Opioid Overdose and Naloxone Delivery Devices in the Community Setting

AJPB® Translating Evidence-Based Research Into Value-Based Decisions®November/December 2016
Volume 8
Issue 6

Although naloxone delivery devices are proven to reduce opioid overdoses, challenges persist in increasing the use of these devices in the community setting.


Opioid analgesics have a useful place in the management of moderate to severe pain. However, in the past few years, the use and abuse of these agents have increased exponentially. Along with the upward trend in the utilization of opioids, there has been a massive increase in opioid overdoses. In 2014, drug overdose was the third leading cause of injury deaths, with opioid prescriptions causing a majority of these deaths.

Naloxone, an opioid antagonist, is currently the drug of choice for the treatment of overdose-induced respiratory depression. When opioid overdose occurs, naloxone—if administered quickly enough—will effectively reverse opioid-induced respiratory depression and therefore decrease the risk of complications and mortality. Because the effectiveness of naloxone is so time-dependent, community administration may lead to greater opportunities to reverse overdose symptoms.

At this time, there are 2 FDA-approved naloxone delivery devices intended for community administration: Evzio auto-injector and Narcan nasal spray. By providing easy-to-use naloxone delivery devices to high-risk opioid users and their families and friends, naloxone devices can shorten the time to overdose rescue, limit damage to the brain and other organs, and reduce the probability of overdose death.

Although the use of naloxone delivery devices has proven benefits, many qualms still exist about supporting these devices in the community setting. By dispelling misconceptions, we can educate the community and save lives nationwide.

Am J Pharm Benefits. 2016;8(6):e96-e100

Opioid analgesics have a useful place in the management of moderate to severe pain. However, in recent years, there has been a significant increase in the utilization of both illicit and prescription opioids. In 2013, the CDC reported a 4-fold increase in the amount of prescription opioids dispensed from 1999 to 2013.1 Along with this trend, the number of Americans who have used heroin in the past year steadily increased from 2002 to 2014.1

The considerable increase in opioid utilization has resulted in an upward trend of mortality due to overdose. Drug overdose was the leading cause of injury death in 2014, causing more deaths than either car accidents or homicide.2 Prescription opioid drugs and heroin were the cause of a majority of these overdose deaths.3 In 2014, 18,893 Americans died from prescription opioid overdose, while 10,574 Americans died from heroin overdoses.3-5

The Pharmacology of Opioids

Opioids exert their action by binding to 3 main opioid receptors: the mu, delta, and kappa receptors. The mu opioid receptor is responsible for the majority of the clinical and adverse effects associated with opioids, such as analgesia, euphoria, constipation, respiratory depression, and dependence.6,7

Severe opioid intoxication can be fatal. The classic clinical features of opioid intoxication are unconsciousness, miosis, bradycardia, and respiratory depression (Table 111). If left untreated, opioid overdose can lead to pulmonary, neurological, cardiovascular, and infectious complications, and ultimately death.8,9

Naloxone: Pharmacology and Delivery Devices

The drug of choice for the reversal of respiratory and central nervous system depression in the presence of an opioid overdose is naloxone.10 Developed in 1960, naloxone was the first pure competitive mu opioid receptor antagonist to be synthesized.11 Due to its high affinity for the mu opioid receptor, naloxone competes with and displaces other opioids at opioid receptor sites, reversing their effect.11

The onset of action of naloxone ranges from 1 to 13 minutes, depending on the route of administration (Table 212-18). The approved routes for naloxone are intravenous (IV), intramuscular (IM), subcutaneous (subQ), and more recently, intranasal (IN). The IV route provides the most rapid and predictable effects. However, for overdoses occurring in the community, obtaining IV access may be difficult, leading to a delay in administration.

Once naloxone is administered, it has a relatively short half-life, and depending upon the route of administration, its duration of action ranges from 20 to 90 minutes.14,19,20 As a result, the duration of most opioids may exceed that of naloxone. Because of this, medical personnel should always be contacted and repeated naloxone doses may be necessary to prevent the return of respiratory depression.

Although the onset of action of the IV naloxone is more rapid than that of other routes of administration, the IV route is not recommended for bystanders to use when encountering a person who has overdosed on opioids.21 The subQ, IM, and IN routes are more suitable for administration in the community.

Currently, 3 naloxone delivery devices have proven beneficial in the treatment of opioid-induced respiratory depression: the naloxone auto-injector (Evzio), the naloxone nasal spray (Narcan), and the off-label IN naloxone kit, which consists of a naloxone vial with a nasal atomizer. Only Evzio and Narcan are FDA-approved for the treatment of opioid overdose, with the latter receiving FDA approval in November 2015. Table 322-25 outlines additional factors, such as cost, for each formulation.

Evzio, the first FDA-approved naloxone delivery device, is a take-home naloxone auto-injector that will administer naloxone either intramuscularly or subcutaneously, depending on the patient’s body fat percentage.26 This device provides voice instructions to assist and guide the user through the administration of the naloxone dose.

Evzio should be injected into the anterolateral aspect of the thigh, and it can be administered through clothing, if necessary. Additionally, it contains a retractable needle system that conceals the needle before, during, and after administration.26

IN administration may be more user-friendly in a community setting. The IN route eliminates the need for needles and thus the risk of needle sticks in settings where HIV and difficult IV access are common.

Prior to the FDA approval of IN naloxone, this delivery device came as an off-label kit that contained a parenteral vial of naloxone, a plastic delivery syringe, an intranasal atomizer, personal protective equipment, and instructions for use. Due to the multiple steps required to assemble this kit, it has been shown to have lower administration success and a longer time of administration.16,27

The major benefit of Narcan nasal spray is that it comes as a single-spray device that requires no assembly or priming prior to use, which decreases the potential lag time for administration. Pre-marketing trials found that the time to reach maximum plasma concentration was comparable with that of the IM naloxone formulation.20

Patients Who May Benefit From Naloxone Distribution

Access to naloxone delivery devices is beneficial to high-risk opioid users who are in a substance-use treatment program, those leaving prison, and those receiving high-dose opioid prescriptions.28-30 The CDC’s 2016 Guidelines on Prescribing Opioids for Chronic Pain recommend that patients receiving ≥50 mg of morphine per day should be co-prescribed naloxone.31

Other high-risk users who may benefit from naloxone include patients who are prescribed opioids and have a diagnosis of sleep apnea and/or pulmonary disease, patients who are concurrently on opioids and benzodiazepines, and patients who have recently abstained from heroin, particularly the injectable form.25,28 By distributing naloxone to high-risk opioid/heroin users and their family and friends, naloxone can shorten the time to overdose rescue, limit potential complications, and reduce the probability of overdose death and overall mortality.32-37

Naloxone Delivery Devices in the Community: Efficacy and Benefits

In an attempt to address the higher rates of prescription opioid and heroin overdose deaths in the United States, recent legislation and many organizations, such as the American Medical Association, have endorsed the use of naloxone distribution to laypersons. As of June 2016, the District of Columbia and 47 states have passed laws to increase naloxone access to laypersons.34

In March 2016, President Obama announced that his administration is working to provide additional initiatives to increase community strategies to prevent overdose deaths. Several pharmacy chains have also followed suit, proposing initiatives to increase the access of naloxone in the community. By the end of 2016, Walgreens and CVS Pharmacy plan to be able to dispense naloxone to patients without an individual prescription in 35 states and Washington, DC.38

These efforts have proven beneficial and effective in decreasing the amount of overdose-related deaths. A study conducted in Massachusetts observed 27% to 46% decreases in opioid overdose-related deaths in communities that distributed naloxone devices.35

Another study found that naloxone distribution would prevent approximately 2000 overdose deaths in a population of 200,000 heroin users.36 This analysis also estimated that 1 overdose death would be prevented for every 164 naloxone kits distributed.35

In addition to its proven effectiveness in decreasing overdose deaths, naloxone distribution has been found to be a cost-effective way to prevent opioid overdose death. Coffin and Sullivan found that naloxone distribution increased lifetime cost by just $53 and the incremental cost of $438 per quality-adjusted life-years (QALYs) gained.36 This estimated incremental cost per QALY is well below $50,000, which is traditionally considered cost effective by policymakers.36,37

Naloxone Distribution Trends

Since 1996, the number of laypersons who have been provided naloxone kits has significantly increased.30 Traditionally, the distribution of naloxone has been provided by community-based naloxone programs; however, there has been an increased focus on naloxone distribution in the outpatient setting through retail pharmacies.

A 2016 study analyzing national trends of naloxone prescriptions—including all available naloxone formulations except Narcan—found that the number of naloxone prescriptions dispensed from US retail pharmacies was low between 2010 and 2013, ranging from 241 to 463 prescriptions per quarter.39

This number has dramatically increased in the past few years, however, with 4291 prescriptions dispensed in the second quarter of 2015.39 Evzio represented 29.3% of these prescriptions. This study also found that primary care physicians accounted for the majority of naloxone prescriptions, suggesting that naloxone prescriptions in the outpatient setting can be a complementary approach (Figure).39

Barriers to Naloxone Distribution

Although naloxone delivery devices have proven benefits, there remains some hesitation to support these devices in the community setting. A common argument is that these devices will encourage opioid abusers to increase their use,40-43 but no published studies support this argument.

Indeed, studies suggest that an increase in the training programs that accompany naloxone distribution reduces the use of opioids and increases the desire of users to seek addiction treatment. Moreover, researchers found this did not encourage users to increase their heroin use.44-46 Additional barriers are addressed in Table 4.40,44-47


As opioid utilization continues to rise, we will likely see a rise in opioid-related mortality and overdose. Therefore, it should be a priority of managed care organizations, public health advocates, and healthcare professionals to collaborate and provide harm-reduction options, such as naloxone distribution for high-risk members in the community.

By addressing many of the misconceptions related to providing naloxone in the community, our hope is to increase support of naloxone delivery devices nationwide, potentially saving many lives.

Author Affiliations: Department of Mental Health (JEC) and Department of Pharmacy (JEC, KW, PN), Veterans Affairs Medical Center, Washington, DC; College of Pharmacy, Howard University (UIE), Washington, DC.

Source of Funding: None.

Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (JC,KW,UE,PN); acquisition of data (JC,KW,UE,PN); analysis and interpretation of data (JC,KW,UE,PN); drafting of the manuscript (JC,KW,UE,PN); critical revision of the manuscript for important intellectual content (JC,KW,UE,PN); statistical analysis (JC,KW,UE,PN); provision of patients or study materials (JC,KW,UE,PN); and supervision (JC).

Address Correspondence to: Jasmine E. Carpenter, PharmD, BCPS, BCPP, 219 S St NE, Washington, DC 20002. E-mail: Jasmine.carpenter@va.gov.


  •  Behaviorial Health Trends in the United States: Results from the 2014 National Survey on Drug Use and Health. Rockville, MD: Substance Abuse and Mental Health Services Administration, September 2015.
  • About underlying cause of death, 1999-2014. CDC website. http://wonder.cdc.gov/ucd-icd10.html. Published 2015. Accessed March 25, 2016
  • Division of Vital Statistics, Mortality Data. Number and age-adjusted rates of drug-poisoning deaths involving opioid analgesics and heroin: United States, 2000-2014. CDC website. http://www.cdc.gov/nchs/data/health_policy/AADR_drug_poisoning_involving_OA_Heroin_US_2000-2014.pdf. Published 2015. Updated January 1,2016. Accessed March 25,2016.
  • Injury prevention and control: data and statistics (WISQARS). Fatal injury data. CDC website. http://www.cdc.gov/injury/wisqars/fatal.html. Published 2014. Updated October 7, 2016 Accessed March 25,2016.
  • Hedegaard H, Chen LH, Warner M. Drug-poisoning deaths involving heroin: United States, 2000-2013. NCHS Data Brief. 2015;(190):1-8.
  • Berland D, Rodgers P. Rational use of opioids for management of chronic nonterminal pain. Am Fam Physician. 2012;86(3):252-258.
  • Pasternak GW, Pan YX. Mu opioids and their receptors: evolution of a concept. Pharmacol Rev. 2013;65(4):1257-1317. doi: 10.1124/pr.112.007138.
  • White JM, Irvine RJ. Mechanisms of fatal opioid overdose. Addiction. 1999;94(7):961-972.
  • Hung OL, Hoffman RS. Reversal of opioid intoxication: therapeutic guidelines. CNS Drugs. 1997;7(3):176-186. doi:10.2165/00023210-199707030-00002.
  • AHFS Drug Information Naloxone Hydrochloride monograph. American Society of Health System Pharmacists. 2009:2251-2254.
  • Dahan A, Aarts L, Smith TW. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology. 2010;112(1):226-238. doi: 10.1097/ALN.0b013e3181c38c25.
  • Kim HK, Nelson LS. Reducing the harm of opioid overdose with the safe use of naloxone: a pharmacologic review. Expert Opin Drug Saf. 2015;14(7):1137-1146. doi: 10.1517/14740338.2015.1037274.
  • Dowling J, Isbister GK, Kirkpatrick CM, Naidoo D, Graudins A. Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers. Ther Drug Monit. 2008;30(4):490-496. doi: 10.1097/FTD.0b013e3181816214.
  • Evans JM, Hogg MI, Lunn JN, Rosen M. Degree and duration of reversal by naloxone of effects of morphine in conscious subjects. Br Med J. 1974;2(5919):589-591.
  • Wanger K, Brough L, Macmillan I, Goulding J, MacPhail I, Christenson JM. Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. Acad Emerg Med. 1998;5(4):293-299.
  • Kelly AM, Kerr D, Dietze P, Patrick I, Walker T, Koutsogiannis Z. Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Med J Aust. 2005;182(1):24-27.
  • Tandberg D, Abercrombie D. Treatm.ent of heroin overdose with endotracheal naloxone. Ann Emerg Med. 1982;11(8):443-445.
  • Mycyk MB, Szyszko AL, Aks SE. Nebulized naloxone gently and effectively reverses methadone intoxication. J Emerg Med. 2003;24(2):185-187.
  • Beletsky L, Ruthazer R, Macalino GE, Rich JD, Tan L, Burris S. Physicians’ knowledge of and willingness to prescribe naloxone to reverse accidental opiate overdose: challenges and opportunities. J Urban Health. 2007;84(1):126-136.
  • NARCAN Nasal Spray [package insert]. Radnor, PA: ADAPT Pharma, Inc; 2015.
  • Robertson TM, Hendey GW, Stroh G, Shalit M. Intranasal naloxone is a viable alternative to intravenous naloxone for prehospital narcotic overdose. Prehosp Emerg Care. 2009;13(4):512-515. doi: 10.1080/10903120903144866.
  • Thomson Reuters Micromedex Clinical Evidence Solutions. Thomson Reuters; c2011. RED BOOK Drug References; 2016. http://thomsonreuters.com/products_services/healthcare/healthcare_products/clinical_deci_support/micromedex_clinical_evidence_sols/med_safety_solutions/red_book/. Accessed May 25, 2016.
  • Therapeutic Research Center. PL detail-document #320537, naloxone for opioid overdose (FAQs). Pharmacist’s Letter/Prescriber’s Letter. 2016;May:1-10.
  • College of Psychiatric & Neurologic Pharmacists. Pharmacy basics. Prescribe to Prevent website. http://prescribetoprevent.org/pharmacists/pharmacy-basics/. Published 2015. Updated February 2015. Accessed June 2, 2016.
  • Adapt Pharma facilitates Narcan (naloxone hydrochloride) nasal spray access to state and local public entities [news release]. Dublin, Ireland: Adapt Pharma; January 14, 2016. http://adaptpharma.com/adapt_press_release/january-14-2016/. Accessed May 25, 2016.
  • Evzio [package insert]. Richmond, VA: Kaleo Inc; 2014.
  • Edwards ET, Edwards ES, Davis E, Mulcare M, Wiklund M, Kelley G. Comparative usability study of a novel auto-injector and an intranasal system for naloxone delivery. Pain Ther. 2015;4(1):89-105. doi: 10.1007/s40122-015-0035-9
  • Darke S, Hall W. Heroin overdose: research and evidence-based intervention. J Urban Health. 2003;80(2):189-200.
  • Angst MS, Lazzeroni LC, Phillips NG, et al. Aversive and reinforcing opioid effects: a pharmacogenomic twin study. Anesthesiology. 2012;117(1):22-37. doi: 10.1097/ALN.0b013e31825a2a4e.
  • Wheeler E, Jones TS, Gilbert MK, Davidson PJ; Centers for Disease Control and Prevention (CDC). Opioid overdose prevention programs providing naloxone to laypersons - United States, 2014. MMWR Morb Mortal Wkly Rep. 2015;64(23):631-635.
  • Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA. 2016;315(15):1624-1645. Review. doi:10.1001/jama.2016.1464.
  • Chaparro LE, Furlan AD, Deshpande A, Mailis-Gagnon A, Atlas S, Turk DC. Opioids compared with placebo or other treatments for chronic low back pain: an update of the Cochrane Review. Spine (Phila Pa 1976). 2014;39(7):556-563. doi: 10.1097/BRS.0000000000000249.
  • Davis CS, Carr D. Legal changes to increase access to naloxone for opioid overdose reversal in the United States. Drug Alcohol Depend. 2015;157:112-120. doi: 10.1016/j.drugalcdep.2015.10.013.
  • The Network for Public Health Law. Legal interventions to reduce overdose mortality: naloxone access and overdose good Samaritan laws. NPHL website. https://www.networkforphl.org/_asset/qz5pvn/network-naloxone-10-4.pdf. Updated June 2016. Accessed October 27,2016
  • Walley A, Xuan Z, Hackman HH, et al. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis. BMJ. 2013;346:f174. doi: 10.1136/bmj.f174.
  • Coffin PO, Sullivan SD. Cost-effectiveness of distributing naloxone to heroin users for lay overdose reversal. Ann Intern Med. 2013;158(1):1-9. doi: 10.7326/0003-4819-158-1-201301010-00003.
  • Lee CP, Chertow GM, Zenios SA. An empiric estimate of the value of life: updating the renal dialysis cost-effectiveness standard. Value Health. 2009;12(1):80-87. doi: 10.1111/j.1524-4733.2008.00401.x.
  • Fact sheet: Obama administration announces additional actions to address the prescription opioid abuse and heroin epidemic [news release]. Washington, DC: The White House Office of the Press Secretary; March 29, 2016. https://www.whitehouse.gov/the-press-office/2016/03/29/fact-sheet-obama-administration-announces-additional-actions-address Accessed June 3, 2016.
  • Jones CM, Lurie PG, Compton WM. Increase in naloxone prescriptions dispensed in US retail pharmacies since 2013. Am J Public Health. 2016;106(4):689-690. doi: 10.2105/AJPH.2016.303062.
  • Bazazi AR, Zaller ND, Fu JJ, Rich JD. Preventing opiate overdose deaths: examining objections to take-home naloxone. J Health Care Poor Underserved. 2010;21(4):1108-1113. doi: 10.1353/hpu.2010.0935.
  • Maxwell S, Bigg D, Stanczykiewicz K, Carlberg-Racich S. Prescribing naloxone to actively injecting heroin users: a program to reduce heroin overdose deaths. J Addict Dis. 2006;25(3):89-96.
  • Seal KH, Thawley R, Gee L, et al. Naloxone distribution and cardiopulmonary resuscitation training for injection drug users to prevent heroin overdose death: a pilot intervention study. J Urban Health. 2005;82(2):303-311.
  • Tobin KE, Sherman SG, Beilenson P, Welsh C, Latkin CA. Evaluation of the Staying Alive programme: training injection drug users to properly administer naloxone and save lives. Int J Drug Policy. 2009;20(2):131-136. doi: 10.1016/j.drugpo.2008.03.002.
  • Seal KH, Downing M, Kral AH, et al. Attitudes about prescribing take-home naloxone to injection drug users for the management of heroin overdose: a survey of street-recruited injectors in the San Francisco Bay Area. J Urban Health. 2003;80(2):291-301.
  • University of Washington Alcohol & Drug Abuse Institute. Washington’s 911 Good Samaritan Drug Overdose Law: initial evaluation results. UW ADAI website. http://adai.uw.edu/pubs/infobriefs/ADAI-IB-2011-05.pdf. Published November 2011. Accessed June 18, 2012.
  • Straus MM, Ghitza UE, Tai B. Preventing deaths from rising opioid overdose in the US - the promise of naloxone antidote in community-based naloxone take-home programs. Subst Abuse Rehabil. 2013;2013(4). doi: 10.2147/SAR.S47463.
  • Burris S, Norland J, Edlin BR. Legal aspects of providing naloxone to heroin users in the United States. Int J Drug Policy. 2001;12(3):237-248.

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