Opioid Deaths: Trends, Biomarkers, and Potential Drug Interactions Revealed by Decision Tree Analyses

Abstract

Opioid abuse is now the primary cause of accidental deaths in the United States. Studies over several decades established the cyclical nature of abused drugs of choice, with a current resurgence of heroin abuse and, more recently, fentanyl’s emergence as a major precipitant of drug-related deaths. To better understand abuse trends and to explore the potential lethality of specific drug–drug interactions, we conducted statistical analyses of forensic toxicological data from the Wayne County Medical Examiner’s Office from 2012–2016. We observed clear changes in opioid abuse over this period, including the rapid emergence of fentanyl and its analogs as highly significant causes of lethality starting in 2014. We then used Chi-square Automatic Interaction Detector (CHAID)-based decision tree analyses to obtain insights regarding specific drugs, drug combinations, and biomarkers in blood most predictive of cause of death or circumstances surrounding death. The presence of the non-opioid drug acetaminophen was highly predictive of drug-related deaths, likely reflecting the abuse of various combined acetaminophen-opioid formulations. The short-lived cocaine adulterant levamisole was highly predictive of a short post-cocaine survival time preceding sudden non-drug-related death. The combination of the opioid methadone and the antidepressant citalopram was uniformly linked to drug death, suggesting a potential drug–drug interaction at the level of a pathophysiological effect on the heart and/or drug metabolism. The presence of fentanyl plus the benzodiazepine midazolam was diagnostic for in-hospital deaths following serious medical illness and interventions that included these drugs. These data highlight the power of decision tree analyses not only in the determination of cause of death, but also as a key surveillance tool to inform drug abuse treatment and public health policies for combating the opioid crisis.

Antidepressants abuse in subjects with opioid use disorders: A 10‐year study in the French OPPIDUM program

“…Escitalopram and citalopram use dropped markedly. This drop occurred after escitalopram and citalopram contraindication with methadone in 2014 because of increased risk of ventricular rhythm disorders [28,29]. Concomitant use of escitalopram or citalopram and methadone only persisted in very few subjects, suggesting that the situation regarding this interaction significantly improved.…”

The Risk of Ventricular Dysrhythmia or Sudden Death in Patients Receiving Serotonin Reuptake Inhibitors With Methadone: A Population-Based Study

“…Among SRIs, citalopram and escitalopram are associated with greater QT prolongation and a higher risk of sudden cardiac death than other agents ( Castro et al, 2013 ; Beach et al, 2014 ; Assimon et al, 2019 ). The potential for a clinically important interaction between citalopram and methadone was highlighted by a study of forensic toxicological records in the United States, in which a strong signal for drug fatality with combined use was detected ( Saad et al, 2018 ).…”

Toxicological Findings in a Possible Drug-drug Interaction Death: A Case Report

“…The occurrence of drug-drug interaction is highly common in hospitalized elderly patients and may lead to death [4]. Fentanyl, tramadol, and carbamazepine are common in multi-drug poisoning deaths [2,5]. This study focuses on a death in which fentanyl, tramadol and carbamazepine were detected.…”