Pharmacological data science perspective on fatal incidents of morphine treatment.

Morphine prescribed for analgesia has caused drug-related deaths at an estimated incidence of 0.3% to 4%. Morphine has pharmacological properties that make it particularly difficult to assess the causality of morphine administration with a patient's death, such as its slow transfer between plasma and central nervous sites of action and the existence of the active metabolite morphine-6-glucuronide with opioid agonistic effects, Furthermore, there is no well-defined toxic dose or plasma/blood concentration for morphine. Dosing is often adjusted for adequate pain relief. Here, we summarize reported deaths associated with morphine therapy, including associated morphine exposure and modulating patient factors such as pharmacogenetics, concomitant medications, or comorbidities. In addition, we systematically analyzed published numerical information on the stability of concentrations of morphine and its relevant metabolites in biological samples collected postmortem. A medicolegal case is presented in which the causality of morphine administration with death was in dispute and pharmacokinetic modeling was applied to infer the administered dose. The results of this analytical review suggest that (i) inference from postmortem blood concentrations to the morphine dose administered has low validity and (ii) causality between a patient's death and the morphine dose administered remains a highly context-dependent and collaborative assessment among experts from different medical specialties.