**Appendices and nomenclature**

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

the M2 and M5 enantiomers exceeded the ones of the M1 enantiomers [10].

dosage group [10].

and M1 are close to 1 [51–54].

individualizing humans [39].

**4. Conclusion**

TR-related fatalities.

**Acknowledgements**

**Conflict of interest**

French Institute of Egypt (STDF-IFE), No. 31133.

The authors declare no conflict of interest.

(−)-enantiomers. The observed reduced levels of the M5 enantiomers were expected. M5 is formed from both M1 and M2. Since PMs only form low amounts of M1 due to the abolished (canceled) function of CYP2D6, the amounts of the M2 enantiomers will accumulate. Another metabolic profile of CYP2D6 IM showed the AUCs of both

The general hypothesis in literature regarding adverse effects following TR administration is that the frequency and intensity is related to the concentrations of (+)-M1. The higher the concentration of (+)-M1, the higher the risk of side effects and toxicity. In Haage et al. study, the individual experiencing most drug reaction symptoms (both fainting and vomiting during the experimental day) was the one with the second lowest maximal concentration and AUC of (+)-M1 in the 100 mg

A recent work reported that the TR/M1 ratio may not accurately reflect the rate of TR *O*-demethylation in clinical patients. This study accounted that due to (i) *postmortem* redistribution (PMR) phenomenon, and (ii) various interval and/ or time between TR administration and death. In addition, TR is metabolized by multiple enzymes (e.g., TR and/or its metabolites are metabolized by CYP2D6, CYP3A4, CYP2B6, UGT1A8, or ABCC2) (**Figure 1**) and may be metabolized at different rates based on body size, liver function, chronicity of TR, general opioid, and/or other drug use [39]. Surprisingly, the first abovementioned cause is not accurate as PMR is not a problem in case of interpretation of fatalities related to TR. Indeed, many studies revealed that cardiac-to-femoral blood ratios obtained for TR

It is suggested that the monogenic model likely introduces error, particularly for samples at the extremes of CYP2D6 activity; a prediction using multiple genes may reduce these discrepancies although this comparison has not been performed. The forensic community has not yet leveraged the power of machine learning for such studies. However, the forensic DNA community has begun developing methods of

This chapter about PG and TR highlights important related issues including pharmacological and genetic aspects of TR. It clarified the interindividual variability in response and toxicity to TR in order to support the use of genetic screening to predict individual responses to pain medications and the risk of adverse events. This in turn will encourage the use of PG as part of clinical practice for TR. Finally, novel machine learning approaches using multigenic model can comprehensively analyze genotype-phenotype relationships that hold significant promise for application to predict response to TR, which may contribute to the relatively high rate of

This work was supported by Science and Technology Development Fund—

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