Currently submitted to: Journal of Medical Internet Research
Date Submitted: Mar 29, 2026
Open Peer Review Period: Mar 30, 2026 - May 25, 2026
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Opioid-related Drug-Drug Interactions and Harm to Hospitalized Patients: A Retrospective Multicenter Cohort Study
ABSTRACT
Background Opioid-related drug–drug interactions (DDIs) are common in hospitalized patients and can lead to serious harm, especially when opioids are combined with central nervous system depressants. Electronic medical records (EMRs) often trigger DDI alerts to warn clinicians of potential DDIs, but the effect of DDI alerts on clinically relevant opioid DDIs and related patient harm remains uncertain. This study evaluated whether EMR-integrated opioid DDI alerts reduce clinically relevant interactions and associated harms in routine hospital care. Objective This study aimed to address this gap by determining whether introducing these alerts reduces the prevalence of potentially and clinically relevant opioid-related DDIs, as well as the rate of DDI-related patient harm in hospitalized patients. Methods This retrospective cohort study was a secondary analysis of a multicenter quasi-experimental controlled pre–post evaluation of EMR implementation across five Australian hospitals. Adult inpatients were randomly selected from all patients who stayed in study hospitals for a one-week period six months before and six months after EMR implementation. Inpatients were included if they had at least one prescribed and administered opioid and one concurrent medication. Interruptive opioid DDI alerts were active only at intervention sites post-EMR. Potential DDIs were identified using Stockley’s Interaction Checker; pharmacists adjudicated clinically relevant DDIs, and clinical pharmacologists assessed DDI-related harm and causality. Clustered logistic regression with generalized estimating equations, adjusting for demographic and clinical variables, estimated the effect of alerts involving opioids on three outcomes: clinically relevant opioid DDIs (primary), any potential opioid DDI, and opioid DDI-related harm. Results Of 1,144 patients prescribed an opioid, 847 (74.0%) had at least one potential opioid DDI and 548 (47.9%) had at least one clinically relevant DDI. EMR alerts were associated with no significant change in clinically relevant DDIs (adjusted odds ratio 1.06, 95% CI 0.72–1.55; p=0.75). There was a significant reduction in potential opioid DDIs (adjusted odds ratio 0.55, 95% CI 0.41–0.74; p<0.001). Of all patients, there were 11 patients with a total of 38 DDIs experienced harm (0.6% of potential and 1.1% of clinically relevant DDIs), with most DDIs involving pharmacodynamic interactions with concomitant CNS depressants. Conclusion EMR opioid DDI alerts reduced overall exposure to potential DDIs but did not decrease clinically relevant interactions or related harm. The low rate of harmful events highlights the limited clinical value of current alert systems and the burden of low-value warnings.
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