Opioid Overdose Antidotes to Avoid: High-Dose Naloxone and Nalmefene Nasal Sprays

Naloxone (KLOXXADO, NARCAN, REXTOVY, REZENOPY, RIVIVE and generics) can be a life-saving antidote to opioid overdose. Naloxone works by mimicking opioids, thereby blocking their continued and potentially fatal effects on the nervous system.

Recently, the Food and Drug Administration (FDA) approved two additional drugs for opioid use disorder, both of which are nasal spray formulations. One drug is high-dose naloxone, and the other drug is a derivative of naloxone known as nalmefene (OPVEE). Although effective, neither high-dose naloxone nor nalmefene should be considered a preferred treatment for opioid overdose. Naloxone nasal spray, which is sold over the counter, is a safer choice. The newer formulations are more expensive, usually no more effective and may trigger longer and more intense withdrawal.

About naloxone and nalmefene

In 1971 the FDA first approved naloxone as an antidote for opioid overdose.[1] In 1995 nalmefene was first approved for that same indication.[2] Nalmefene is nearly identical in structure to naloxone except for two relatively small chemical group changes. At similar doses, nalmefene binds to opioid receptors for a longer period of time than naloxone.

When first approved, both naloxone and nalmefene were available only as injectable formulations. Over-the-counter nasal spray formulations of naloxone are an important advance for opioid overdose reversal drugs, as discussed in the November 2023 issue of Worst Pills, Best Pills News.[3] Nalmefene nasal spray, however, is available by prescription only.

Nalmefene nasal spray was first approved by the FDA in May 2023[4] and had an average wholesale price of $59 per 2.7-milligram (mg) dose.[5] The product is approved for use in immediate response to a known or suspected opioid overdose in people aged 12 years and older, in conjunction with as-needed CPR and repeatedly as needed to elicit a response (movement, verbalizations) that includes restoration of breathing to a minimum of approximately 12 breaths per minute.[6] Emergency medical assistance should be called immediately upon administering the first dose, as is the case with naloxone use. Post-overdose care usually does not require hospitalization, but it should include substance use disorder counseling and treatment referral, including the possible initiation of buprenorphine treatment.

Over-the-counter doses of nasal spray naloxone (Narcan, Rivive and generics) are 3 to 4 mg each. Prescription-only versions of the nasal spray (Kloxxado) that deliver twice those doses or more have recently been approved. In 2021 the FDA approved an 8-mg spray priced at $75 per dose.[7] In April 2024 the agency approved a 10-mg spray (Rezenopy; price not available).[8]

Comparative safety and effectiveness

The drug labels for high-dose naloxone and nalmefene nasal sprays have almost identical warnings. Acute treatment concerns for both include recurrent respiratory depression (slowed or absent breathing), limited effectiveness to reverse overdose caused by buprenorphine (a common treatment for opioid use disorder), severe withdrawal symptoms and cardiovascular events. When nalmefene is used, the reintroduction of opioids to ease withdrawal symptoms can lead to unexpected overdose.

Nalmefene is not the first-choice drug to reverse opioid overdose, because naloxone is typically effective and because nalmefene’s half-life in the body is longer than naloxone’s.[9] Although nalmefene was developed as a faster- and longer-acting alternative to naloxone, these attributes also increase the risk of intense and prolonged withdrawal.[10]

Despite the potency of now-ubiquitous synthetic opioids like fentanyl, standard doses of naloxone usually are sufficient to reverse an overdose.[11] High-dose naloxone is more expensive and usually not needed.

Cost, accessibility and stigma

The demand for naloxone nasal spray has been substantial: At least 20 million over-the-counter or prescription doses were distributed by just a single company in 2023, according to a recent NBC News report.[12] However, the rollout of the over-the-counter naloxone nasal spray has been inconsistent; many pharmacies have not carried the drug or have placed it in locations that were hidden from consumers. Convenience stores and gas stations may not carry the product at all.

A two-dose box of over-the-counter naloxone nasal spray costs about $45; previously, some community health centers or insurers had offered the prescription drug for free. Although over-the-counter naloxone is a “no-brainer” as a matter of public health, profiteering has driven up the price of this lifesaving medicine, which costs only pennies per dose to manufacture, according to a recent commentary in STAT News.[13]

This expert commentary also noted the endurance of stigmatizing myths that can discourage naloxone use, such as misinformation suggesting that opioid reversal drugs increase opioid consumption.

What You Can Do

Keeping a ready supply of naloxone is recommended for people (or anyone close to a person) at substantial risk of opioid overdose, including people using opioids illegally or as a treatment for a substance use disorder. It is unlikely that an individual will be able to self-administer naloxone during an overdose.

Signs of opioid overdose include unresponsiveness, shallow breathing, limpness, blue lips, slow or irregular heartbeat or pinpoint pupils.[14],[15] Naloxone should be administered to anyone experiencing a known or suspected opioid overdose; additional doses may be necessary if the person does not respond in two to three minutes or responds and then relapses into respiratory depression.[16],[17]

The nasal sprays are administered by inserting the tube containing the medication slightly into one nostril of the affected individual and depressing the plunger. Do not prime the plunger; only push it after it has been inserted into the nose. Immediately after the first dose is administered, call for emergency medical support.

A person revived by naloxone may experience agitation, nausea, vomiting, diarrhea, yawning, tearing and runny nose, as well as other opioid withdrawal symptoms.[18] Abnormal cardiovascular function, violent behavior and drug craving may also occur.
 

References

[1] Summit Biosciences Inc. Label: naloxone hydrochloride nasal spray (REZENOPY). April 2024 https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215487s000lbl.pdf. Accessed July 9, 2024.

[2] Opiant Pharmaceuticals. Label: nalmefene nasal spray (OPVEE). May 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217470Orig1s000.pdf. Accessed July 4, 2023.

[3] Over the counter availability of naloxone(NARCAN) nasal spray. Worst Pills, Best Pills News. November 2023. https://www.worstpills.org/newsletters/view/1567. Accessed June 25, 2024.

[4] U.S. Food and Drug Administration. Information about naloxone and nalmefene. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-about-naloxone-and-nalmefene. Accessed July 9, 2024.

[5] Nalmefene: drug information. UpToDate. June 2024.

[6] Stolbach A, Hoffman RS. Acute opioid intoxication in adults. UpToDate. May 2024.

[7] U.S. Food and Drug Administration. FDA approves higher dosage of naloxone nasal spray to treat opioid overdose. April 30, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-higher-dosage-naloxone-nasal-spray-treat-opioid-overdose. Access July 9, 2024.

[8] U.S. Food and Drug Administration. FDA roundup: April 23, 2024. https://www.fda.gov/news-events/press-announcements/fda-roundup-april-23-2024. Accessed July 9, 2024.

[9] Stolbach A, Hoffman RS. Acute opioid intoxication in adults. UpToDate. May 2024.

[10] The Associated Press. A new nasal spray to reverse fentanyl and other opioid overdoses gets FDA approval. May 23, 2023. https://www.npr.org/2023/05/22/1177597319/fda-approves-opvee-naloxone-opioid-overdose-fentanyl. Accessed July 5, 2025.

[11] Stolbach A, Hoffman RS. Acute opioid intoxication in adults. UpToDate. May 2024.

[12] Miller SG, Lovelace B. Where's the Narcan? At pharmacies across the U.S., the OTC antidote can be hard to find. NBC News, Health & Medical Unit. March 11, 2024. https://www.yahoo.com/news/wheres-narcan-pharmacies-across-u-110000394.html. Accessed June 28, 2024.

[13] Stoltman JJK, Terplan M. OTC naloxone is a baby step toward making the life-saving medication accessible. STAT+. April 17, 2023.

[14] Food and Drug Administration. Access to naloxone can save a life during and opioid overdose. Undated. https://www.fda.gov/consumers/consumer-updates/access-naloxone-can-save-life-during-opioid-overdose. Accessed September 18, 2023.

[15] Strang J, McDonald R, Campbell G, et al. Take-home naloxone for the emergency interim management of opioid overdose: the public health application of an emergency medicine. Drugs. 2019;79(13):1395-1418.

[16] Emergent. Label: naloxone (Narcan). 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/208411Orig1s006lbl.pdf. Accessed September 18, 2023.

[17] So many loved one can still be saved. Revive.com. https://rivive.com/. Accessed September 18, 2023.

[18] Strang J, McDonald R, Campbell G et al. Take-home naloxone for the emergency interim management of opioid overdose: the public health application of an emergency medicine. Drugs. 2019;79(13):1395-1418.