Comparison of the Pharmacokinetic Properties of Naloxone Following the Use of FDA‐Approved Intranasal and Intramuscular Devices Versus a Common Improvised Nasal Naloxone Device

Abstract

For more than a decade, first responders and the general public have been able to treat suspected opioid overdoses using an improvised nasal naloxone device (INND) constructed from a prefilled syringe containing 2 mg of naloxone (1 mg/mL) attached to a mucosal atomization device. In recent years, the U.S. Food and Drug Administration (FDA)-approved Ezvio, an autoinjector that delivers 2 mg by intramuscular injection and Narcan nasal spray (2-and 4-mg strengths; 0.1 mL/dose) for the emergency treatment of a known or suspected opioid overdose. The present study was conducted to compare the pharmacokinetics of naloxone using the FDA-approved devices (each administered once) and either 1 or 2 administrations using the INND. When naloxone was administered twice using the improvised device, the doses were separated by 2 minutes. The highest maximum plasma concentration was achieved using the 4-mg FDA-approved spray. The highest exposures at 5 minutes postdose, based on AUC values, were after administration with the autoinjector and the 4-mg FDA-approved spray; at 10, 15, and 20 minutes postdose, the latter yielded the greatest exposure. Even after 2 administrations, the INND failed to achieve naloxone plasma levels comparable to the FDA-approved devices at any time. The ease of use and higher plasma concentrations achieved using the 4-mg FDA-approved spray, compared with the INND, should be considered when deciding which naloxone device to use.

Take-Home Naloxone for the Emergency Interim Management of Opioid Overdose: The Public Health Application of an Emergency Medicine

“…Subsequent examination of patent records located data confirming only poor bioavailability (approximately 10% of dose administered) [82] and recent direct pharmacokinetic comparison of the improvised kits vs. the new concentrated naloxone nasal spray formulations found bioavailability of only approximately 20% with the improvised kits vs. more than 40% with the new concentrated naloxone sprays [83]. Nevertheless, the evident successful reversals of opioid overdoses with these improvised kits [75–77] should raise questions about the dose necessary for layperson reversal which, in these instances, appears to have been achieved with much lower absorbed concentrations of naloxone.…”

“…Most importantly, these high-concentrate sprays deliver therapeutic doses (0.4–2.0 mg) in a single 0.1-mL spray, and a second spray gives a proportionate rise in serum concentrations. In contrast, dilute nasal spray (2 mg/2 mL) administered via the MAD only had 11–20% absolute bioavailability, implying that a sub-therapeutic dose of approximately 0.2–0.4 mg was delivered [74, 82, 83]. A recent study confirmed that, even after two administrations, dilute nasal spray (2 mg/2 mL, administered via a MAD) failed to achieve naloxone plasma concentrations comparable to concentrate nasal sprays (2 mg/0.1 mL, 4 mg/0.1 mL) at any time [83].…”

Factors associated with withdrawal symptoms and anger among people resuscitated from an opioid overdose by take-home naloxone: Exploratory mixed methods analysis

“…One variable that was considered but reluctantly excluded was a naloxone dose variable. Whilst it would have been theoretically possible to convert the naloxone given at each overdose into a standardised dose, this would likely have produced misleading data as the amount of naloxone absorbed from different kits and formulations varies significantly (McDonald et al, 2018;Krieter et al, 2019). After several attempts to calculate a variable for 'naloxone dose absorbed', the team were not satisfied that the results were sufficiently reliable and so decided to use variables for 'intramuscular versus intranasal administration' and 'one naloxone dose versus more than one naloxone dose' instead.…”

Rapid systemic uptake of naloxone after intranasal administration in children

“…1,2 There are only a few previous studies describing the pharmacokinetics of intranasal naloxone, and in these, the concentration of naloxone used is higher than in the commonly marketed solution. [3][4][5][6] In children, there are only case reports on the use of intranasal naloxone. 7 Our group has previously shown that in adult healthy volunteers, intranasal administration of the commonly marketed solution of naloxone, 0.4 mg/ml, has a bioavailability that is comparable to intramuscular injection.…”

“…Naloxone is often administrated intravenously, but there is a growing interest in the intranasal route, mainly in treating patients with opioid overdose 1,2 . There are only a few previous studies describing the pharmacokinetics of intranasal naloxone, and in these, the concentration of naloxone used is higher than in the commonly marketed solution 3–6 . In children, there are only case reports on the use of intranasal naloxone 7 .…”