**1.3 Adverse reactions**

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

CYP2D6 phenotype.

**1.1 Tramadol (TR)**

and morphine allergy [11].

**1.2 Epidemiological data**

85%, respectively) [12].

with the TR crisis [14, 15].

reported misuse of TR [16].

antifungal, and anti-HIV medications [11].

Tramadol (TR) is a worldwide used pain killer drug. Since TR was marketed, it has been widely prescribed because of its relatively safe profile among opioids. Nevertheless, intoxication can occur and overdose can lead to fatal outcomes. Surprisingly, in some fatalities for which death is attributable to TR alone, *postmortem* blood concentration levels overlap with the therapeutic concentration range (0.1–0.8 mg/L) [5–8]. These fatal cases might be explained by pharmacokinetic and pharmacodynamic properties of TR that are known to be influenced mainly by the

TR is a synthetic centrally acting analgesic drug worldwide used for the treatment of moderate to severe pain [9, 10]. TR is used as a pain killer in different types of pain such as osteoarthritic, endodontic or dental, chronic cancer, acute renal, neuropathic, and postoperative pain. It is also used in case of acute myocardial infarction, postoperative shivering in lower abdominal surgery, Brugada syndrome,

However, several precautions should be taken before TR prescription. It should not be administrated below the age of 16 years, and some forms as Ultram should be administrated above the age of 18 years. TR should not be prescribed during pregnancy, in case of lactating and expecting mothers, person with epilepsy, mental illness or suicide attempt, heart or respiratory problems, stomach or intestinal blockage, liver, kidney, or metabolic disease, TR sensitivity, addiction to drug or alcohol, intake of some drugs as sedatives, tranquilizers, narcotics, 2 weeks intake of monoamine oxidase inhibitor (MAOI), methylene blue injection, antibiotics,

The changes in opioid consumption have been described worldwide. In Europe, they were characterized by an increasing use of TR. Between 2006 and 2015 in France, TR (alone or in combination use) were the second most commonly used mild opioids. There was an increased consumption of TR over the 10-year period (+62%) in France. In recent reports, France ranked third place for mild opioid consumption, with TR (alone or in combination use) being one of the most used substance (48%). In other European countries, TR is also the most commonly used mild opioids in Germany, Italy, Spain, and Denmark (98, 82, 78, and

In the same time, there is a particular concern about the rise of nonmedical use of analgesics, especially opioids. Much has been written about the opioid crisis in the USA, but a similar crisis engulfing the Middle East, North, and West Africa is receiving little attention [13]. Therefore, drug world report 2018 mentioned the critical challenge in some countries in Africa and other regions needing to grips

The 2017 report of the National Survey of Substance Abuse in Egypt was subsequently presented to the WHO which revealed that the abuse of TR is still a national concern in Egypt despite it became a schedule IV controlled substance since 2012. This may be because of wide-scale abuse of this analgesic. In the 2012/2013 survey, 7.6% of the general population abused drugs: of these 31.5%

Because TR is widely used either as licit or illicit drug, FDA has only approved the medical use by prescription. Although TR has become a schedule IV controlled substance in the USA since 2014, this did not hinder legitimate access. In 2014, there

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The WHO Global Database reports of suspected adverse drug were studied to investigate TR. There has been a sudden increase in reports (nearly 5-fold) for TR: from 200 reports in 2013 to 800 in 2018 [9].

In overdose, the multiple systematic symptoms are reflecting the multimodal activity of TR. Acute adverse effects associated with TR are like those of other weak opioids. Common side effects include dizziness, nausea, constipation, and headache. TR overdose presented with multiple systematic symptoms ranging from cardiovascular toxicity to significant neurologic toxicity including lethargy, nausea, tachycardia, agitation, seizures, coma, hypertension, and respiratory depression [9].

The smallest amount of TR associated with a seizure was 200 mg occurred within 6 hours after ingestion. The mechanism underlying TR toxicity has been closely related to both opioid and MAOI activity [18]. The enhanced risk of seizure was attributed to the increased risk from serotoninergic toxicity due to the expected prolonged half-life of the ingested parent compound resulting in slower drug metabolism [19]. Both TR and M1 inhibit the reuptake of serotonin and noradrenaline. Hence, the concomitant use of serotonergic drugs such as serotonin reuptake inhibitors and MAOIs, increase the risk of adverse events, including seizure and serotonin syndrome.

The parent drug of TR causes sedation (but does not impair ventilation) and the M1 metabolite causes both sedation and respiratory depression [now termed opioid-induced ventilatory impairment (OIVI)] which is responsive to naloxone [20]. Both monoaminergic and opioid mechanisms contribute to this effect. In a case series study of TR overdose, respiratory depression occurs only in severe cases of overdose with very high doses [9, 21].

On the other hand, other work suggested that poor metabolizers (PMs) of TR tend to experience more adverse effects of the drug. The results showed that intermediate metabolizers (IMs) were found to have a statistically higher incidence of adverse drug reactions (dizziness, headache, nausea, sweating, and dry mouth) when compared with the groups that metabolize TR faster [ultra-rapid metabolizers (UMs) and extensive metabolizers (EMs)]. Other studies found no difference in term of adverse events such as nausea and vomiting between patients with the CYP2D6 UMs, PMs, IMs, and EMs [22].

Regarding the chronicity, the main problem observed was the significant increase in comorbid anxiety, depressive, and obsessive-compulsive symptoms while there was no increase in psychotic symptoms [9].

Concerning dependence potential, the International Narcotics Control Board reported in 2018 widespread misconceptions regarding TR among the general population in North Africa and the Middle East. Some consider TR to be a mood enhancer that increases sexual stamina and/or boosts energy during work. However, mood elevation is often reported and leads to the consumption of higher doses of the drug, psychological or physical dependence, and increased risk of overdose [9, 23].

The development of physical dependence to TR is dose-related, and administrations of supra-therapeutic doses lead to a similar dependence profile to morphine, whereas the risk of physical dependence is lower than prototypic opioids when lowdose TR is used over an extended period. However, these are not exclusively related to its opioid effects and may reflect withdrawal from catecholamine and serotonin receptors and present as atypical sequelae [9].

#### **1.4 TR-related fatalities**

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

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 center in 2012 [26].

## **2. Pharmacology**

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

#### **2.1 Pharmacokinetics**

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 not exceed 400 mg/day [9].

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 and less fluctuation in plasma concentrations [9].

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

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 as unchanged drug.

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].

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*Pharmacogenetics and Tramadol-Related Fatalities DOI: http://dx.doi.org/10.5772/intechopen.98250*

UDP glucuronosyltransferase 1–8 (UGT1A8) [22].

(for example genetic variants of pharmacogenes) [34].

**2.3 Pharmacogenetics (PG)**

*2.3.1 Definitions*

*2.3.2 PG strengths*

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

PG is the inherited variation study in relation to drug response. Its goal is to develop novel ways to minimize toxicity and maximize drug efficacy for the patient [34]. PG is an important innovation in clinical medicine as a result of progression of genomic science to determine the correct drug with the correct dose as a specific treatment with the use of genetic information [35]. Personalized medicine has the potential to select the most appropriate drug for certain patients, to predict optimal dosage for a drug, and to develop cost-effective treatments. Individualized response to treatment may be attributed to biological (for example age, sex, nature of disease), behavioral (for example smoking, drug interactions), or genetic factors

Personalized medicine has the finality of improving drug safety and efficacy. PG application in clinical practice promises more effective decision-making in relation to diagnostic testing, individualized drug selection, and dosing. This depends on the genetic variations that affect the observed differences in drug response which can be classified into two groups: pharmacokinetic and pharmacodynamic. The genes that influence the pharmacokinetic properties of a drug influence the drug absorption, distribution, metabolism, and excretion. The genes that affect the pharmacodynamic of a drug influence the mechanism of the drug's target and how

**2.2 Pharmacodynamics**
