Tolerant or Intolerant? Learning From Studying Drug Concentrations in the Living and the Dead.

A bstract: Tolerance is the diminished response to a drug that occurs when that drug is repeatedly used, and the body adapts to its continued presence. This means that greater blood concentrations are required to achieve desired effects, produce impairment, or cause death. Without case-specific information, the pharmacodynamic impacts of a drug on an individual are difficult to ascertain based on its concentration alone. One starting point, however, is to compare reported findings with reference ranges associated with therapeutic, toxic, and lethal outcomes. Toxicologists have observed concentrations dramatically increase over time in the living population for some drugs to concentrations that can easily be associated with impairment and lethal outcomes. It is, therefore, important to continually monitor and be familiar with drug concentrations found in the living to interpret postmortem concentrations. To emphasize this approach, we compared fentanyl concentrations from JAN 2010 to OCT 2023 in individuals investigated for driving under the influence of drugs to postmortem cases. This comparison highlights the changing nature of tolerance, stresses the importance of not relying solely on reference ranges for result interpretations, and discusses the importance of the autopsy in identifying or ruling out other potential causes of death.