**9. Hepatic system**

In another study on 97 patients with seizure, electroencephalographic (EEG) evaluations were normal in seven and isolated sharp slow-wave feature of EEG was seen in one patients. Brain CT was normal in all and magnetic resonance imaging (MRI) was normal in five patients [77]. Tramadol-induced seizure can cause trauma, intra-articular dislocation, and

In a study on 70 rats, it was revealed that tramadol could inhibit electron transfer cycle (ETC), cause ATP depletion, and disrupt the mitochondrial integrity. Apoptosis may also happen due to tramadol use [83]. In the neonates, tramadol can trigger pentylenetetrazole-induced seizure in an age-dependant manner causing fewer seizures in the neonatal period and more seizures

Administration of tramadol hydrochloride to a zebrafish caused abnormal behaviors, reduced activity, and reduced brain and body weight. In the zebrafish brain, functional cytoskeletal proteins engaged in the energy metabolism had changed due to tramadol. Lower levels of ATP synthetase, creatine kinase, pyruvate dehydrogenase, kinase, and aldolase C could be due to the impaired production of energy because of tramadol. Weak regulation of the proteins engaged in the oxidative stress, mitochondrial functional abnormalities, and impaired production and destruction of the proteins represented the

> **Cause of ingestion**

by physician

by physician in 18.9% Abuse in 81.1%

by physician

Acute pulmonary hypertension and right heart failure are the uncommon presentations reported in a young tramadol-overdosed patient [86]. Cardiopulmonary arrest was reported

**Sex Co-**

Female History of seizure

96% M History of

**administration or comorbidity**

epilepsy in 13.2%, abuse of antidepressant in 5.8%, alcohol in 5.8%, opiate in 23.3%

F/M \_ 100 mg IV

**Dosage**

100 mg IV

oral

50-1500 mg IV or

tongue laceration [67,81,82].

106 Toxicology Studies - Cells, Drugs and Environment

after the lactating period [84].

neurotoxicity of tramadol (Table 1) [85].

**year**

Petramfar et al.[140] 2010 106 Prescribed

**Number of patients**

2012 1 Prescribed

2005 2 Prescribed

**Authors Publication**

**Table 1.** Studies on tramadol-induced seizures

**8. Cardiopulmonary effects of tramadol**

Raigeret al. [139]

Mehrpour M [141]

Sixteen cases of non-fatal hepatobiliary dysfunction due to tramadol ingestion have been reported [74]. Tramadol has caused centrilobular congestion and focal necrosis of the liver cells and minimal vacuolization in the kidney tubular cells of the rats. No changes were detected in the lactate dehydrogenase, blood urea nitrogen (BUN), aspartate aminotransferase (AST), and malondialdehyde (MDA); however, alanine aminotransferase (ALT) increased signifi‐ cantly showing the possible hepatotoxicity of tramadol [91]. It was shown that acute or chronic toxicity did not affect liver weight or cause histopathological changes in its tissue [17,92].

In the rats, mu receptor activation increases glucose use or decreases the liver gluconeogenesis which results in the low levels of plasma glucose in diabetic rats [88,93]. It has been shown that tramadol improves the peripheral metabolism of glucose by central activation of the mu receptors. Therefore, central and peripheral metabolisms of glucose unite and cause hypogly‐ cemia. It has also been suggested that tramadol changes the liver glucose output regulated by other organs (likely CNS) [93].
