Provider Letter: Opioid Overdose Reversal Medications

The following letter was originally posted for providers on July 3, 2024, and was updated on August 22, 2024. 

In recent months, there has been increasing public focus on newly approved opioid antagonist medications that reverse opioid overdose. The currently available opioid antagonist medications include, but are not limited to, naloxone 4mg intranasal spray and injection, naloxone 8 mg intranasal spray, and the recently approved nalmefene, a long-acting opioid antagonist, intranasal spray. Table 1 provides a complete list of FDA-approved opioid overdose reversal medications.

We have heard questions from community members and providers about whether the standard doses of naloxone 4mg could effectively reverse the effects of fentanyl and fentanyl analogues, the primary drivers of overdose mortality in New York State and nationwide. As a response to these questions, and given the availability of new treatment options, this document reviews the current evidence regarding opioid antagonist medications to inform clinical decision-making and to disseminate as community education.

Before discussing the evidence, we want to emphasize that a delayed response of up to 5 minutes between the administration of any opioid antagonist medication and the return of normal breathing is expected. Second doses of antagonist medication may be administered if normal breathing has not resumed after 5 minutes.  After administering the first dose of medication, providing cardiorespiratory resuscitation (CPR) and activating emergency medical services are life-saving measures.    

Table 1

FDA approved opioid overdose reversal medications

Table Abbreviations: IM, intramuscular; IV, intravenous; Rx, prescription; OTC, over the counter.

Although there are several options available for opioid overdose reversal, more than 50 years of high-quality data have demonstrated that naloxone 4mg is both clinically effective and cost-effective in reversing opioid overdose.

Key Points

• Effectiveness of naloxone 4mg intranasal spray and 4mg injection for opioid overdose reversal has been demonstrated in multiple settings, including emergency departments, public areas, and homes.⁴
• Naloxone 4mg is effective for reversing overdoses involving fentanyl and fentanyl analogs.⁵
• Current research shows that there are no added benefits to administering 8-mg versus 4-mg doses of naloxone in suspected overdoses.^6,7
• Naloxone 8mg intranasal spray has no proven survival benefit compared to naloxone 4mg.  However, compared to naloxone 4mg, higher doses of naloxone can cause more adverse events, including a more severe acute opioid withdrawal syndrome. ^6,8,9,10
• Although proponents praise nalmefene’s potentially longer-acting effects—existing data currently indicate that it does not increase survival rates over naloxone 4 mg and may lead to a more severe and protracted opioid withdrawal syndrome.^3,6,7,10
• Naloxone is the only overdose reversal medication that is approved for people of all ages and people who are pregnant.¹¹

Important Considerations

• The person in a state of severe acute or protracted opioid withdrawal may attempt to manage their symptoms by using large amounts of opioids to overcome the opioid blockade, leading to an increased risk of overdose death.
• Some have expressed concerns that people who have experienced an overdose treated with naloxone 8mg with subsequent severe acute opioid withdrawal syndrome, may be more reluctant to seek needed healthcare in a future overdose given the negative experience. ^6,8,9,10
• Important aspects of naloxone 4mg’s effectiveness are that it has high acceptability by a diverse range of communities, it is approved for use in people of all ages and people who are pregnant, and it is available as a generic medication in most communities at low or no cost to the individual.

Decades of experience with naloxone 4mg as an effective medication to treat opioid overdose, in addition to its availability over the counter, continues to support naloxone 4mg as the first line medication for opioid overdose reversal. Research examining the use of naloxone 8mg or the long- acting nalmefene have not demonstrated superior efficacy compared to naloxone 4mg.

There are some medically supervised settings where severe, acute, and protracted withdrawal can be more easily managed, such as inpatient services and emergency departments, where naloxone 8mg or long-acting nalmefene may have a role, but this will require further study.

Comments and Questions 

Email [email protected]

References

1. FDA citation for information: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-about-naloxone-and-nalmefene.
2. Naloxone 3mg approved intranasally in 2023; available in New York State at opioid overdose prevention programs.
3. Naloxone 4mg approved intranasally in 2015 and made available over-the-counter in 2023.
4. McDonald R, Strang J. Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria. Addiction. Jul 2016;111(7):1177-87. doi:10.1111/add.13326
5. Britch SC, Walsh SL. Treatment of opioid overdose: current approaches and recent advances. Psychopharmacology (Berl). Jul 2022;239(7):2063-2081. doi:10.1007/s00213-022-06125-5
6. Stolbach AI, Mazer-Amirshahi M, 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. J Med Toxicol. Jan 2024;20(1):64-67. doi:10.1007/s13181-023-00981-z
7. Payne ER, Stancliff S, Rowe K, Christie JA, Dailey MW. Comparison of Administration of 8-Milligram and 4-Milligram Intranasal Naloxone by Law Enforcement During Response to Suspected Opioid Overdose - New York, March 2022-August 2023. MMWR Morb Mortal Wkly Rep. Feb 8 2024;73(5):110-113. doi:10.15585/mmwr.mm7305a4
8. Bohler RM, Hodgkin D, Kreiner PW, Green TC. Predictors of US states’ adoption of naloxone access laws, 2001–2017. Drug and alcohol dependence. 2021;225:108772.
9. Infante AF, Elmes AT, Gimbar RP, Messmer SE, Neeb C, Jarrett JB. Stronger, longer, better opioid antagonists? Nalmefene is NOT a naloxone replacement. International Journal of Drug Policy. 2024/02/01/ 2024;124:104323. doi:https://doi.org/10.1016/j.drugpo.2024.104323
10. Strauss DG, Li Z, Chaturbedi A, et al. Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose: A Simulation-Based Randomized Clinical Trial. JAMA Network Open. 2024;7(1):e2351839-e2351839. doi:10.1001/jamanetworkopen.2023.51839

11. Committee Opinion Opioid Use and Opioid Use Disorder in Pregnancy. Obstet Gynecol. Aug 2017;130(2):e81-e94. doi:10.1097/aog.0000000000002235