**3. Tramadol toxicity**

Most of the analgesic effects of tramadol are likely secondary to its monoaminergic central

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**b.** Affecting noradrenergic pathways causing inhibition of norepinephrine reuptake in

**c.** Affecting serotonergic pathways causing inhibition of serotonin reuptake in the CNS;

**d.** Affecting GABAergic pathways causing increased GABA neurotransmitter in the brain

Tramadol is currently available as tablets, oral drops, solution for injection, and suppository [8] with the oral rout being the most common rout of its administration. Tramadol has a high volume of distribution (3 L/kg) [3,7]. Bioavailability of an oral dose of tramadol is 75% which can reach almost 100% with a programmed schedule [7]. The common therapeutic dose of tramadol is 50 to 100 mg (50 mg oral, 50-100 mg intramuscular [IM], and/or100 mg rectal; 1.5 mg/kg/day in a 60-kg patient) three to four times a day. Doses higher than 400 mg/day are generally not necessary [8,17,23]. However, evaluation of five rheumatologic disorder patients over 65 years of age revealed that a daily tramadol dose of 300 to 1200 mg was needed for them

Analgesic effects of tramadol are dose-related. The relation between serum level and analgesic effect is not the same among different people. It is estimated that the normal therapeutic serum level of tramadol and its metabolite are 0.1 to 0.3 mg/L and 0.03 to 0.04 mg/L, respectively [3,25-27]. According to the information from International Association of Forensic Toxicolo‐ gists, therapeutic, toxic, and fatal levels of tramadol in adults are 0.1-0.8 mg/L, 1-2 mg/L, and over 2 mg/L, respectively [26]. Tramadol is completely and rapidly absorbed after oral use. Sustained-release tablets affect within 12 hours and their serum level peaks at 4-9 hours postingestion [6]. In the mice, tramadol is more available and effective at the final phase of the darkness and most of the mortalities happen at the mid phase of the darkness; such an effect

pathways [3,10,20]. Tramadol acts through some different pathways including:

H3C

N

CH3

H3C

**a.** Affecting mu receptors causing the opioid-like effects;

central nervous system (CNS);

[2,8,13,17,21,22].

**Figure 1.** Tramadol structure

102 Toxicology Studies - Cells, Drugs and Environment

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to relieve their pain [24].

has not been detected in human volunteers [28,29].

Tramadol is considered to be a safe drug. However, mortality has been reported with its use [35,36]. Toxicity can happen accidentally. Patients with the previous history of addiction are at extreme danger for such toxicity and according to FDA warnings, tramadol administration should be performed cautiously in these patients [6,37].

Toxicity of tramadol can be predicted by P450 polymorphism [38,39]. Few studies have shown the difference in the postsurgical analgesic serum levels of tramadol among people which is probably due to the genetic polymorphism in the activity of CYP2D6 [40,41]. Diversity in the response depends on the CYP2D6 genotype. Ultra-rapid metabolizers have a higher risk of tramadol toxicity with higher plasma levels of O-desmethyltramadol. They experience higher analgesic effects and nausea in comparison to the group who are extensive metabolizers [38].
