This article was published on July 22, 2022.
Given the seriousness of the fentanyl epidemic and the huge number of people who are dying each year due to it, all articles on this website about fentanyl and fentanyl analogs are being made available to everyone and not only to our Members (subscribers). Please share these articles widely by email, social media, and other means.
Here are the links to the articles about fentanyl and fentanyl analogs:
The use of fentanyl or a fentanyl analog—intentional or unintentional—has become an extremely important and urgent issue in the United States.
The use of synthetic opioids like fentanyl or a fentanyl analog—alone or with another substance—is responsible for a staggering number of deaths each year. In 2020, in the United States, there were about 56,000 deaths in one year that involved synthetic opioids other than methadone—mainly, fentanyl (source).
There are important differences in how naloxone has to be used if it is suspected that fentanyl or fentanyl analog may be involved in the overdose.
Unfortunately, we may have to usually proceed on the assumption that fentanyl or a fentanyl analog may have been involved in the overdose because these synthetic opioids are increasingly added to a wide variety of illicit substances, frequently without the user’s knowledge (Volkow, 2021).
Higher doses of naloxone are needed for opioid overdoses involving fentanyl
The average dose of naloxone given in opioid overdose cases has increased over the years (Abdelal et al., 2022). It is believed that this is mainly due to the increased use of synthetic opioids like fentanyl.
To treat fentanyl overdoses, higher doses of naloxone are typically needed compared to overdoses on other opioids.
Higher-dose naloxone injection
In 2021, the FDA approved a higher-dose naloxone injection (brand name Zimhi®). This product is a single-dose, prefilled syringe that delivers 5 mg of naloxone and can be given intramuscularly or subcutaneously. As a comparison, injectable naloxone (brand name Narcan®) has been available in the United States in two strengths—0.4 mg and 2 mg.
In July 2022, a carton containing two of these 5 mg naloxone syringes cost about $140 (source: goodrx.com).
Higher-dose naloxone nasal spray
Similarly, in 2021, the FDA approved a higher-dose naloxone nasal spray (brand name Kloxxado®) that contains 8 mg of naloxone to be sprayed into one nostril. In comparison, the previously available naloxone nasal spray (generic or brand Narcan®) contains only half that amount of naloxone, that is, 4 mg.
Compared to the previously available naloxone nasal spray (4 mg) the new, 8 mg preparation:
– Reaches peak serum concentration faster (in 15 minutes versus 30 minutes)
– Not surprisingly, produces a peak serum concentration that is more than twice that of the 4 mg preparation.
In July 2022, a carton containing two of these 8 mg naloxone nasal sprays cost about $140, the same as two 5 mg naloxone syringes (source: goodrx.com).
More naloxone administrations are needed for overdoses involving fentanyl
A review of studies found that, in different studies, the percentages of cases of opioid overdose in which multiple doses of naloxone were required varied from about 10% to about 90% (Abdelal et al., 2022). Also, this percentage has increased over the years (Abdelal et al., 2022).
This may be because of the increased use of fentanyl—alone or combined with other opioids. In overdoses involving fentanyl, a greater number of administrations of naloxone are likely to be needed compared to overdoses with other opioids. This is because the half-life of naloxone is about 2 hours while the half-life of fentanyl is roughly 8 hours (Volkow, 2021).
Point of futility
The need for higher doses and a greater number of administrations of naloxone for overdoses in which fentanyl was involved an indirect clinical significance with regard to a rule of thumb that was previously used.
Those administering naloxone should be aware that, due to the widespread use of fentanyl and fentanyl analogs, the previous assumption that “if the person does not respond to 15 mg of naloxone, then it is unlikely that this was an opioid overdose” can no longer be made (Pergolizzi et al., 2021b).
Simple and Practical Medical Education thanks (alphabetically) Jonathan Beatty MD, and Marina Goldman, MD, for peer-reviewing and approving this article (in July and August 2022).
Dr. Beatty is a board-certified addiction psychiatrist in Philadelphia, Pennsylvania, who has extensive clinical experience in treating patients with substance use disorders. His clinical practice website is https://wavetreatmentcenters.com.
Dr. Goldman is a board-certified addiction psychiatrist. She is a Clinical Assistant Professor and Core Faculty in the Addiction Medicine & Addiction Psychiatry Fellowships at Thomas Jefferson University, Philadelphia, Pennsylvania. She also has a busy private practice in Jenkintown, Pennsylvania.
Opioid use disorder
Opioid use disorder—Management
Substance use disorders
Abdelal R, Banerjee AR, Carlberg-Racich S, Darwaza N, Ito D, Epstein J. The need for multiple naloxone administrations for opioid overdose reversals: A review of the literature. Subst Abus. 2022;43(1):774-784. doi: 10.1080/08897077.2021.2010252. PMID: 35112993.
Alaei S, Omidian H. Opioid overdose, interventions, and challenges. Bioimpacts. 2022;12(3):179-181. doi: 10.34172/bi.2022.24093. Epub 2022 Mar 8. PMID: 35677662; PMCID: PMC9124880.
Carpenter J, Murray BP, Atti S, Moran TP, Yancey A, Morgan B. Naloxone Dosing After Opioid Overdose in the Era of Illicitly Manufactured Fentanyl. J Med Toxicol. 2020 Jan;16(1):41-48. doi: 10.1007/s13181-019-00735-w. Epub 2019 Aug 30. PMID: 31471760; PMCID: PMC6942078.
Higher-Dose Naloxone Nasal Spray (Kloxxado) for Opioid Overdose. JAMA. 2021 Nov 9;326(18):1853-1854. doi: 10.1001/jama.2021.15948. PMID: 34751711.
Moe J, Godwin J, Purssell R, O’Sullivan F, Hau JP, Purssell E, Curran J, Doyle-Waters MM, Brasher PMA, Buxton JA, Hohl CM. Naloxone dosing in the era of ultra-potent opioid overdoses: a systematic review. CJEM. 2020 Mar;22(2):178-186. doi: 10.1017/cem.2019.471. PMID: 31955714.
Pergolizzi JV Jr, Dahan A, Ann LeQuang J, Raffa RB. Overdoses due to fentanyl and its analogues (F/FAs) push naloxone to the limit. J Clin Pharm Ther. 2021b Dec;46(6):1501-1504. doi: 10.1111/jcpt.13462. Epub 2021 Jun 10. PMID: 34111307.
Volkow ND. The epidemic of fentanyl misuse and overdoses: challenges and strategies. World Psychiatry. 2021 Jun;20(2):195-196. doi: 10.1002/wps.20846. PMID: 34002497; PMCID: PMC8129846.
Wightman RS, Nelson LS. Naloxone Dosing in the Era of Fentanyl: The Path Widens by Traveling Down It. Ann Emerg Med. 2022 May 25:S0196-0644(22)00263-3. doi: 10.1016/j.annemergmed.2022.04.014. Epub ahead of print. PMID: 35643776.
Copyright © 2022, Simple and Practical Medical Education, LLC. All rights reserved. May not be reproduced in any form without express written permission.
Disclaimer: The content on this website is provided as general education for medical professionals. It is not intended or recommended for patients or other laypersons or as a substitute for medical advice, diagnosis, or treatment. Patients must always consult a qualified health care professional regarding their diagnosis and treatment. Healthcare professionals should always check this website for the most recently updated information.