What are the differences in efficacy and safety of intranasal naloxone versus nalmefene?

Background:
Since the start of increased opioid prescribing to treat pain in the 1990s, there has been a steady and significant rise of opioid overdose-related deaths.¹ From 1999 to 2021, over 645,000 people in the United States have died from a prescription or illicit opioid-related overdose, contributing to the opioid overdose epidemic. These deaths represent only a fraction of the population who are affected by opioid misuse and addiction, otherwise known as opioid use disorder (OUD).²

To combat this national crisis, the Centers for Disease Control and Prevention (CDC) and many professional organizations, such as Substance Abuse and Mental Health Services Administration (SAMHSA) and American Society of Addiction Medicine (ASAM), have been advocating for increased accessibility of opioid antagonists, life-saving agents used during acute opioid overdoses.^1-3 An opioid overdose can cause sedation, hypotension, severe respiratory depression, and/or central nervous system depression, possibly leading to death if left untreated. Opioid antagonists can be used emergently to reverse the effects of opioids and restore an individual’s respiratory drive.^2,4,5 Historically, the most commonly used medication in this drug class is naloxone.

Naloxone is a pure opioid antagonist that competitively displaces opioids at μ, κ and δ opioid receptors.⁶ It is highly lipophilic and has rapid distribution to the brain, causing an abrupt displacement of the opioids to reverse their effects within 3 to 17 minutes with the intranasal (IN) formulation.^4,7 Naloxone is available in 2 main dosage forms that can be given through various routes of administration.⁷ Injectable naloxone given via intravenous (IV) push is commonly used by healthcare professionals and is preferred when IV access is available. If IV access is unobtainable, the injectable formulation can be administered intramuscularly or subcutaneously. In an attempt to provide a more accessible formulation for use by the general public without supervision by a healthcare professional, a pre-filled IN naloxone spray was developed, that is now available as a prescription and over-the-counter (OTC) formulation.^5,7-9

Although naloxone has been shown to be a life-saving antidote, it is not without its drawbacks. The major concern is its relatively short duration of action.^4,7 Depending on the route of administration, naloxone’s duration is between 30 to 120 minutes. As many opioids are long-acting, this short duration of action puts patients at risk for recurrence of respiratory depression. Furthermore, synthetic opioids are shown to be more potent, requiring patients to receive higher or repeated doses of naloxone.^1,2,7 Intranasal nalmefene spray (Opvee) was recently approved by the US Food and Drug Administration (FDA) for the reversal of opioid toxicity.^10,11 The objective of this article is to compare the efficacy and safety of IN naloxone and IN nalmefene for the treatment of acute opioid overdose.

Introduction to nalmefene:
Nalmefene is a novel nasal spray that was FDA-approved in May 2023 for acute opioid overdose reversal.^10,11 Nalmefene, like naloxone, is a competitive opioid receptor antagonist; however, it has a longer duration of action and a higher affinity for opioid receptors.⁷ Its recommended dose for opioid overdose reversal is 2.7 mg (1 nasal spray), as a single dose in 1 nostril, which can be repeated every 2 to 5 minutes as necessary in alternating nostrils.^7,11 Although nalmefene nasal spray is a newly approved medication, nalmefene itself is not a new drug. It was originally FDA-approved for injection in 1995 for the treatment of opioid overedose.¹⁰ However, due to poor sales, injectable nalmefene was eventually taken off the market in 2008. The recently approved nalmefene nasal spray has been shown to be bioequivalent and pharmacokinetically equivalent to the previously available injectable product.^10-12 Due to its long half-life (11.4 hours) and quick onset of action (2.5 to 5 minutes), its pharmacokinetic profile could be advantageous for patients in acute overdose.^6,10-12

However, there is also concern and skepticism about nalmefene’s role in opioid overdose reversal. First, the new IN formulation did not require new clinical data for approval.^10-13 Instead, the IN nalmefene was approved after demonstrating bioequivalence and pharmacokinetic equivalence to injectable nalmefene. Most importantly, there is limited clinical data studying the use of IN nalmefene in patients being treated for opioid overdose reversal.^11,13,14 Furthermore, the same pharmacokinetic factors that are considered a possible advantage, may pose their own problems. Nalmefene’s long duration of action could, in turn, cause severe and prolonged withdrawals, which may lead individuals to use more opioids to stave off the symptoms of withdrawal.^11-14 Additionally, nalmefene is currently only available by prescription, unlike naloxone which was recently approved for OTC access. Nalemfene will likely not be available OTC until there is more data to establish its safety and efficacy. Due to these reasons, further research on this product’s safety and efficacy in comparison to IN naloxone is needed before it can be considered a viable alternative.

Nalmefene versus naloxone
Since the approval of IN nalmefene, there has been 1 head-to-head study comparing IN nalmefene to IN naloxone.¹⁵ This open-label, crossover, non-inferiority trial compared the pharmacodynamic effects of using 4 mg IN naloxone or 2.7 mg IN nalmefene to reverse remifentanil-induced respiratory depression, as estimated by reductions of minute ventilation (MV). Patients were initially administered a hypercapnic gas mixture to produce an elevation in MV. Remifentanil was then administered to cause a reduction in MV, similar to opioid-induced respiratory depression. The primary objective of the study was to demonstrate IN nalmefene’s non-inferiority of reversing remifentanil-induced MV reductions at 5 minutes post-administration compared to IN naloxone. This procedure and surrogate outcome was chosen to safely mimic opioid-induced respiratory depression, as intentionally causing an opioid overdose would be unethical. A non-inferiority margin was set at 80% of the estimated reversal produced by naloxone, with anything higher than 80% representing a clinically significant difference.

Sixty-nine healthy participants were randomized to the 2 treatment groups.¹⁵ Fifteen minutes after the initiation of the remifentanil infusion, the participants were administered either IN nalmefene 2.7 mg or IN naloxone 4 mg. Both naloxone and nalmefene were effective at reversing the MV reductions in the first 20 minutes after administration. The primary outcome of least-squares mean difference of MV at 5 minutes post-administration was 5.74 L/min in the nalmefene group and 3.01 L/min in the naloxone group. The difference between naloxone and nalmefene demonstrated non-inferiority (−2.73 L/min) and was statistically significantly (p-value < 0.0009), favoring nalmefene.

In this trial, change in MV was used as a measure for speed of onset of each drug, and nalmefene demonstrated both non-inferiority and superiority when compared to naloxone.¹⁵ Nalmefene reversal was rapid, reaching an apparent complete reversal within 5 minutes, compared to naloxone that demonstrated a more gradual reversal, taking 20 minutes to restore MV values. However, this trial also had limitations. The use of change in MV as a primary outcome limits interpretation to clinical outcomes. It is unknown how change in MV may relate to outcomes in an actual overdose situation. Furthermore, as the study was stopped after 120 minutes post-administration of nalmefene or naloxone, the effects of nalmefene’s longer duration of action on safety considerations such as withdrawal were not able to be monitored.

As mentioned above, IN nalmefene and IN naloxone have differences in their pharmacokinetic profiles.^4,7,11 The following table describes a few important pharmacokinetic characteristics that may be considered for the selection of one product over another.

Concerns with use of nalmefene
Although this trial has shown evidence of IN nalmefene’s pharmacokinetic efficacy and potential pharmacological advantages, there is limited additional clinical evidence to replace naloxone as the primary opioid antidote.¹⁵ Since the approval of IN nalmefene, the American College of Medical Toxicology (ACMT) has released a statement addressing their concerns about its use.¹⁴ As mentioned above, IN nalmefene did not require new clinical data to be approved, but instead was approved after demonstrating bioequivalence and pharmacokinetic equivalence to injectable nalmefene. The trials comparing injectable naloxone and nalmefene were predominantly done before the twenty-first century and there is limited additional data to assess IN nalmefene’s efficacy with newer, more potent synthetic opioids.

In general, there is limited clinical data available on the use of IN nalmefene in patients being treated for opioid overdose reversal.^11,13,14 The ACMT also mentioned concerns that a longer-acting reversal agent would not improve current practices and could potentially cause harm, as longer-acting opioid antagonists may lead to longer lasting precipitated withdrawals.¹⁴ Due to these 2 main concerns, ACMT has recommended to continue using naloxone as the preferred first-line agent for acute opioid reversal, until there is higher quality data supporting the use of IN nalmefene.

Conclusions:
The newly approved IN nalmefene has shown promise as a potential new option for acute opioid overdose reversal due to its quick onset and long duration of action.^7,12,15 However, with limited clinical data available on its use, there are concerns about its routine use when compared to IN naloxone. For this reason, it is important to conduct further studies of IN nalmefene in the anticipated patient population and utilize clinical judgment when using this drug. Professional organizations still recommend the use of IN naloxone over IN nalmefene at this time.^1-3,5

References

1. Understanding the opioid overdose epidemic. Centers for Disease Control and Prevention. Updated August 8, 2023. Accessed April 10, 2024. https://www.cdc.gov/opioids/basics/epidemic.html
2. Medications for opioid use disorder for healthcare and addiction professionals, policymakers, patients, and families: Treatment improvement protocol 63. Substance Abuse and Mental Health Services Administration. August 2021. Accessed April 10, 2024. https://store.samhsa.gov/sites/default/files/pep21-02-01-002.pdf
3. The national practice guideline for the treatment of opioid use disorder: 2020 focused updated. American Society of Addiction Medicine. 2020. Accessed April 10, 2024. https://www.asam.org/quality-care/clinical-guidelines/national-practice-guideline
4. Naloxone hydrochloride nasal spray. Package insert. Teva Pharmaceuticals Inc. 2023.
5. Lifesaving naloxone. Centers for Disease Control and Prevention. April 21, 2023. Accessed April 10, 2024. https://www.cdc.gov/stopoverdose/naloxone/index.html
6. Mycyk MB, Szyszko AL, Aks SE. Nebulized naloxone gently and effectively reverses methadone intoxication. J Emerg Med. 2003;24(2):185-187. doi:10.1016/s0736-4679(02)00723-0
7. UpToDate Lexicomp. Wolters Kluwer. 2024. Accessed April 10, 2024. https://www.uptodate.com/contents/search
8. FDA approves first over-the-counter naloxone nasal spray. US Food and Drug Administration. March 29, 2023. Accessed April 10, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-over-counter-naloxone-nasal-spray
9. FDA approves second over-the-counter naloxone nasal spray product. US Food and Drug Administration. July 28, 2023. Accessed April 10, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-second-over-counter-naloxone-nasal-spray-product
10. FDA approves prescription nasal spray to reverse opioid overdose. US Food and Drug Administration. May 22, 2023. Accessed April 10, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-prescription-nasal-spray-reverse-opioid-overdose
11. Opvee (nalmefene) nasal spray. Package insert. Opiant Pharmaceuticals. 2023.
12. Crystal R, Ellison M, Purdon C, Skolnick P. Pharmacokinetic properties of an FDA-approved intranasal nalmefene formulation for the treatment of opioid overdose. Clin Pharmacol Drug Dev. 2024;13(1):58-69. doi:10.1002/cpdd.1312
13. Infante AF, Elmes AT, Gimbar RP, Messmer SE, Neeb C, Jarrett JB. Stronger, longer, better opioid antagonists? Nalmefene is not a naloxone replacement. Int J Drug Policy. 2024;124:104323. doi:10.1016/j.drugpo.2024.104323
14. Stolbach AI, Mazer-Amirshahi ME, Nelson LS, Cole JB. American College of Medical Toxicology and the American Academy of Clinical Toxicology position statement: nalmefene should not replace naloxone as the primary opioid antidote at this time. Clin Toxicol (Phila). 2023;61(11):952-955. doi:10.1080/15563650.2023.2283391
15. Ellison M, Hutton E, Webster L, Skolnick P. Reversal of opioid-induced respiratory depression in healthy volunteers: comparison of intranasal nalmefene and intranasal naloxone. J Clin Pharmacol. 2024. doi:10.1002/jcph.2421

Prepared by:
Shankari Sureshbabu, PharmD
PGY1 Pharmacy Practice Resident
John H. Stroger, Jr. Hospital of Cook County

Reviewed by:
Rachel Brunner, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2024

The information presented is current as of April 3, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.