Quantifying enhanced risk from alcohol and other factors in polysubstance-related deaths

•Co-ingested ethanol and opioids is associated with lower opioid concentrations.•Multiple regression models were used for each log-opioid concentration studied.•Multiple opioid presence associated with lower opioid concentrations in deaths.•Stimulants presence associated with lower oxycodone and hydrocodone concentrations.•Drug abuse diagnosis associated with lower oxycodone, hydrocodone concentrations. To quantify how alcohol, polysubstance use and other factors influence opioid concentrations in drug-related deaths in West Virginia (WV), United States. Multiple linear regression models were employed to identify relationships among alcohol, other factors, and the concentrations of four commonly identified opioids (fentanyl, hydrocodone, oxycodone, methadone), accounting for demographic, toxicological and comorbid characteristics in WV drug-related deaths from 2005 to 2018. Alcohol concentrations of 0.08% or above were associated with significant reductions in blood concentrations of fentanyl (27.5%), hydrocodone (30.5%) and methadone (32.4%). Significantly lower predicted concentrations of all opioids studied were associated with multiple opioid vs. single opioid presence, with predicted concentration reductions ranging from 13.7% for fentanyl to 65–66% for hydrocodone and oxycodone. Benzodiazepine presence was associated with small, non-statistically significant changes in opioid concentrations, while stimulant presence was associated with statistically significant reductions in hydrocodone and oxycodone concentrations. Co-ingestion of alcohol, multiple opioids or stimulants were associated with significantly decreased predicted concentrations of commonly identified opioids in drug deaths. Further evidence is provided for enhanced risks from polysubstance use with opioids, which has important public health implications.