Abstract / Summary
Opioid overdose deaths in the United States have surged over the past two decades, driven largely by the proliferation of illicitly manufactured fentanyls (IMFs). Concerns that standard naloxone doses may be insufficient for reversing IMF-related overdoses have prompted FDA approval of high-dose naloxone formulations and the long-acting antagonist nalmefene. Synthesized evidence on these agents is lacking. To evaluate the existing literature on high-dose/concentrated naloxone and nalmefene for opioid overdose reversal, with a focus on efficacy, effectiveness, safety, and tolerability. This scoping review followed PRISMA-ScR guidelines. PubMed, Ovid Medline, and APA PsycINFO were searched in September 2025. Studies published since 2015 that evaluated intramuscular or intranasal high-dose naloxone (> 4 mg) or nalmefene for overdose reversal were eligible. Intravenous formulations and preclinical studies were excluded. Two independent reviewers screened titles/abstracts and full texts, with a third reviewer resolving disagreements. Ten studies met the inclusion criteria—five examining high-dose naloxone and five examining nalmefene. All were pharmacokinetic and/or pharmacodynamic studies, and all but one were conducted with healthy volunteers. High-dose naloxone demonstrated dose-proportional increases in maximum serum concentration, with absorption rates comparable to those of standard doses. Nalmefene exhibited a longer terminal half-life and a faster restoration of respiratory drive than naloxone. Both agents were generally well tolerated, with no serious adverse events reported across studies. Current evidence on high-dose naloxone and nalmefene is confined to controlled pharmacokinetic investigations with limited generalizability in real-world overdose settings. Robust clinical outcome studies in community populations are urgently needed to guide evidence-based overdose response strategies.