**2. Pharmacology**

Tramadol is a synthetic analogue of codeine with central effects [2,6,9-13]. It is not an opioid derivative or non steroidal anti-inflammatory (NSAID) medication. Actually, tramadol has low affinity for opioid receptors [14,15] and has a hydrochloride structure (Figure 1) [1,16].

Tramadol is used as a racemic mixture in the treatments [15]. This mixture is a 1:1 ratio of two enantiomers with synergistic analgesic effects [17]. The (+) and (-) enantiomers weakly connect to mu opioid receptors [18]. Enantiomer (+) is the opioid part but increases serotonin release and inhibits its re-uptake, as well. Enantiomer (-) is a noradrenaline re-uptake inhibitor [17-19].

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O

**Figure 1.** Tramadol structure

Most of the analgesic effects of tramadol are likely secondary to its monoaminergic central pathways [3,10,20]. Tramadol acts through some different pathways including:


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 to relieve their pain [24].

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

In postmortem evaluations using gas chromatography, tramadol level is at the most in heart, liver, peripheral blood, urine, kidney, lung, spleen, bile, and brain without any distribution into the muscles [6,25,30].

Tramadol is generally metabolized through N-demethylation, O-demethylation, glucuroni‐ dation, and/or sulfation. Metabolization of tramadol is performed by cytochrome P450 enzymes. CYP2D6 is responsible for O-demethylation while N-demethylation is done by CY2B6 and CY3A4 [6,31,32]. Tramadol can be used in renal failure although decreased doses are recommended in renal problems and liver cirrhosis [33].

In a study on six alpacas (some kind of camel), the half-life of all three metabolites of tramadol (O-, N-, and Di-desmethyltramadol) was reported to be more than the parent drug [34]. The main metabolite (O-desmethyltramadol) has a 200-time affinity for mu receptors and its analgesic effect is twice the parent medication, as well [2,15,26].
