{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:04:01Z","timestamp":1790863441113,"version":"4.1.0"},"reference-count":133,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.3390\/ijms27188332","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:18:26Z","timestamp":1790860706000},"page":"8332","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacogenetic Evidence in Opioid-Related Toxicity and Death with an Appraisal of Emerging Multi-Omics Studies: A Systematic Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5162-7151","authenticated-orcid":false,"given":"Tommaso","family":"D\u2019Anna","sequence":"first","affiliation":[{"name":"Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy"},{"name":"Tumor Immunology Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"},{"name":"Legal Medicine Unit, University Hospital \u201cPaolo Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0508-6523","authenticated-orcid":false,"given":"Angelo","family":"Montana","sequence":"additional","affiliation":[{"name":"Section of Legal Medicine, Department of Biomedical Sciences and Public Health, Marche Polytechnic University, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"La Magna","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3687-9560","authenticated-orcid":false,"given":"Marco","family":"Piraino","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Pecorella","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8458-4108","authenticated-orcid":false,"given":"Maria Giovanna","family":"Scioli","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Terriaca","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9668-0925","authenticated-orcid":false,"given":"Beatrice","family":"Belmonte","sequence":"additional","affiliation":[{"name":"Tumor Immunology Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-5854","authenticated-orcid":false,"given":"Augusto","family":"Orlandi","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1101-0864","authenticated-orcid":false,"given":"Stefania","family":"Zerbo","sequence":"additional","affiliation":[{"name":"Legal Medicine Unit, University Hospital \u201cPaolo Giaccone\u201d, 90127 Palermo, Italy"},{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco Paolo","family":"Busard\u00f2","sequence":"additional","affiliation":[{"name":"Section of Legal Medicine, Department of Biomedical Sciences and Public Health, Marche Polytechnic University, 60126 Ancona, Italy"},{"name":"Research Center of Legal Medicine and Risk Management, Cardiovascular Department, Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9964-0184","authenticated-orcid":false,"given":"Antonina","family":"Argo","sequence":"additional","affiliation":[{"name":"Legal Medicine Unit, University Hospital \u201cPaolo Giaccone\u201d, 90127 Palermo, Italy"},{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"897","DOI":"10.15585\/mmwr.mm6634a2","article-title":"Trends in deaths involving heroin and synthetic opioids excluding meth-adone\u2013United States, 2006\u20132015","volume":"66","author":"Gladden","year":"2017","journal-title":"MMWR Morb. 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