholism and Drug D ependence ISSN: 2329-6488 Journal of Alcoholism Drug Dependence Owoade et al. J Alcohol Drug Depend 2019 7:2 Research article Open Access J Alcohol Drug Depend an open access journal ISSN:2329-6488 Volume 7 • Issue 2 • 1000326

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tramadol dose at 50 mg/kg/day. Group IV received tramadol dose at 100 mg/kg/day. Tramadol was constituted in saline solution and administered through the oral route with the use of oral gavage. During the experiment the animals were allowed free access to food and distilled water. Afer 28 days of tramadol treatment and afer an overnight fast animals were sacrifced by cardiac puncture under light ether anaesthesia into ethylene diamine tetra-acetic acid EDTA sample bottles for haematological analysis and heparinised sample bottles for biochemical analysis. Liver and kidney were removed from the animals for biochemical analyses. Blood samples in heparinized bottles were centrifuged to separate plasma and red blood cells. All samples were stored at -20°C until analysed. Biochemical analyses Determination of urea creatinine total protein and ALP AST activities in plasma: Plasma concentrations of alkaline phosphatase ALP aspartate aminotransferase AST urea creatinine and total protein were determined using enzymatic kits CYPRESS® Diagnostics Langdorp Belgium according to the manufacturer’s instructions. Preparation of liver and kidney homogenates: Prior to biochemical analyses the liver and kidney samples were cut into small pieces and homogenized in Phosphate bufer saline PBS with a homogenizer to give a 10 w/v liver and kidney homogenate. Te homogenates were then centrifuged at 12000 rpm for 15 min. Te supernatant obtained was used for the assay of superoxide dismutase catalase gluthathione thiobarbituric acid reactive substances TBARS content and protein estimation. Determination of hepatic and renal antioxidant enzyme activities and MDA levels: Hepatic and renal superoxide dismutase SOD activities were assayed in the tissue homogenates by the method of Kakkar et al. 18 at 560 nm. One unit of enzyme activity was defned as that amount of enzyme which caused 50 inhibition of nitrobluetetrazolium reduction/mg protein. Catalase CAT activity was determined at room temperature by using the method of Aebi 19 and the absorbance of the sample was measured at 240 nm in a UV spectrophotometer. Te concentration of reduced glutathione GSH in liver and kidney homogenates was measured as described by Jollow et al. 20. Te extent of lipid peroxidation was estimated as the concentration of thiobarbituric acid-reactive product malondialdehyde MDA using the method of Draper and Hadley 21. All of the enzyme activities were expressed as per mg of protein and the tissue protein was estimated according to the method of Lowry et al. 22 using bovine serum albumin BSA as a standard. Haematological study Freshly collected blood samples in EDTA bottles were analysed for haematological assay using an automatic haematological assay analyser ERMA PCE 210 ERMA Japan. Diferent tested haematological parameters were as follows: White Blood Cell WBC Red Blood Cells RBC Haemoglobin HGB Haematocrit HCT Red cells RDW Red cells Distribution W idth RDW Mean Corpuscular Haemoglobin MCH Mean Corpuscular Haemoglobin Concentration MCHC Platelet PLT Mean Platelet Volume MPV Mean Corpuscular Volume MCV Platelet crit PCT Platelet distribution width PDW. Statistical analysis Results are expressed as mean ± S.E.M. Te levels of homogeneity among the groups were assessed using One-way Analysis of Variance ANOV A followed by Turkey’s test. All analyses were done using Graph Pad Prism Sofware Version 5.00 and p-value0.05 were considered statistically signifcant. Results Efect of tramadol administration on creatinine urea and total protein Administration of tramadol at 10 mg/kg 50 mg/kg and 100 mg/kg doses signifcantly increased plasma creatinine concentration by 93.98 148.19 and 361.45 respectively and increased plasma urea concentration by 95.29 183.69 and 210.80 respectively while total proteins levels were decreased by 30.35 57.79 and 48.02 respectively by administration of 10 mg/kg 50 mg/kg and 100 mg/kg doses of tramadol when compared with the normal rats Table 1. Parameters Creatinine mg/dL Urea mg/dL Total protein g/dL Control 0.83 ± 0.08 23.79 ± 1.64 8.60 ± 0.73 10 mg/kg/day tramadol 1.61 ± 0.25 46.46 ± 3.94 5.99 ± 0.36 50 mg/kg/day tramadol 2.06 ± 0.32 67.49 ± 3.01 3.63 ± 0.49 100 mg/kg/day tramadol 3.83 ± 0.49 73.94 ± 4.32 4.47 ± 0.68 Each value represents the mean of five rats. significantly different from control p0.05. Table 1: Efect of tramadol administration on creatinine urea and total protein. Efect of tramadol administration on ALP and AST activities Administration of tramadol at 10 mg/kg 50 mg/kg and 100 mg/kg doses signifcantly increased the activity of ALP by 39.72 74.45 and 142.91 respectively and AST activity by 90.09 204.77 and 181.36 respectively when compared with the normal rats Figure 1. Efect of tramadol administration on TBARS levels Hepatic TBARS levels of rats treated with 10 mg/kg 50 mg/kg and 100 mg/kg tramadol doses were dose-dependently signifcantly increased by 58.25 201.84 and 252.25 respectively when compared with the normal rats. Similarly administration of tramadol at 10 mg/kg 50 mg/kg and 100 mg/kg doses signifcantly increases renal TBARS levels by 57.59 129.00 and 127.18 respectively when compared with the control rats Figure 2. Citation: Owoade AO Adetutu A Olorunnisola OS 2019 Hematological and Biochemical Changes in Blood Liver and Kidney Tissues under the Effect of Tramadol Treatment. J Alcohol Drug Depend 7: 327. Page 2 of 7 J Alcohol Drug Depend an open access journal ISSN:2329-6488 Volume 7 • Issue 2 • 1000326

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Figure 1: Efect of tramadol administration on plasma ALP and AST levels of rats. Values are mean ± SEM n5. signifcantly diferent from control p0.05. Figure 2: Efect of tramadol administration on hepatic and renal TBARS levels of rats. Values are mean ± SEM n5. signifcantly diferent from control p0.05. Efect of tramadol administration on SOD activity Administration of tramadol at 10 mg/kg 50 mg/kg and 100 mg/kg doses signifcantly reduced hepatic SOD levels by 39.06 59.66 and 51.21 respectively and reduced renal SOD levels by 37.70 48.28 and 60.37 respectively when compared with normal rats Figure 3. Figure 3: Efect of tramadol administration on hepatic and renal SOD levels of rats. Values are mean ± SEM n5. signifcantly diferent from control p0.05. Efect of tramadol administration on catalase activity Administration of tramadol at 10 mg/kg 50 mg/kg and 100 mg/kg doses signifcantly reduced hepatic catalase levels by 28.89 65.33 and 80.00 respectively and reduced renal catalase levels by 45.92 51.52 and 62.24 respectively when compared with normal rats Figure 4. Figure 4: Efect of tramadol administration on hepatic and renal catalase levels of rats. Values are mean ± SEM n5. signifcantly diferent from control p0.05. Efect of tramadol administration on GSH activity Hepatic GSH levels of rats treated with 10 mg/kg 50 mg/kg and 100 mg/kg tramadol doses were signifcantly reduced by 37.04 50.86 Citation: Owoade AO Adetutu A Olorunnisola OS 2019 Hematological and Biochemical Changes in Blood Liver and Kidney Tissues under the Effect of Tramadol Treatment. J Alcohol Drug Depend 7: 327. Page 3 of 7 J Alcohol Drug Depend an open access journal ISSN:2329-6488 Volume 7 • Issue 2 • 1000326

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and 58.89 respectively when compared with the normal rats. Similarly administration of tramadol at 10 mg/kg 50 mg/kg and 100 mg/kg doses signifcantly reduced renal GSH levels by 33.06 49.04 and 59.07 respectively when compared with the control rats Figure 5. Figure 5: Efect of tramadol administration on hepatic and renal GSH levels of rats. Values are mean ± SEM n5. signifcantly diferent from control p0.05. Haematological Parameters Te efects of tramadol administration on haematological parameter were depicted in Table 2. No signifcant changes in the parameters of HCT MCV MCH RDW-SD MPV PDW and PTC were found when compared with control animals. However administration of tramadol signifcantly lowered p0.05 white blood cell WBC count red blood cell RBC count haemoglobin and platelet PLT while the value of Mean Corpuscular Haemoglobin MCH and Mean Corpuscular Haemoglobin Concentration MCHC were increased when compared with control animals. Parameter Control 10 mg/kg tramadol 50 mg/kg tramadol 100 mg/kg tramadol WBC × 109/L 8.30 ± 0.16 8.73 ± 0.32 5.40 ± 0.06 4.84 ± 0.36 HGB g/dl 10.58 ± 0.39 9.26 ± 0.33 9.06 ± 0.36 8.98 ± 0.26 RBC × 10 12 /L 6.92 ± 0.31 5.32 ± 0.22 5.19 ± 0.20 5.11 ± 0.17 HCT 31.64 ± 0.97 28.74 ± 1.16 27.76 ± 0.97 29.00 ± 1.00 MCV fl 55.50 ± 0.87 56.46 ± 1.42 53.90 ± 0.34 54.22 ± 0.94 MCH pg 15.28 ± 0.31 17.36 ± 0.15 17.48 ± 0.27 17.58 ± 0.32 Citation: Owoade AO Adetutu A Olorunnisola OS 2019 Hematological and Biochemical Changes in Blood Liver and Kidney Tissues under the Effect of Tramadol Treatment. J Alcohol Drug Depend 7: 327. Page 4 of 7 J Alcohol Drug Depend an open access journal ISSN:2329-6488 Volume 7 • Issue 2 • 1000326

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MCHC g/L 275.64 ± 1.93 309.26 ± 9.78 325.00 ± 5.27 321.40 ± 5.46 RDW-CV 17.22 ± 0.31 17.06 ± 0.48 13.60 ± 0.39 13.78 ± 0.27 RDW-SD fl 31.82 ± 0.15 31.00 ± 0.59 27.88 ± 0.58 27.52 ± 0.62 PLT × 10 9 /L 583.00 ± 1.26 571.26 ± 20.88 536.20 ± 11.82 521.00 ± 7.88 MPV fl 7.00 ± 0.06 6.80 ± 0.04 7.30 ± 0.10 7.28 ± 0.06 PDW 16.08 ± 0.32 16.02 ± 0.13 15.88 ± 0.22 15.62 ± 0.21 PTC 0.39 ± 0.00 0.56 ± 0.03 0.43 ± 0.02 0.40 ± 0.01 Each value represents the mean of five rats. significantly different from control p0.05. Table 2: Efect of tramadol administration on haematological parameters of rats. Discussion Tramadol is a synthetic analogue of codeine which is centrally acting analgesic for treatment of moderate to severe acute or chronic pain 223. In this study we studied tramadol as a drug not as analgesics because there is alarming increase in tramadol abuse among Nigerian youths due to the believe that tramadol could lengthen the duration of intercourse before ejaculation in men whom have problems with premature ejaculation and causes mood changes. Tis study evaluated the toxicity of tramadol on systemic body organs because of people addition to the drug. Te role of the liver and the kidneys in tramadol metabolism and excretion predisposes them to toxic injury 24. Almost every drug has been associated with hepatotoxicity due to the essential role of liver in drug metabolism 2526. Metabolites of drugs are excreted in the kidneys and some may cause cellular damage which could lead to kidney dysfunction 27. In the present study the liver functions were impaired in tramadol-treated group as refected by elevation in the activities of ALP and AST in the plasma when compared with the control rats this fnding is similar to previous studies that reported signifcant increase in the levels of serum ALT AST and LDH lactate dehydrogenase in rats afer long term usage of tramadol 2829. Te liver is an organ that detoxifed toxic elements and chemical drugs in the body the increased in the activities of AST and ALP in plasma in this study are indicative of liver damage 30. Te increased secretion of these liver enzymes may be accompanied by acute cell necrosis therefore the increased plasma level of these enzymes in rats treated with tramadol could be due to necrosis or damage to liver cell membrane which leak the enzymes into the blood circulation 31. Blood creatinine and urea levels are common biochemical parameters used to determine renal functions. Te level of plasma creatinine is used to determined glomerular fltration rate while urea is used to determine the nephrotoxic profle of xenobiotics 32. In this study impairment of the renal functions in tramadol-treated rats was indicated by a signifcant increase in urea and creatinine concentration in the plasma as compared to the control group. Tis observation is in support of previous studies 293334 and it is an indication of renal toxicity which cause decrease in glomerular fltration rate leading to the build-up of creatinine and urea in the blood. A large amount of polyunsaturated fatty acids found in all the biological membranes is susceptible to peroxidative attacks by oxidants resulting in lipid peroxidation. So lipid peroxidation production was used as a marker of oxidant-induced cell injury. In our study we recorded a signifcant increase in hepatic and renal malonaldehyde MDA levels in tramadol-treated group when compared with the control. It was reported that elevated MDA is indicating an increase of free radical generation and it is considered a useful measure of oxidative stress status 35. Our results are in support of earlier studies 3637 who reported an increase in the MDA level in tramadol-treated animals. Te toxic efect of tramadol administration leads to a large population of unquenched free radicals leading to the state of oxidative stress. Tis is evidence in inhibition in the activities of antioxidant enzymes superoxide dismutase SOD catalase CAT and reduced glutathione GSH in liver and kidney of rats in this study. SOD CAT and GSH are important antioxidant enzymes which played a pivotal role in scavenging of oxidative free radicals 38. Te inhibition of these antioxidant enzymes observed in this study could be linked to exhaustion of these enzymes as a result of oxidative stress caused by tramadol administration. Free radicals and reactive oxygen species are generated by chemicals and pollutants such as factory waste toxic gases and they are known to disrupt haematological parameters in organisms 39. Te deviation from normal haematological parameters levels represents the presence of toxicity or disease conditions 40. In this study tramadol administration caused a signifcant reduction in red blood cell counts RBC white blood cells Haemoglobin and PLT. Te observed decrease in the number of RBCs suggest that tramadol administration resulted in blood loss due to serious gastrointestinal tract bleeding red blood cell haemolysis and poor iron absorption in the intestine. White blood cells fght infections defend the body against foreign organisms’ invasion and produce antibodies in immune response 41. Animals with low WBC are at high risk of disease infection while high WBC results in high resistance to diseases 41. Te reduction of WBC by tramadol observed in this study suggest that tramadol use supresses the immune system and this could expose individuals that use the drug to infectious disease. Haemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates 42. Since haemoglobin is contained only in red blood cells a low number of RBCs would lead to low level of haemoglobin 43 as observed in this study. Tis fnding is in support of earlier study which reported reduction in haemoglobin concentration in morphine dependent people 44. Blood platelets are involved in blood clotting and its low level will prolong the process of clot-formation resulting in excessive Citation: Owoade AO Adetutu A Olorunnisola OS 2019 Hematological and Biochemical Changes in Blood Liver and Kidney Tissues under the Effect of Tramadol Treatment. J Alcohol Drug Depend 7: 327. Page 5 of 7 J Alcohol Drug Depend an open access journal ISSN:2329-6488 Volume 7 • Issue 2 • 1000326

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blood loss during injury. A decreased number of platelet thrombocytopenia by tramadol in this study is in supports of pervious work which observed that morphine administration induced thrombocytopenia 45. Tramadol administration also resulted in increased in the levels of mean corpuscular haemoglobin MCH and mean corpuscular volume MCHC while the changes observed in other haematological parameters such as HCT RDW RDW MCV MPV PCT PDW in this study were largely found to be non- signifcant an observation that may be diferent if tramadol administration period was much longer than 28 days used for this study. We strongly believe that disruption in haematological parameters observed in this study may be due to increased population of unquenched free radicals caused by tramadol administration. Conclusion Our results evidence that tramadol administration may cause hepatotoxicity nephrotoxicity and haematoxicity its use should therefore be limited to prescription only. Our fndings underlined the need to avoid indiscriminately and prolong use of tramadol since prolonged daily use of the drug either at a therapeutic dose or the extreme dose may lead to damage accumulation. Authors’ Contributions Tis work was carried out in collaboration between all authors. All authors read and approved the fnal manuscript. Confict of Interests Authors have declared that no competing interests exist. References 1. Marquardt KA Alsop JA Albertson TE 2005 Tramadol exposures reported to state wide poison control system. Ann Pharmacother 39: 1039-1044. 2. Nossaman VE Ramadhyani U Kadowitz PJ Nossaman BD 2010 Advances in perioperative pain management: Use of medications with dual analgesic mechanisms tramadol and tapentadol Anesthesiol. Clin 28: 647-666. 3. Barsoum MW 1995 Comparison of the efcacy and tolerability of tramadol pethidine and nalbuphine in children with postoperative pain. Clin Drug Invest 9: 183-190. 4. 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35. Pan HZ Zhang H Chang D Li H Sui H 2008 Te change of oxidative stress products in diabetes mellitus and diabetic retinopathy. Br J Ophthalmol 92: 548-551. 36. Atici S Cinel L Cinel I Doruk N Aktekin M et al. 2004 Opioid neurotoxicity: comparison of morphine and tramadol in an experimental rat model. Int J Neurosci 114: 1001-1011. 37. Elkhateeb A El Khishin I Megahed O Mazen F 2015 Efect of Nigella sativa Linn oil on tramadol-induced hepato- and nephrotoxicity in adult male albino rats. Toxicol Rep 2: 512-519. 38. Kruidenier L Kuiper I Van-Duijn W Mieremet-Ooms MA Van- Hogezand RA et al. 2003 Imbalanced secondary mucosal antioxidant response in infammatory bowel disease. J Pathol 201: 17-27. 39. Celik I Suzek H 2008 Te hematological efects of methyl parathion in rats. J Hazard Mater 153: 1117-1121. 40. Oyedemi SO Bradly G Afolayan AJ 2010 Toxicological efects of the aqueous stem bark extract of Strychnos henningsii Gilg in W istar rats. J Nat Pharm 1: 33-39. 41. Soetan KO Akinrinde AS Ajibade TO 2013 Preliminary studies on the haematological parameters of cockerels fed raw and processed guinea corn Sorghum bicolor. Proceedings of 38th Annual Conference of Nigerian Society for Animal Production 2013: 49-52. 42. Maton A Hopkins RL McLaughlin JC Johnson S Warner CW et al. 1993 Human Biology and Health. Englewood Clifs New Jersey USA: Prentice Hall. 43. Sonora Quest Laboratories 2017 Understanding the complete blood count CBC. V iewed August 11 2018. 44. Sapira JD Jasinski DR Gorodetzky CW 1968 Liver disease in narcotic addicts. II. Te role of the needle. Clin Pharmacol Ter 9: 725-739. 45. Cimo PL Hammond JJ Moake JL 1982 Morphine-induced immune thrombocytopenia. Arch Intern Med 142: 832-834. Citation: Owoade AO Adetutu A Olorunnisola OS 2019 Hematological and Biochemical Changes in Blood Liver and Kidney Tissues under the Effect of Tramadol Treatment. J Alcohol Drug Depend 7: 327. Page 7 of 7 J Alcohol Drug Depend an open access journal ISSN:2329-6488 Volume 7 • Issue 2 • 1000326

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