High-Dose Naloxone Formulations Are Not as Essential as We Thought

Naloxone is a U.S. Food and Drug Administration (FDA) approved opioid antagonist for reversing opioid overdoses. Naloxone is available to the public, and can be administered through intramuscular (IM), intravenous (IV), and intranasal spray (IN) routes. Our literature review aimed to improve understanding regarding the adequacy of the regularly distributed two doses of low-dose IM or IN naloxone in effectively reversing fentanyl overdoses and whether high-dose naloxone formulations (HDNF) formulations are an optimal solution to this problem. Moreover, our initiative incorporated the perspectives and experiences of people who use drugs (PWUD), enabling a more practical and contextually-grounded analysis. We began by discussing the knowledge and perspectives of Tennessee Harm Reduction, a small peer-led harm reduction organization. A comprehensive literature review was then conducted to gather relevant scholarly works on the subject matter. The evidence indicates that, although higher doses of naloxone have been administered in both clinical and community settings, the vast majority of fentanyl overdoses can be successfully reversed using standard IM dosages with the exception of carfentanil overdoses and other more potent fentanyl analogs, which necessitate three or more doses for effective reversal. Multiple studies documented the risk of precipitated withdrawal using high doses of naloxone. Notably, the possibility of recurring overdose symptoms after resuscitation exists, contingent upon the half-life of the specific opioid. Considering these findings and the current community practice of distributing multiple doses, we recommend providing at least four standard doses of IN or IM naloxone to each potential bystander, and training them to continue administration until the recipient achieves stability, ensuring appropriate intervals between each dose. Based on the evidence, we do not recommend HDNF in the place of providing four doses of standard naloxone due to the higher cost, risk of precipitated withdrawal and limited evidence compared to standard IN and IM. All results must be taken into consideration with the inclusion of the lived experiences, individual requirements, and consent of PWUD as crucial factors. It is imperative to refrain from formulating decisions concerning PWUD in their absence, as their participation and voices should be integral to the decision-making process.