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Commentary|Articles in Press

Naloxone Over the Counter: Increasing Opportunities and Challenges for Health Providers

Published:February 04, 2023DOI:https://doi.org/10.1016/j.amjmed.2023.01.027
Naloxone Over the Counter: Increasing Opportunities and Challenges for Health Providers
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      On November 15, 2022, the US Food and Drug Administration (FDA) issued a request for data from manufacturers of naloxone to support a switch from prescription to over-the-counter (OTC) formulations.

      US Food and Drug Administration (FDA). FDA announces preliminary assessment that certain naloxone products have the potential to be safe and effective for over-the-counter use: agency continues to encourage sponsor applications for their over-the counter naloxone products. Available at:https://www.fda.gov/news-events/press-announcements/fda-announces-preliminary-assessment-certain-naloxone-products-have-potential-be-safe-and-effective. Accessed December 31, 2022.

      Specifically, the FDA said that a nasal spray and an auto-injector could potentially be safe and effective for OTC distribution. On December 26, 2022, the FDA granted a priority review to Harm Reduction Therapies, a pharmaceutical nonprofit, to market an OTC formulation of naloxone.

      Cision PR Newswire. Harm reduction therapeutics' new drug application for RiVive™ over-the-counter naloxone nasal spray accepted and granted priority review by FDA. Available at:https://www.prnewswire.com/news-releases/harm-reduction-therapeutics-new-drug-application-for-rivive-over-the-counter-naloxone-nasal-spray-accepted-and-granted-priority-review-by-fda-301710002.html. Accessed December 31, 2022.

      We commend the FDA for these efforts. In this Commentary, we conclude that the far wider availability of naloxone, which would occur with the anticipated approval by the FDA for OTC distribution, would pose both opportunities and challenges for health providers.
      Naloxone is an opioid receptor antagonist that rapidly reverses or blocks the effects of opioids, restores normal respiration and heart rhythm, and reverses the potentially fatal effects of an overdose. The side effects are generally minimal and consist of mostly those symptoms related to opioid withdrawal. In some cases, naloxone can precipitate noncardiogenic pulmonary edema, with rates ranging from 0.2%-3.6%,

      Jordan MR, Morrisonponce D. Naloxone. Treasure Island, FL: Stat Pearls Publishing; 2022. Available at: https://www.ncbi.nlm.nih.gov/books/NBK441910. Accessed December 31, 2022.

      typically within 4 hours of administration.
      • Farkas A
      • Lynch MJ
      • Westover R
      • et al.
      Pulmonary complications of opioid overdose treated with naloxone.
      Ann Emerg Med. 2019; 75: 39-48
      Despite the low absolute risks of pulmonary edema associated with the administration of naloxone, we believe that health providers should be aware that the lifesaving benefit vastly exceeds the risk.
      The United States accounts for <4.5% of the world's population but accounts for >13% (or 2.1 million) of the more than 16 million opioid addicts, as well as >20% of the more than 500,000 deaths worldwide.
      • Chang HY
      • Kharrazi H
      • Bodycombe D
      • Weiner JP
      • Alexander GC.
      Healthcare costs and utilization associated with high-risk prescription opioid use: a retrospective cohort study.
      BMC Med. 2018; 16: 69-80
      From April 2020 to April 2021, the United States experienced 100,306 deaths from drug overdoses, a 28.5% increase from the prior year, with 75,673 of those deaths attributed to opioids.

      Centers for Disease Control, National Center for Health Statistics. Drug Overdose Deaths in the U.S. Top 100,000 Annually. Available at: https://www.cdc.gov/mmwr/volumes/71/wr/mm7150a2.htm?s_cid=mm7150a2_2022. Accessed December 31, 2022.

      Synthetic opioids, primarily fentanyl and natural and semi-synthetic opioids, are major contributors.

      United States Department of Justice; Drug Enforcement Administration. Drug fact sheet. Fentanyl. October 2022. Available at: https://www.dea.gov/factsheets/fentanyl. Accessed December 31, 2022.

      In addition, illicitly manufactured fentanyl is often added to other recreational drugs because of its low cost and increased potency; thus, the risk of fatal overdose increases for all users, especially first-time or occasional users. It is sobering to note that about 6 of 10 fentanyl-laced illegal drugs sold on the street now contain a potentially lethal dose of fentanyl.

      United States Drug Enforcement Administration. Public Safety Alert. DEA laboratory testing reveals that 6 out of 10 fentanyl-lacked fake prescription pills now contain a potentially lethal dose of fentanyl. Available at:https://www.dea.gov/alert/dea-laboratory-testing-reveals-6-out-10-fentanyl-laced-fake-prescription-pills-now-contain Accessed December 31, 2022.

      About 1 in 5 patients prescribed opioids for chronic pain have overdosed, and more than half take other prescription drugs that may cause overdose, as well as abuse alcohol. Many patients who are prescribed high doses of opioids have witnessed overdoses, but <3% have naloxone available for immediate use.

      United States Department of Justice; Drug Enforcement Administration. Drug fact sheet. Fentanyl. October 2022. Available at: https://www.dea.gov/factsheets/fentanyl. Accessed December 31, 2022.

      Health providers should counsel all their patients who use drugs, and their families, to have a naloxone nasal spray or auto-injector in the household. Cost could be cited as a potential barrier, but the average retail price of naloxone is under $100, far less expensive than the approximately $400 for epinephrine auto-injectors for emergency treatment of anaphylaxis.

      GoodRx. Generic Narcan naloxone. Available at: https://www.goodrx.com/narcan. Accessed December 31, 2022.

      ,

      GoodRx. Generic EpiPen epinephrine. Available at: https://www.goodrx.com/epipen. Accessed December 31, 2022.

      In addition, Harm Reduction Therapies stated in its press release that the company would donate 10% and sell the remainder to drug stores and health providers for cost, or about $18 per dose.

      Cision PR Newswire. Harm reduction therapeutics' new drug application for RiVive™ over-the-counter naloxone nasal spray accepted and granted priority review by FDA. Available at:https://www.prnewswire.com/news-releases/harm-reduction-therapeutics-new-drug-application-for-rivive-over-the-counter-naloxone-nasal-spray-accepted-and-granted-priority-review-by-fda-301710002.html. Accessed December 31, 2022.

      Patients for whom the benefit-to-risk ratio is positive include, but are not limited to, the 22.5 million people, or about 8.5% of the US population aged 12 years or older, who need professional treatment for an illicit drug or alcohol use disorder.
      • Dunn KE
      • Barrett FS
      • Yepez-Laubach C
      • et al.
      Opioid overdose experience, risk behaviors, and knowledge in drug users from a rural versus an urban setting.
      J Subst Abuse Treat. 2016; 71: 1-7
      Two-thirds of patients who are participating in syringe service programs, detoxification, or opioid treatment programs previously had witnessed an overdose, but only 17% had naloxone available to them at the time.
      • Dunn KE
      • Barrett FS
      • Yepez-Laubach C
      • et al.
      Opioid overdose experience, risk behaviors, and knowledge in drug users from a rural versus an urban setting.
      J Subst Abuse Treat. 2016; 71: 1-7
      Ideally, health care providers in substance use disorder treatment programs should include nasal or auto-injector naloxone in their treatment program, both teaching how to use it as well as providing it upon discharge from the program. Health providers should also prescribe naloxone for any patient who is prescribed a high-dose or long half-life opioid, whether for pain or any other condition. In the United States, over 142 million patients are prescribed opioids, yielding a prescribing rate of approximately 43.3 per 100 persons.

      Centers for Disease Control and Prevention (CDC). Opioid dispensing rate maps. Available at: https://www.cdc.gov/drugoverdose/rxrate-maps/index.html. Accessed December 31, 2022.

      Compared with a daily dose of 20 morphine milligram equivalents (MME) or less, a daily dose of 50 or more MME doubles the risk of opioid overdose death, and at 90 MME, the risk of opioid overdose death increases tenfold. Although naloxone is included in the recommendations by the US Centers for Disease Control and Prevention, the drug is currently prescribed to <1 in 70 patients prescribed high-dose opioid prescriptions.

      Centers for Disease Control and Prevention (CDC). Opioid dispensing rate maps. Available at: https://www.cdc.gov/drugoverdose/rxrate-maps/index.html. Accessed December 31, 2022.

      In addition, we urge all emergency medicine providers to counsel and provide naloxone to any patient presenting with an opioid overdose, including accidental.
      We also encourage health providers at college-based student health services to initiate campaigns across their campuses to increase naloxone availability and distribution as well as provide guidance to students about the overall safety and life-saving benefits of emergent use of naloxone. Fortunately, opioid addiction and overdoses are rarer on college campuses than among young adults in the general population. Nonetheless, on March 11, 2022, 6 football players from the US Military Academy at West Point in New York traveled to south Florida on spring break and accidentally overdosed on fentanyl-laced cocaine. Emergency medical responders found them in cardiac arrest and immediately administered naloxone. Of the 6, 2 died and the other 4 recovered after 2 of them were admitted to the hospital in critical condition.

      Bella T. West Point cadets overdose on fentanyl while on spring break in South Florida, police say. Washington Post March 12, 2022. Available at:https://www.washingtonpost.com/nation/2022/03/12/west-point-cadets-overdose-fentanyl/. Accessed December 31, 2022.

      It also seems beneficial to have nasal or auto-injector naloxone available wherever there are portable defibrillators, especially because the drug could be life saving for those who have cardiac arrest due to opioid toxicity.
      Naloxone access laws to increase availability and access are presently under the control of each individual state.
      • Bohler RM
      • Hodgkin D
      • Kreinder PW
      • Green T
      Predictors of US states’ adoption of naloxone access laws, 2001-2017.
      Drug Alcohol Depend. 2021; 225108772
      We believe that all state medical societies should advocate for less restrictive naloxone access laws. It may also be worthwhile for medical societies to require prescribing physicians to counsel patients on the availability, efficacy, safety, and relatively low cost of OTC naloxone, when available.
      While the United States has been more reactive than proactive with the epidemics of COVID-19
      • Alter SM
      • Maki DG
      • LeBlang S
      • Shih RD
      • Hennekens CH
      The menacing assaults on science, FDA, CDC, and health of the US public.
      EClinicalMedicine. 2020; 27100581
      and gun violence, especially among young Black men
      • Hennekens CH
      • Drowos J
      • Levine RS
      Mortality from homicide among young Black men: a new American tragedy.
      Am J Med. 2013; 126: 282-283
      and school children,
      • Rubenstein A
      • Wood SK
      • Levine RS
      • Hennekens CH
      Alarming trends in mortality from firearms among United States schoolchildren.
      Am J Med. 2019; 132: 992-994
      now is the time to become more proactive, especially in the fight against opioid-related deaths. As of today, the epidemic of drug overdose deaths due to opioids is second only to COVID-19 in the United States in potentially avoidable premature deaths. Health providers should counsel patients who use drugs, as well as their families, to have a nasal spray or auto-injector of naloxone in the household. Health providers should more widely provide naloxone, and increasing the distribution to emergency personnel could avert >20% of opioid overdose deaths.
      • Irvine MA
      • Oller D
      • Boggis J
      • et al.
      Estimating naloxone need in the USA across fentanyl, heroin, and prescription opioid epidemics: a modelling study.
      Lancet Public Health. 2022; 7: e210-e218
      In conclusion, we propose a call to action for all health providers and state medical societies to ensure the widest distribution and easy availability of naloxone, including over the counter, which is likely to be FDA-approved very soon. As Sir Richard Doll so eloquently stated, “Death in old age is inevitable but death before old age is not.”

      Wikipedia. Quote from plaque on Richard Doll Building. Available at:https://en.wikipedia.org/wiki/Richard_Doll_Building. Accessed December 31, 2022.

      References

      1. US Food and Drug Administration (FDA). FDA announces preliminary assessment that certain naloxone products have the potential to be safe and effective for over-the-counter use: agency continues to encourage sponsor applications for their over-the counter naloxone products. Available at:https://www.fda.gov/news-events/press-announcements/fda-announces-preliminary-assessment-certain-naloxone-products-have-potential-be-safe-and-effective. Accessed December 31, 2022.

        View in Article

      2. Cision PR Newswire. Harm reduction therapeutics' new drug application for RiVive™ over-the-counter naloxone nasal spray accepted and granted priority review by FDA. Available at:https://www.prnewswire.com/news-releases/harm-reduction-therapeutics-new-drug-application-for-rivive-over-the-counter-naloxone-nasal-spray-accepted-and-granted-priority-review-by-fda-301710002.html. Accessed December 31, 2022.

        View in Article

      3. Jordan MR, Morrisonponce D. Naloxone. Treasure Island, FL: Stat Pearls Publishing; 2022. Available at: https://www.ncbi.nlm.nih.gov/books/NBK441910. Accessed December 31, 2022.

        View in Article
        • Farkas A
        • Lynch MJ
        • Westover R
        • et al.
        Pulmonary complications of opioid overdose treated with naloxone.
        Ann Emerg Med. 2019; 75: 39-48
        View in Article
        • Chang HY
        • Kharrazi H
        • Bodycombe D
        • Weiner JP
        • Alexander GC.
        Healthcare costs and utilization associated with high-risk prescription opioid use: a retrospective cohort study.
        BMC Med. 2018; 16: 69-80
        View in Article

      6. Centers for Disease Control, National Center for Health Statistics. Drug Overdose Deaths in the U.S. Top 100,000 Annually. Available at: https://www.cdc.gov/mmwr/volumes/71/wr/mm7150a2.htm?s_cid=mm7150a2_2022. Accessed December 31, 2022.

        View in Article

      7. United States Department of Justice; Drug Enforcement Administration. Drug fact sheet. Fentanyl. October 2022. Available at: https://www.dea.gov/factsheets/fentanyl. Accessed December 31, 2022.

        View in Article

      8. United States Drug Enforcement Administration. Public Safety Alert. DEA laboratory testing reveals that 6 out of 10 fentanyl-lacked fake prescription pills now contain a potentially lethal dose of fentanyl. Available at:https://www.dea.gov/alert/dea-laboratory-testing-reveals-6-out-10-fentanyl-laced-fake-prescription-pills-now-contain Accessed December 31, 2022.

        View in Article

      9. GoodRx. Generic Narcan naloxone. Available at: https://www.goodrx.com/narcan. Accessed December 31, 2022.

        View in Article

      10. GoodRx. Generic EpiPen epinephrine. Available at: https://www.goodrx.com/epipen. Accessed December 31, 2022.

        View in Article
        • Dunn KE
        • Barrett FS
        • Yepez-Laubach C
        • et al.
        Opioid overdose experience, risk behaviors, and knowledge in drug users from a rural versus an urban setting.
        J Subst Abuse Treat. 2016; 71: 1-7
        View in Article

      12. Centers for Disease Control and Prevention (CDC). Opioid dispensing rate maps. Available at: https://www.cdc.gov/drugoverdose/rxrate-maps/index.html. Accessed December 31, 2022.

        View in Article

      13. Bella T. West Point cadets overdose on fentanyl while on spring break in South Florida, police say. Washington Post March 12, 2022. Available at:https://www.washingtonpost.com/nation/2022/03/12/west-point-cadets-overdose-fentanyl/. Accessed December 31, 2022.

        View in Article
        • Bohler RM
        • Hodgkin D
        • Kreinder PW
        • Green T
        Predictors of US states’ adoption of naloxone access laws, 2001-2017.
        Drug Alcohol Depend. 2021; 225108772
        View in Article
        • Alter SM
        • Maki DG
        • LeBlang S
        • Shih RD
        • Hennekens CH
        The menacing assaults on science, FDA, CDC, and health of the US public.
        EClinicalMedicine. 2020; 27100581
        View in Article
        • Hennekens CH
        • Drowos J
        • Levine RS
        Mortality from homicide among young Black men: a new American tragedy.
        Am J Med. 2013; 126: 282-283
        View in Article
        • Rubenstein A
        • Wood SK
        • Levine RS
        • Hennekens CH
        Alarming trends in mortality from firearms among United States schoolchildren.
        Am J Med. 2019; 132: 992-994
        View in Article
        • Irvine MA
        • Oller D
        • Boggis J
        • et al.
        Estimating naloxone need in the USA across fentanyl, heroin, and prescription opioid epidemics: a modelling study.
        Lancet Public Health. 2022; 7: e210-e218
        View in Article

      19. Wikipedia. Quote from plaque on Richard Doll Building. Available at:https://en.wikipedia.org/wiki/Richard_Doll_Building. Accessed December 31, 2022.

        View in Article

      Article info

      Publication history

      Published online: February 04, 2023
      Accepted: January 17, 2023
      Received: January 16, 2023

      Publication stage

      In Press Journal Pre-Proof

      Footnotes

      Funding: None.

      Conflicts of Interest: ADA, BF, LF, GRL, DGM, LC, and AF report no disclosures. CHH reports that he serves as an independent scientist in an advisory role to investigators and sponsors as Chair of Data Monitoring Committees for Amgen, British Heart Foundation, Cadila, Canadian Institutes of Health Research, DalCor, and Regeneron; to the Collaborative Institutional Training Initiative (CITI), legal counsel for Pfizer, the US Food and Drug Administration, and UpToDate; receives royalties for authorship or editorship of 3 textbooks and as co-inventor on patents for inflammatory markers and cardiovascular disease that are held by Brigham and Women's Hospital; has an investment management relationship with the West-Bacon Group within Truist Investment Services, which has discretionary investment authority; does not own any common or preferred stock in any pharmaceutical or medical device company.

      Authorship: All authors had access to the data and have participated in the preparation of the manuscript.

      Identification

      DOI: https://doi.org/10.1016/j.amjmed.2023.01.027

      Copyright

      © 2023 Elsevier Inc. All rights reserved.

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