Introduction: Introduction: Paramedics frequently make immediate life-altering decisions with minimal clinical information. This applies to their decision to treat an unconscious patient with naloxone when the history of an opioid overdose cannot be readily established. Among patients treated by paramedics with naloxone, our objective was to compare patient demographics, treatment interventions and clinical response between patients with and without a confirmed history of an opioid overdose. Methods: Methods: This was a retrospective cohort study design of consecutive patients treated with naloxone by paramedics between January 1, 2016, and June 30, 2017. Patients were classified based on whether paramedics did or did not document a history of an opioid overdose. Baseline characteristics, treatment interventions, and response to naloxone were compared between groups. Comparisons were done using a chi-squared or Fishers exact test. Results: Results: We identified 294 patients of whom 113 (38%) did not have a confirmed history of an opioid overdose. The groups were similar in gender, bystander CPR, and bystander administration of naloxone. There were no differences in the presence of pinpoint pupils, initial oxygen saturation, initial Glasgow Coma Score (GCS), respiratory rate, or time on scene. Both patient groups were managed similarly with respect to route of naloxone administration and the use of a bag valve mask. All patients who were intubated were in the no confirmed history group (n=5; p=.003). Post naloxone there were no differences in last recorded vital signs except the no confirmed history group was less likely to achieve a GCS 10 (57% versus 89%; p<.001). The overall post-naloxone development of agitation (9%) was moderate while the need for physical/chemical restraint (2%) was low with no differences between groups. All patients were transported to the hospital. Conclusion: Conclusion: A substantial proportion of patients who received naloxone did not have a confirmed history of an opioid overdose. These patients closely resembled those with a confirmed history with respect to demographics and physical characteristics. The primary difference was a lower proportion of patients with no confirmed history who achieved a post naloxone GCS 10. Despite a moderate development of post naloxone agitation, paramedics were able to manage most of these patients without the use of physical/chemical restraints.