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Home » A New High-Dose Naloxone: Life Saver or Punishment?

A New High-Dose Naloxone: Life Saver or Punishment?

July 3, 2021
Noah Capurso, MD
From The Carlat Addiction Treatment Report
Issue Links: Learning Objectives | Editorial Information | PDF of Issue
Noah Capurso, Editor-in-ChiefNoah Capurso, MD 

Dr. Capurso has disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.


The FDA approved a new intranasal formulation of naloxone on April 30, 2021. Called KLOXXADO, this formulation distinguishes itself from other delivery systems by its higher dose, with each nasal spray containing 8 mg of naloxone. In comparison, the most widely used naloxone product, Narcan Nasal Spray, contains 4 mg of naloxone.

What’s the rationale behind this higher-dose formulation? Recall that intranasal naloxone is used to quickly reverse opioid overdoses. The most common scenario is that someone who has used heroin or fentanyl passes out, and one of their friends (who may use drugs themselves) or family members finds them and must take quick action to save the person’s life. Assuming they have a vial of naloxone, the bystander sprays a dose into the overdose victim’s nostril and waits 2–3 minutes for a response—and may have to readminister in the other nostril if the victim remains obtunded. The idea behind KLOXXADO is that doubling the first dose of naloxone is more likely to revive the victim on the first try, preventing a potentially fatal delay. Hikma, the manufacturer of KLOXXADO, claims the need for multiple doses is becoming more common due to the abundance of fentanyl and fentanyl derivatives in the illicit opioid supply.

FDA approval was granted based on the results of two pharmacokinetic studies in which healthy volunteers received naloxone intramuscularly, intravenously, or via KLOXXADO, then had their plasma concentrations of naloxone measured over time. Naloxone is readily absorbed through the nasal mucosa, so it was no surprise that it was detectable just a few minutes after a dose of KLOXXADO. Naloxone is also effective at overdose reversal when given intramuscularly, and the studies showed both KLOXXADO and intramuscular doses reached their maximum concentrations at the same time point (about 15 minutes).

Approval was not granted based on efficacy data, but we know naloxone is safe and effective at reversing opioid overdoses, so we can be confident KLOXXADO will be safe and effective as well. However, some harm reduction experts dispute that fentanyl overdoses inherently require more naloxone to reverse than overdoses caused by other opioid agonists. In fact, some data indirectly suggest that fentanyl overdoses might not require any more naloxone than heroin overdoses (Bell A et al, Subst Abus 2019;40(1):52–55).

If these experts are right, KLOXXADO might be designed to deliver an unnecessarily high dose of naloxone, and this is likely to worsen the discomfort of those having their overdoses reversed. A double dose of naloxone means twice as many antagonist molecules are suddenly available to displace the opioid agonist from mu receptors, increasing risk and severity of precipitated withdrawal. Some worry that people who use opioids might see this harsher withdrawal as punitive, and that this could discourage users from acquiring naloxone rescue kits in the first place.

CATR’s TAKE
Without firm evidence of its necessity—not to mention its likely high price tag—consider KLOXXADO only for patients who have received multiple naloxone doses in the past. Far more important than the number of milligrams per spray is that patients who use opioids have naloxone on hand, regardless of the particular formulation.


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Addiction Treatment
KEYWORDS harm-reduction naloxone opioid-use-disorder
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    Noah Capurso, MD

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