**2.2 Pharmacodynamics**

*Forensic Analysis - Scientific and Medical Techniques and Evidence under the Microscope*

"high") that led to strong myocardial stunning [24].

In a report about a young Caucasian female admitted to hospital with refractory cardiac arrest and high levels of both TR and M1, the genetic analysis revealed the patient had a duplicated wild-type allele, indicative of a CYP2D6 UM phenotype. The event was specifically ascribed to the inhibition of noradrenaline reuptake and excessive blood adrenaline levels following binge-type ingestion of TR (to gain a

In France, the number of deaths related to TR toxicity increased from 32 in 2013 to 49 in 2017. TR was the first most commonly cause of death due to analgesics [25]. In Egypt, about 18% of fatalities are related to TR in the national poison center. TR was the second most commonly cause of death among cases attended in the poison

TR is a complex drug that is administered as a racemate with the (+)- and (−)-enantiomers of the parent compound and related metabolites showing various pharmacological effects. It is metabolized by polymorphic enzymes including CYP2D6 and CYP3A4 to its more potent metabolites particularly *O-*desmethyltramadol (ODT,

TR is marketed as the hydrochloride salt. It is available in a variety of pharmaceutical formulations for oral, sublingual, intranasal, rectal, intravenous, subcutaneous, and intramuscular administration. It is also available in combination with acetaminophen, immediate-release and extended-release formulations. Tablets and capsules are the most commonly used and easily available formulations. The recommended daily dose is in the range of 100–400 mg. The maximum dose should

After oral administration, TR is rapidly absorbed (with a time lag of 30 min for capsules). The bioavailability of TR is around 70% after single-dose administration, but increases to 90–100% after repeated administration as a result of the saturation of the hepatic first pass effect [9, 27]. TR sustained release capsules had identical bioavailability to TR immediate-release capsules with lower peak concentrations

The analgesic potency of TR itself is about 10% that of morphine following parenteral administration but more potent if administered orally because of the activity of M1. The production of analgesia is consistent with M1 formation, which

The TR volume of distribution has been reported to be 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The plasma binding of TR is approximately 20% [28]. TR crosses the blood-placental barrier and a very small amount of the drug is excreted in breast milk [29]. TR is mainly excreted through the kidneys, the remaining being excreted in feces [30]. About 60% of TR dose is excreted as metabolites, meanwhile 30% is excreted in the urine

The elimination half-lives range of racemic TR and M1 have been reported to be about 5–7 h [31]. The longer elimination time of TR in case of overdose (about 9.24 h) gives an indication about the capacity limited of TR metabolism, which is dependent upon the rate of metabolism by the P450 enzymatic system [9].

commences an hour postadministration and peaks 2–3 h later [9].

M1) as well as *N,O-*didesmethyltramadol (NODT, M5) [9, 10].

**1.4 TR-related fatalities**

center in 2012 [26].

**2. Pharmacology**

**2.1 Pharmacokinetics**

not exceed 400 mg/day [9].

and less fluctuation in plasma concentrations [9].

**162**

as unchanged drug.

TR acts in a multimodal fashion to bring about analgesia that involves the μ-opioid receptor system, the noradrenergic system, and the serotonergic system. TR has some affinity for the μ-opioid receptor, whereas the active hepatic metabolite, M1 has high relative greater affinity for the μ-opioid receptor [32]. The affinity of morphine for this same receptor is approximately 10–100 times greater than M1 and 300 times greater than TR. TR is approximately 10-fold less potent than codeine. A weak agonistic TR effect was revealed at the δ-opioid receptors, and a weaker TR affinity was shown at κ-opioid receptors. TR acts by other mechanisms on the central nervous system including monoaminergic activity through weak noradrenaline and serotonin reuptake inhibition to prevent pain transmission [33].

TR is administered as a racemate, with the (+)- and (−)-enantiomers of the parent compound and their respective metabolites displaying different effects to achieve synergistic pain relief. The (+)-enantiomer of TR is most potent in serotonin reuptake inhibition, while (−)-enantiomer is a noradrenaline reuptake inhibitor. The (+)-enantiomer of the M1 has the highest affinity and potency up on the μ-opioid receptors. It also exerts most of the opioid effects. The (+)-ODT is the most potent stereoisomer in relieving pain as well as in causing adverse effects [10].

TR is mainly metabolized by two pathways: *N*- and *O*-demethylation (phase I reactions) and conjugation (phase-II reactions). There are at least 11 known metabolites of TR (M1–M5). The metabolites *N-*desmethyltramadol (M2), M3 and M4 of TR have negligible affinity for the human μ-opioid receptor. The *O*-demethylation of TR to M1 is catalyzed by cytochrome P450 (CYP) 2D6, whereas *N*-demethylation to M2 is catalyzed by CYP2B6 and CYP3A4 (**Figure 1**) [9]. M1, the active metabolite of TR, is metabolized through glucuronidation in the liver, mostly via UGT2B7 and UDP glucuronosyltransferase 1–8 (UGT1A8) [22].
