Take-home naloxone distribution is a key harm-reduction strategy in emergency departments and community programs to prevent opioid overdose deaths. Intranasal naloxone is commonly provided as either single-step devices or multi-step kits requiring assembly. Device complexity may influence the effectiveness of take-home naloxone programs, particularly among lay responders without prior training, yet usability among individuals most likely to witness or experience overdose is not well characterized.

We conducted a randomized usability study in an urban emergency department. Participants without prior naloxone training were randomized to administer naloxone using either a commercially manufactured single-step intranasal device or an improvised multi-step kit during a standardized simulated overdose scenario designed to assess first use usability. The primary outcome was successful completion of predefined critical steps; secondary outcomes included time to administration and participant-reported usability.

Forty participants were enrolled (20 per group). During the pre-education simulation, successful completion of all critical steps occurred in 17/20 (85%) participants assigned to the single-step device compared to 4/20 (20%) assigned to the multi-step device (risk difference 65 percentage points; 95% CI 42–83; p   <  .001). Median time to successful administration was shorter with the single-step device (30 s [IQR 24–38] vs 58 s [45–75]; p   <  .001). Following a brief structured educational intervention, success rates improved and no longer differed significantly (100% vs 90%; p  = .29), although administration time remained shorter with the single-step device (22 s [18–29] vs 35 s [28–47]; p  = .002).

In this simulated overdose scenario among at-risk individuals, a single-step intranasal naloxone device produced higher first attempt success rates and faster administration than an improvised multi-step kit. Although brief structured education substantially improved performance with the multi-step device, administration times remained shorter with the single-step device. These findings suggest that device complexity may influence the real-world effectiveness of emergency department and community naloxone distribution programs, particularly when structured training is not consistently available.