OBJECTIVES: The role of prescribed opioids and benzodiazepines as risk factors for opioid overdose (OOD) are well established, however, their role as potential ‘triggers’ of OOD has not been formally investigated. The objective of this study was to utilize a case-crossover design to evaluate the temporal relationship between controlled substance acquisition and OOD.

METHODS: This study utilized the Arkansas Prescription Drug Monitoring Program (PDMP) data from 2014 through 2020 to assess controlled substance acquisition and fatal and non-fatal OOD using linked death certificate, inpatient discharge and emergency department data. All persons residing in Arkansas who experienced an OOD or had ≥ 1 AR PDMP prescription fills were included. Controlled substance (CS) characteristics were described in the 7 days prior to overdose and compared to the CS characteristics in 11 weekly (7 day) control windows prior to overdose. Binary CS variables indicating presence or absence of: any CS, opioid, benzodiazepine, opioid and benzodiazepine, stimulant, sedative, carisoprodol, and pregabalin were created. Additionally, cumulative morphine milliequivalents were calculated for each time window. Conditional logistic regression models were estimated and adjusted odds ratios for each CS characteristic after accounting for other CS and prior overdose events are reported. For sensitivity analysis, time windows were adjusted to 3-day intervals.

RESULTS: A total of 2,818,135 individuals (45.10% male; 39.94 mean age) were included, of which 28,670 (1.02%) experienced ≥1 OOD(s). There was a significant association between OOD and the acquisition of a CS (OR=1.856; p<0.001), opioid (OR=1.982; p<0.001), benzodiazepine (OR=1.358; p<0.001), opioid and benzodiazepine (OR=2.302; p<0.001), stimulant (OR=0.723; p=0.029), and carisoprodol (OR=1.490; p<0.001) in the 7 days prior to an OOD event. A similar relationship was found in the sensitivity analysis.

CONCLUSIONS: The recent acquisition of a CS prescription, specifically opioids, benzodiazepines, and carisoprodol, was associated with increased risk of OOD.