The Need for Multiple Naloxone Administrations for Opioid Overdose Reversals: A Review of the Literature

Abstract

Background A growing challenge in the opioid epidemic is the rise of highly potent synthetic opioids, (i.e., illicitly manufactured fentanyl [IMF]) entering the US non-prescription opioid market. Successful reversal may require multiple doses of naloxone, the standard of care for opioid overdose. We conducted a narrative literature review to summarize the rates of multiple naloxone administrations (MNA) for opioid overdose reversal. Methods: A MEDLINE search was conducted for published articles using MESH search terms: opioid overdose, naloxone and multiple naloxone administration. Of the 2,101 studies identified, articles meeting inclusion/exclusion criteria were reviewed, categorized by primary and secondary outcomes of interest and summarized by data source and study design. Results: A total of 24 articles meeting eligibility criteria were included. Among EMS-based studies, MNA rates ranged from 9% to 53%; in general, bystander-reported studies were notably higher, from 16% to 89%. Variation in study design, data sources, year and geography, may have contributed to these ranges. Three studies that included longitudinal results reported a significant percent increase between 26% and 43% in annual MNA rates or a significant increase in mean naloxone doses over time (p < .001). Conclusions: This summary found that multiple naloxone administrations during opioid overdose encounters vary widely, have occurred in up to 89% of all opioid overdoses, and have significantly increased over time. Higher naloxone formulations may fulfill an unmet need in opioid overdose reversals, given the rising rates of overdoses involving IMF. Further studies are needed to gain a better understanding of MNA during opioid overdose encounters, particularly across a wider geographic region in the US in order to inform continuing efforts to combat the opioid epidemic.

Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose

“…At a 2016 FDA advisory committee meeting on community use of naloxone, there was general agreement that the risk of underdosing naloxone far outweighs the potential risk of precipitating opioid withdrawal; however, a consensus could not be reached on certain aspects related to dosing recommendations, due to a lack of evidence . There are conflicting data in the literature on whether higher or more doses of naloxone are needed in the current era of illicitly manufactured fentanyl . Most studies are single-center retrospective analyses, with limitations such as only including patients who survived an overdose or combining naloxone data from different routes of administration without considering the differences in the time profile of naloxone plasma concentration.…”

“…Intranasal naloxone products are sold in packages with 2 single-use nasal sprays and are approved for administration as a single dose with repeat doses every 2 to 3 minutes if the patient does not respond. Questions have emerged as to whether current naloxone dosing is adequate in the era of illicitly manufactured fentanyl, because of fentanyl’s potential to induce rapid respiratory depression and death and the observation that higher naloxone doses have been required . In addition, there are limited clinical data on repeat intranasal dosing, which can result in less-than-dose-proportional increases in plasma concentration with intranasal drugs …”

Pharmacokinetic Properties of an FDA‐approved Intranasal Nalmefene Formulation for the Treatment of Opioid Overdose

“…The high affinity of nalmefene at μ opioid receptors 19‐21 and its durability of action to reverse opioid‐induced respiratory depression 36 are attributes that, when used in an IN formulation producing rapid delivery of high plasma concentrations, have the potential to provide an important new intervention for victims of an opioid overdose used in a community setting. These pharmacological attributes may be especially important in an era when almost 90% of opioid overdose deaths are linked to synthetic opioids 1 and there is emerging evidence 4‐10 that higher doses of naloxone are needed to reverse a synthetic (eg, fentanyl) opioid overdose compared to both natural and semisynthetic opiates (eg, morphine and heroin).…”

“…2,3 In the face of a continued rise in opioid overdose deaths, the competitive μ opioid receptor antagonist naloxone remains the "gold standard" reversal agent. 1 Nonetheless, converging lines of evidence, ranging from preclinical studies [4][5][6] to clinical reports, [7][8][9] quantitative systems modeling, 10 and a CDC advisory warning indicate higher doses of naloxone are required to reverse an overdose produced by synthetics compared to either natural or semisynthetic opiates. Leaders of the National Institutes of Health 11 have called for the development of "stronger, longer acting formulations of antagonists…" in response to the rise in fatalities linked to synthetics, a position endorsed by The President's Commission on Combatting Drug Addiction and the Opioid Crisis.…”

Real-World Study of Multiple Naloxone Administrations for Opioid Overdose Reversal among Emergency Medical Service Providers

“…15,16 Real-world evidence indicates that a percentage of opioid reversals require multiple naloxone administrations (MNA) for successful reversal, and that the frequency of MNA is increasing over time. [17][18][19][20] Notably, patients presenting in emergency departments (EDs) with overdoses involving IMF have been found to have excessively higher levels of drug concentration, requiring prolonged naloxone infusions, multiple bolus doses, or higher than standard naloxone doses for reversal. 18,[21][22][23] Using the National Emergency Medical Services Information System (NEMSIS) data, Faul et al 19 indicated that the rate of MNA increased by 26%, from 14.5% in 2012 to 18.2% in 2015.…”