Naloxone dosing in the era of ultra-potent opioid overdoses: a systematic review

Abstract

ObjectivesEvaluate the relationship between naloxone dose (initial and cumulative) and opioid toxicity reversal and adverse events in undifferentiated and presumed fentanyl/ultra-potent opioid overdoses.MethodsWe searched Embase, MEDLINE, Cochrane Central Register of Controlled Trials, DARE, CINAHL, Science Citation Index, reference lists, toxicology websites, and conference proceedings (1972 to 2018). We included interventional, observational, and case studies/series reporting on naloxone dose and opioid toxicity reversal or adverse events in people >12 years old.ResultsA total of 174 studies (110 case reports/series, 57 observational, 7 interventional) with 26,660 subjects (median age 35 years; 74% male). Heterogeneity precluded meta-analysis. Where reported, we abstracted naloxone dose and proportion of patients with toxicity reversal. Among patients with presumed exposure to fentanyl/ultra-potent opioids, 56.9% (617/1,085) responded to an initial naloxone dose ≤0.4 mg compared with 80.2% (170/212) of heroin users, and 30.4% (7/23) responded to an initial naloxone dose >0.4 mg compared with 59.1% (1,434/2,428) of heroin users. Among patients who responded, median cumulative naloxone doses were higher for presumed fentanyl/ultra-potent opioids than heroin overdoses in North America, both before 2015 (fentanyl/ultra-potent opioids: 1.8 mg [interquartile interval {IQI}, 1.0, 4.0]; heroin: 0.8 mg [IQI, 0.4, 0.8]) and after 2015 (fentanyl/ultra-potent opioids: 3.4 mg [IQI, 3.0, 4.1]); heroin: 2 mg [IQI, 1.4, 2.0]). Where adverse events were reported, 11% (490/4,414) of subjects experienced withdrawal. Variable reporting, heterogeneity and poor-quality studies limit conclusions.ConclusionsPractitioners have used higher initial doses, and in some cases higher cumulative naloxone doses to reverse toxicity due to presumed fentanyl/ultra-potent opioid exposure compared with other opioids. High-quality comparative naloxone dosing studies assessing effectiveness and safety are needed.

Adverse events related to bystander naloxone administration in cases of suspected opioid overdose in British Columbia: An observational study

“…At program inception each THN kit contained two naloxone ampoules. In response to the rise of ultra-potent synthetic opioids on the illicit market, and evidence suggesting a need for higher naloxone dosing [27,28], a third ampoule was added to the kits in March 2016. We determined the health region by recoding the city or community where the overdose occurred.…”

“…McDonald and Strang also consolidated data on adverse events, and report 65 instances of withdrawal symptoms for the 2336 naloxone administrations included a rate of 2.8%. A recent systematic review by Moe et al 2020 [27] found that 11% of individuals experienced withdrawal, and 1% experienced pulmonary edema, after naloxone administration in community settings or emergency departments. Our study reported a higher estimate compared to Moe et al and McDonald & Strang; 15.4% of the sample reported moderate or severe withdrawal [27,37] In most BC health regions, the number of naloxone ampoules administered increased over time.…”

Steep increases in fentanyl-related mortality west of the Mississippi River: synthesizing recent evidence from county and state surveillance

“…Increasing the standard dose of naloxone is also warranted because overdoses involving synthetic opioids like fentanyl and fentanyl analogues often require more naloxone to reverse. (47, 48)…”

Take-home naloxone programs for suspected opioid overdose in community settings: a scoping umbrella review

“…We identified five systematic reviews focused on comparing the effectiveness between injectable (e.g., intravenous, subcutaneous, intramuscular) and noninjectable (e.g., intranasal, buccal, sublingual) naloxone routes of administration [30,39,40,42,44]. A final systematic review published in 2020 aimed to evaluate sufficient naloxone doses during an era of ultra-potent synthetic opioid use [39].…”