BACKGROUND: Fatalities from opioid overdose have risen by 117% over the past 10 years. Increasing access to the opioid antagonist, naloxone can combat this trend and saves lives. This study investigates the various routes of naloxone administration for opioid reversal in the prehospital setting. METHODS: PubMed, Ovid, and Google Scholar were searched for references that included the words naloxone and prehospital. Inclusion criteria were peer reviewed publications after 1995, English language, studies conducted in an outpatient setting, and intramuscular, intranasal, intravenous, or subcutaneous formulations; exclusion criteria were review articles or editorials. RESULTS: 8 articles met the inclusion criteria: intramuscular, intranasal, intravenous, and subcutaneous dosage forms of naloxone were analyzed to compare their time to administration, time to efficacy, financial impact, administrator safety, and administrator preference. CONCLUSION: There is little consensus on the optimal route of naloxone administration in the prehospital setting. Little training is required for proper administration of the intramuscular auto-injector; however, the high price of this device is a barrier to access. Intranasal naloxone appears to be the optimal dosage form when considering cost, effectiveness, and administrator safety. Pharmacists must be aware of trends in naloxone use, dosage forms, and administration when caring for patients and their communities.