Pharmacogenetic Evidence in Opioid-Related Toxicity and Death with an Appraisal of Emerging Multi-Omics Studies: A Systematic Review
6 affiliations
- 1Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy
- 2Tumor Immunology Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
- 3Legal Medicine Unit, University Hospital “Paolo Giaccone”, 90127 Palermo, Italy
- 4Section of Legal Medicine, Department of Biomedical Sciences and Public Health, Marche Polytechnic University, 60126 Ancona, Italy
- 5Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
- 6Research Center of Legal Medicine and Risk Management, Cardiovascular Department, Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Italy
Abstract
Interpretation of opioid-related toxicity and death requires integration of exposure, measured toxicology, individual susceptibility, and alternative causes. We systematically reviewed human pharmacogenetic/pharmacogenomic (PGx) and multi-omic studies published from 1 January 2008 to March 2026, identified through MEDLINE/PubMed, Scopus, and Web of Science Core Collection. JBI tools informed risk-of-bias assessment, and findings underwent effect-size-oriented narrative synthesis and descriptive mapping. The 75-study corpus was predominantly PGx (51 studies, 68.0%); only 17 studies addressed transcriptomic/epigenetic, metabolomic, proteomic, or integrated approaches, and seven retained other molecular classifications. These domains therefore differ substantially in evidential maturity. The most coherent PGx findings concerned CYP2D6-dependent codeine and tramadol bioactivation, CYP2B6-dependent methadone disposition, and ABCB1-related tissue distribution. Omics findings were exploratory, with limited external validation and specificity for fatal causation; proteomics rested on a single investigation. Forensic interpretative directness was high or moderate in 36 studies and low or absent in 39. No nitazene-specific study met this review’s molecular eligibility criteria. Certainty was very low for the four outcome-focused bodies assessed with GRADE; integration utility and confounder control were appraised narratively. Molecular findings may explain discordance between inherited susceptibility, parent-drug/metabolite patterns, and the observed phenotype. Downstream signatures may also reflect chronic exposure, terminal hypoxia, or postmortem change. Neither the descriptive evidence-map scores nor individual molecular markers provide validated estimates of forensic risk or establish cause of death independently.
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BibTeX
@article{danna2026pharmacogenetic,
title = {{Pharmacogenetic Evidence in Opioid-Related Toxicity and Death with an Appraisal of Emerging Multi-Omics Studies: A Systematic Review}},
author = {Tommaso D’Anna and Angelo Montana and Giulia La Magna and Marco Piraino and Antonella Pecorella and Maria Giovanna Scioli and Sonia Terriaca and Beatrice Belmonte and Augusto Orlandi and Stefania Zerbo and Francesco Paolo Busardò and Antonina Argo},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27188332},
url = {https://www.mdpi.com/1422-0067/27/18/8332},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pharmacogenetic Evidence in Opioid-Related Toxicity and Death with an Appraisal of Emerging Multi-Omics Studies: A Systematic Review
AU - Tommaso D’Anna
AU - Angelo Montana
AU - Giulia La Magna
AU - Marco Piraino
AU - Antonella Pecorella
AU - Maria Giovanna Scioli
AU - Sonia Terriaca
AU - Beatrice Belmonte
AU - Augusto Orlandi
AU - Stefania Zerbo
AU - Francesco Paolo Busardò
AU - Antonina Argo
PY - 2026
DA - 2026/09/19
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27188332
UR - https://www.mdpi.com/1422-0067/27/18/8332
AB - Interpretation of opioid-related toxicity and death requires integration of exposure, measured toxicology, individual susceptibility, and alternative causes. We systematically reviewed human pharmacogenetic/pharmacogenomic (PGx) and multi-omic studies published from 1 January 2008 to March 2026, identified through MEDLINE/PubMed, Scopus, and Web of Science Core Collection. JBI tools informed risk-of-bias assessment, and findings underwent effect-size-oriented narrative synthesis and descriptive mapping. The 75-study corpus was predominantly PGx (51 studies, 68.0%); only 17 studies addressed transcriptomic/epigenetic, metabolomic, proteomic, or integrated approaches, and seven retained other molecular classifications. These domains therefore differ substantially in evidential maturity. The most coherent PGx findings concerned CYP2D6-dependent codeine and tramadol bioactivation, CYP2B6-dependent methadone disposition, and ABCB1-related tissue distribution. Omics findings were exploratory, with limited external validation and specificity for fatal causation; proteomics rested on a single investigation. Forensic interpretative directness was high or moderate in 36 studies and low or absent in 39. No nitazene-specific study met this review’s molecular eligibility criteria. Certainty was very low for the four outcome-focused bodies assessed with GRADE; integration utility and confounder control were appraised narratively. Molecular findings may explain discordance between inherited susceptibility, parent-drug/metabolite patterns, and the observed phenotype. Downstream signatures may also reflect chronic exposure, terminal hypoxia, or postmortem change. Neither the descriptive evidence-map scores nor individual molecular markers provide validated estimates of forensic risk or establish cause of death independently.
SN - 1422-0067
ER -