Pharmacogenetics and Tramadol-Related Fatalities

*Sanaa M. Aly, Jean-Michel Gaulier and Delphine Allorge*

### **Abstract**

Tramadol (TR) is a widely prescribed pain killer 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. These fatal cases might be explained by pharmacokinetic and pharmacodynamic properties of TR that are known to be both enantioselective and influenced by genes. Indeed pharmacogenetics (PG) is of great importance in this issue as it has the ability to elucidate the genetic variation contributing to drug absorption, distribution, metabolism, excretion, and response so that adverse drug reactions, toxicity, and even death can be avoided. The aim of this chapter is to present this issue.

**Keywords:** tramadol, pharmacogenetics, toxicology, *post-mortem* investigation, molecular autopsy

### **1. Introduction**

There is large interindividual variability in drug response and toxicity, as well as in drug concentrations after administration of the same dosage [1]. The genetic makeup could be the reason of variation in drug response among individuals [2]. In general, genetic factors are estimated to account for 15–30% of interindividual differences in drug response, but for certain drugs, this can be as high as 95% [1].

The genetic variations contribute to absorption, distribution, metabolism, excretion, response, and adverse drug reactions, which could be explored by pharmacogenetics (PG). PG could also characterize differential enzyme activity (e.g., the cytochrome P450 system) informing appropriate drug dosage on the individual (personalized medicine) and population levels. The advancement of genetic modalities will enable more accurate predictions of drug-related death determinations and contribute to the growing not only in forensic toxicology context but also in clinical settings [2].

The main application of molecular autopsy involves investigation of drugrelated deaths by exploiting several molecular techniques, especially those of genetic nature [3].

The PG use as an adjunct for molecular autopsy would add to the understanding of potential genetic contribution to metabolism of certain drug (such as tramadol), thus enabling and improving the practice of *antemortem* drug therapy [4].

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 CYP2D6 phenotype.

#### **1.1 Tramadol (TR)**

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, and morphine allergy [11].

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, antifungal, and anti-HIV medications [11].

#### **1.2 Epidemiological data**

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 85%, respectively) [12].

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 with the TR crisis [14, 15].

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% reported misuse of TR [16].

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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overdose [9, 23].

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

from 200 reports in 2013 to 800 in 2018 [9].

**1.3 Adverse reactions**

serotonin syndrome.

of overdose with very high doses [9, 21].

CYP2D6 UMs, PMs, IMs, and EMs [22].

while there was no increase in psychotic symptoms [9].

receptors and present as atypical sequelae [9].

in the USA in 2016, 2017, and 2018, respectively [17].

was a total of 43.7 million, 39.8 million, and 36.5 million TR prescriptions dispensed

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:

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, tachycar-

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

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

Regarding the chronicity, the main problem observed was the significant increase in comorbid anxiety, depressive, and obsessive-compulsive symptoms

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

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

dia, 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

was a total of 43.7 million, 39.8 million, and 36.5 million TR prescriptions dispensed in the USA in 2016, 2017, and 2018, respectively [17].
