Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

Needleless treatment options for medical problems

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Intranasal Naloxone for acute opiate overdose: Reducing needle stick risk, improving time to medication delivery

Table of Contents:

Introduction to intranasal naloxone (click here)

Reducing needle stick risk in the prehospital environment (click here)

Literature overview and discussion

Lay person naloxone home treatment (click here)

Paramedic use of intra-nasal naloxone (click here)

Personal insights from experienced clinicians (click here)

Treatment protocol (click here)

Teaching Materials (click here)

Bibliography (click here)

Delivering intranasal naloxone to a heroin overdose in an emergency situation

Delivering intranasal naloxone to a patient suffering from an opiate overdose

W.H.O. (World Health Organization) 2014 recommendations regarding Community management of opioid overdose - download the PDF


There is currently a world wide epidemic of opiate overdoses and deaths due to accidental opiate overdose which is especially apparent in the United States. The majority of those deaths are related not to heroin, but instead to prescription drugs. This diagram from Unik et al points to the dramatic rise that has occurred over the last 15 years.[28] (Click here for full article link)

Unik graph showing deaths from opiates

Furthermore, Intravenous drug users (IVDUs) requiring naloxone after heroin overdose are a unique population that place prehospital health care providers (paramedics/EMTs and other ambulance personnel) at an especially high risk for blood borne pathogen exposure.[1-3] Since all of these patients rarely need intravenous access for any reason beyond the administration of naloxone (Narcan), a method of administering naloxone without a needle would be preferable.[4-6] Fortunately, naloxone is a small molecule that easily crosses the nasal mucosal membranes. After intranasal (IN) administration, naloxone exhibits opiate antagonist effects almost as rapidly as the IV route with bioavailability approaching 100%.[7, 8] Based on this information two compelling reasons exist to consider IN delivery of naloxone for acute opiate overdoses: The reduction of needle stick risk to rescue providers and the possibility of lay person naloxone delivery.

Reducing needle stick risk in the prehospital environment:

While the intranasal option for delivering naloxone is not necessarily more effective than traditional intramuscular or intravenous injection methods, it is easier to deliver and often works as well as an injection. Most importantly to health care workers, intranasal naloxone delivery eliminates the risk of a contaminated needle stick. Needle stick injury is not a minor issue. Blood borne exposures are an occupational hazard that healthcare providers face daily. The CDC estimates that 600,000-800,000 percutaneous injuries with contaminated sharps occur yearly in the United States.[9] With the increasing prevalence of blood born pathogens such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) accidental needle stick injury may pose a life-changing and possibly life-ending event for affected health care workers. This risk is higher in the prehospital environment where a combination of patient and environmental factors make needle stick injury more likely.[10] Marcus et al found an HIV seroprevalence rate of 4.1 to 8.9 per 100 patient visits in three inner-city ED populations.[1] Because the annual blood contact for an individual EMS worker (Emergency Medical Services – paramedic) has been estimated to be as high as 12.3 per year, concern exists regarding the risk of viral seroconversion in EMS providers.[11] Several authors have validated this concern. Valenzuela et al reported a five-fold higher prevalence of Hepatitis B (HBV) infection in paramedics than that observed in a comparable population from the same city.[12] Pepe et al noted a strong association between years of employment and the rate of HBV infections in EMS workers.[13] Although there is less risk today with the advent of HBV vaccines and use of universal precautions, the risk for other exposures remains significant.

An especially high-risk patient population to EMS providers is the IVDU. These patients have HIV, HBV and Hepatitis C (HBC) seroprevalence rates that are far higher than the baseline population.[2] In addition, EMS personnel commonly are involved in their care for life threatening illnesses such as respiratory arrest from opiate overdose. Furthermore, unique EMS environmental conditions such as combative patients, uncontrolled scene issues, poor lighting and moving ambulances make the probability of suffering a needle stick even more likely than in more controlled medical settings. Since opiate overdose patients rarely need an IV for any reason beyond the administration of naloxone, a needleless method of administering naloxone would eliminate needle stick risk and potential transmission of blood borne pathogens.[4-6] Effective methods of reducing needles stick risk to emergency providers in this situation should be welcomed. Intra-nasal naloxone is one such therapeutic intervention that may have a role in opiate toxic patients.[14, 15] The literature review that follows will discuss the results of currently published trials investigating IN naloxone in the prehospital environment.

Literature overview and discussion

Lay person and BLS naloxone treatment

Trials utilizing home injections of naloxone for heroin overdoses have demonstrated some success, but routine application of this concept is limited by the need for injection training and by state laws.[16] These issues have led some investigators to consider intranasal naloxone since it can be delivered without a needle very easily by the lay public including family members, law enforcement and first aid workers.[17] There is no need to learn 1) How to administer an injection, 2) Sterile technique methods, or 3) Intravenous cannulation or injection techniques. In addition, administration by the nasal route may be more appealing to IVDU who fear needles. Finally the risk of needle stick injury will be eliminated during administration. Many states have now adopted home layperson administered intranasal naloxone into their state regulations.[18, 22]

As of 2014 the clinical need for layperson administered naloxone has become overwhelming due to evidence of its efficacy (see data below) and the epidemic of opiate induced deaths that have occurred world wide but especially in the USA where 80% of all prescription opioids are consumed. This had led to a plethora of new laws approving layperson and BLS administered naloxone and great deal of literature on the topic.

Massachusetts, specifically the Boston area, has been one of the ground breaking areas in terms of advancing the cause of expanded naloxone access to basic life support personnel (Firefighters, EMT basics, police) and the lay public. They have also led the country in academic level research on the topic. In 2014 they provided a plethora of new insights into this topic.

From their EMS agency we get a large review of experience with BLS level data from 2006-2012. Weiner et al conducted a retrospective review of 7 years data where the city of Boston BLS providers administered intranasal naloxone to suspected opiate overdose patients.[32] A total of 793 uses were identified and 724 charts were found to match with ED records. 689 (95.2%) of patients given naloxone by BLS providers responded to the drug. Only 8.8% required another dose in the ED. 507 (70%) were discharged home. The authors conclude that out-of-hospital administration of BLS naloxone was effective in the vast majority of opiate overdose cases and only a small percentage of patients required additional ED interventions. (In 2013 the BLS service administered another 458 doses of naloxone in the field).[33] Davis et al provide additional insights into BLS administered (firefighter and police first responders)  naloxone in the area surrounding Boston.[33][Free open access article click here] These communities already have demonstrable reductions in fatalities from opiate overdoses due to lay public administered naloxone and now have another layer of safety introduced to intervene in the current epidemic of opiate induced deaths.

Other communities are now showing promising results from naloxone programs. Rando et al report historical data on a community’s  death rate from opioid overdose (Lorraine OH) before and after introduction of police administered nasal naloxone. [50] The death rate per quarter increased from 5.5 in 2011 to 15.3 for 2012 and peaked at 16.3 for 2013. After introduction of police officer delivered naloxone the death rate receded to 13.4 over the next year.  Ray et al demonstrated that the police are very supportive of these police administered naloxone programs even though it puts additional burdens upon them.[47] Fareed et al provide data showing us that the Veterans health administration has implemented an initiative to provide education to veterans and their families about opioid overdoses and to provide nasal naloxone rescue kits.[51] They recommend that public health administrators and policy makers advocate for the implementation of these programs to reduce the rising number of overdose deaths in the United states and worldwide. Dwey et al discuss the feasibility and efficacy of overdose education and home naloxone use when implemented out of an ER setting. They found it was feasible to implement but difficult to quantify efficacy due to difficult follow-up.[52] Dahlem et al provide insights into developing a take home IN naloxone program at a homeless shelter. They found this program effective and safe and recommend implementation in clinical practice.[53] Han et al noted that introducing home IN naloxone programs to outpatient centers provides an intervention that makes the doctors and providers more satisfied with their interactions with this difficult patient population.[60]


As of 2017 there are many studies that all support the fact that layperson use of IN naloxone is feasible, safe and life saving.[55-59]

Does naloxone distribution increase risky behavior?  The answer is no - in fact the opposite is more likely:

Researchers from Boston also have addressed the concern by some that naloxone distribution may result in increased risky behavior by opiate users.  Doe-Simkins et al review the data concerning this issue and provide their own additional experience in an article from Biomed Central.[34] [open access – click here for full article] Part of this concern regarding  increasing use of heroin due to providing an antidote stems from a survey conducted by Seal et al. in 2003. [35] These authors interviewed 84 injection drug users and were told by 35% of respondents that if they were provided with a naloxone rescue kit they might be more comfortable using heroin more often. However, this opinion was refuted by actual evidence when these same authors trained 12 pairs of injection drug users (24 people) to perform CPR and to give naloxone on the street.[36] In the next 6 months these individuals reported seeing 20 overdoses for which the performed CPR and/or gave naloxone in 19 (95%). All victims survived. The “providers” trained to do these interventions actually began using less heroin, not more heroin. Similar findings are reported by Wagner in a 2010 article.[37] In a 2014 article Wagner reports on interviews conducted with a cohort of active injection users who were trained to use naloxone and actually found that these trained drug users moved up in the social strata of their community due to the lifesaving skill they acquired.[38] This resulted in greater feelings of self-worth. The majority of those trained reported using less heroin and some actually left this social group to reduce their exposure to this risky behavior.[open access data – click here for articles - Wagner article is at the end of the series] Galea’s data from 2006 and Doe-Simkins data from 2014 also showed no increase drug use following the introduction of rescue naloxone kits. [34, 39]

In 2014 there has been a great deal of activity on this topic throughout the USA with multiple state legislatures recently approving layperson and BLS use of naloxone, pharmacists pushing for increased ability to provide this therapy and emergency physicians addressing this need at a national level.  Bailey and Wermeling advocate for a greater role of pharmacists in identifying high risk patients (licit users of high-dose prescription opioids or injection drug users and abusers of prescription medications) and either contacting their provider for a prescription for IN or IM naloxone or if legal, prescribing the naloxone themselves (with appropriate training for use).[40] Hammet et al further elucidate the legal aspects related to this.[45] The American College of Emergency Physicians (ACEP) revisited the concept of expanded access to naloxone at a BLS and lay public level and the concept of physician prescribed naloxone to high risk patients. As a point of history, these proposals were rejected by the council in 2013, but resurfaced at their national meeting in Chicago during the month of October 2014. Both proposals have now been passed, garnering support for these policies from yet another important player involved in the care of this illness. Both Maryland and Rhode Island are moving forward with educational programs to expand access to naloxone.[41] Additional reports of layperson administered naloxone are surfacing from around the world. Green et al describe two cases of opioid overdose reversal in former prisoners who were trained to use IN naloxone upon prison release. In both cases the patients were able to assist their partners in  giving them the naloxone and reversing their overdose. The authors advocate training and equipping former prisoners and all at risk patients and families of these patients.[42] Multiple Australian states have recently implemented programs for peer administration and prescription status for naloxone.[43] At the end of 2014 the W.H.O. (World Health Organization) published a position paper recommending community access to naloxone in an effort to stem the tide of accidental deaths from Opioids. (Click here for the WHO document)

Information related to layperson administration of naloxone continues to emerge. In 2015 Behar et al note that brief educational training (only 5-10 minutes) was sufficient to ensure adequate knowledge in layperson users for using take home naloxone.[46] Ray et al interviewed police officers following their training to use IN naloxone as a recue therapy. They found that “The officers had overwhelmingly positive feelings about the training, that it was not difficult, and that other officers should be trained to use naloxone.” [47] Richert interviewed users attitudes to recue therapy and concluded that the simplest method of naloxone delivery (Intranasal) was probably the most likely method that users would be willing to administer.[48] Wermeling continues to publish review topics on the concept with the most up to date information related to new drug formulations including that which his company is producing.[49]

Layperson administer naloxone kits:

One ampule of naloxone 2 mg/2ml

One Luer attached atomizer

Intranasal naloxone layperson kit

The state of New Mexico allows both their basic life support [BLS] providers (police and highway patrol) to administer IN naloxone and they send IN delivery kits home with families of known opiate addicts in an attempt to reduce the high rate of opiate overdose deaths in their state.[18] Similar community efforts are now ongoing in multiple states including Massachusetts (NOMAD program), New York and North Carolina (Project Lazarus).  Maya Doe-Simkins published preliminary data form the greater Boston area experience with lay person administered intranasal naloxone, noting a total 385 participants trained and 74 successful opiate overdose reversals - leading to reduced EMS and ER utilization and likely reduced mortality.[22] (Click here for the article) . Since the publication of the article, the system (INPEDE OD study - N.O.M.A.D. program) now reports 755 opioid overdose reversals with that number growing daily. (click here for 2011 report).

The February 17,  2012 Morbidity and Mortality Weekly Report (MMWR) published by the CDC discusses the community based opioid overdose prevention programs that exist in the USA, most of which pass out naloxone as either intranasal or intramuscular forms of delivery. (Click here for a link). This report states that over 53,000 laypersons have been trained with a reported successful reversal of over 10,000 patients who have overdosed. At least 15 states have existing programs. This report was featured in Time magazine (click here for link) where the authors suggest this should be made an over the counter therapy (another link on this here) and suggest that the FDA will be considering this in the spring of 2012.

Massachusetts N.O.M.A.D. program (Not One More Anonymous Death overdose prevention project)

As described above the NOMAD program has been quite successful using layperson administered intranasal naloxone combined with rescue breathing until the naloxone has had a chance to work. As of September 2011 they report over 1000 successful overdose reversals.

Here is a link to the protocol / photos of what the NOMAD program teaches the lay public:

N.O.M.A.D. Not One More Anonymous Death overdose prevention project protocol (Click Here)

The same group who was involved in the NOMAD program established an Overdose education and naloxone distribution (OEND) program for patients in Massachusetts who were being started on methadone.[27] They distributed kits to 1553 new methadone maintenance patients and reported 92 naloxone rescues as a result. Interestingly, though prescription opiates are now more commonly associated with death than heroin, in this group of methadone patients, the vast majority of the naloxone rescues occurred on witnessed heroin overdoses.

New York City also reports approximately 300 opiate reversals and growing using a similar program.

Intranasal and intramuscular naloxone program in New York City - Power Point - (click here)

CVS pharmacy kits:

As of the fall of 2015, CVS pharmacy now sells naloxone kits over the counter in 14 states: Those states include Arkansas, California, Minnesota, Mississippi, Montana, New Jersey, North Dakota, Pennsylvania, South Carolina, Tennessee, Utah, and Wisconsin. Naloxone is already available over the counter at CVS stores in Rhode Island and Massachusetts.

New York City nasal naloxone device:

IN naloxone device

New commercially available Nasal Naloxone

In 2019 Krieter et al present initial pharmacokinetic data regarding the newly available prepackaged IN naloxone product marketed by Aptar.  Bottom line is that IN naloxone (4 mg) results in higher plasma concentrations of drug than the intramuscular dose (0.4 mg) yet does not require any injection. They also found that over 90% of the lay public could use the product with no prior training. [68, 74]

Other commercially available nasal naloxone products are entering the market.[71]  All are highly concentrated and therefore should improve efficacy following nasal delivery. Maybe the competition will lead to a fair price

If these products are priced at an affordable cost, I predict it will displace all other forms and could become a huge commercial success going home with everyone on long term opiates. However, given recent (2016) obvious greed and over-pricing of life saving home medications such as Epi Pens, I will believe this when I see it.


Availability and cost of nasal naloxone in pharmacies and to hospitals:

Unfortunately the trend, as with many pharmaceuticals now, is an upward push on prices for any drug that is controlled by a single manufacturer. Rosenberg reports a similar trend for all forms of naloxone.[64]

In 2017 researchers found that only 1/3 of Philadelphia pharmacies carried nasal naloxone and 1/3 of those required a prescription to obtain it – this despite a law passed two years earlier allowing pharmacies to stock and dispense the drug without any prescription. To make matters worse pharmacies in the areas with the highest opiate overdose rates had the lowest naloxone availability. Drug costs were a mean of $145 ($119-150).[66]

In contrast to Philadelphia, Wu et al surveyed Massachusetts pharmacies and found 98% stocked the drug and 96% did not require a prescription. Costs however were similar with mean price being $128.[67]

Others confirm the regional variability in access to this life saving medication.[72, 73]

Blurb on the tragic costs of naloxone:

Given the concern of skyrocketing costs and drug shortages, Pruyn et al sought to determine if expired naloxone vials contained drug that was still effective.[70] They tested samples of naloxone with expiration dates ranging from 1990 to 2018. They found that most samples still contained over 90% naloxone (not is breakdown product) – even samples from the 1990’s. Though there was a slight degradation correlating with time they found no significant degradation that would effect the drugs use. The conclude that “Extending the shelf-life of naloxone products may have important financial and public health consequences in addressing future drug shortages and meeting the needs for this critical drug.”

Editorial comment: Naloxone prices have skyrocketed in the last 20 years. (The opposite of traditional supply/demand economics because our pharmaceutical industry does not lie within a traditional economic system). One solution, minor though it is, might be to use expired drug if it is still effective. Pruyn showed that to be the case implying that if you have stored your naloxone out of the light and heat it is likely still fine. Test a vial – if it works – maybe you should use it. I know for a fact (having been in the industry) that expiration dates in medical supplies are set based almost entirely on time required to distribute the product to the shelf with an expiration date of about 6-12 months or so later. Expiration dates for these non-spoilable product have almost nothing to do with the actual shelf life of a product.  The medical industry generally does not test to see how LONG their product will last, they only test to be sure it can last to the date of delivery plus 6-12 months beyond.

BLS provider administration of IN naloxone

Multiple states and city's allow IN naloxone delivery by lay persons so it makes sense that they allow their BLS providers to also administer this potentially lifesaving medication. In 2005 Boston EMS approved IN naloxone for their EMS providers. In 2006 they reported a 75% success rate in reversal of opioid overdose when BLS providers delivered IN naloxone. (Click here for a slide presentation on the topic.) In a more complete 5 years study they found IN naloxone delivered by BLS to be 70% effective with rare incidence of acute agitation. they did find it to seem to be slower than injectable naloxone (which is similar to Kerr data from Australia) - not perfect but no need for a shot. (Click here for slide presentation for Boston 2005-2009 BLS data).

Coffin and Sullivan used all the above data along with many other studies related to home use of injectable naloxone and did a cost analysis of the utility and expense related to home naloxone therapy.[29] Although this is a very statistically complex article, it assesses a very important issue relating to layperson delivery of naloxone (whether via IN or IM delivery). The authors cite a common concept used to determine the value of a medical intervention in terms of costs per year of additional life – the concepts is called “quality adjusted life years” or  QALY. Researchers and public health officials commonly use a value of $50,000 per year of life gained as a cost effective number when calculating QAKY. In other words – if you can  provide a therapy such as cancer care, organ transplantation or delivery of naloxone for a cost of $50,000 or less per additional year of life it is considered cost effective medicine.  Using this cut off as the maximum, the authors then utilized all the published literature available on the topic of heroin overdose, death rates, etc and made some assumptions both at the low and high end of costs with an assumption that an overdose results in death only 1% of the time, that only 13.6% of distributed naloxone will be used in a year and that naloxone kits cost between $15 and $30. They found that the cost for one QALY was $438. On the outside using the assumption that a heroin user who does not die costs society more than they provide – the outside highest QALY was $2429. Using the absolute worst case scenario where overdoses were rarely witnessed and naloxone was rarely used, barely effective and very expensive they still found on QALY to be $14,000. They hypothesize similar cost effectiveness for use of naloxone to reverse accidental overdose from prescription opiates (which is now the leading cause of death in young adults in the United States.)

In an accompanying editorial, Compton et al [30] review the FDA views on the topic – which are extremely favorable towards prescription home naloxone and eventually over the counter naloxone. At this point the FDA is fully aware of the off-label lay person use of naloxone both nasally and Intramuscularly and applauds this movement but hopes to encourage the pharmaceutical industry to develop easily administered and more highly controlled forms of this medication.

Editorial comment: Is a year of your life worth $438-$14,000? Is it worth saving someone else's life – often a young adult -  so they can go on to experience life for decades to come? I doubt this is a very hard decision and I find it amazing and sad when I hear some clinicians or politicians comment on the ethics of distributing naloxone to lay people and their concern that it will increase risk taking.  They are spouting uninformed rumors rather than evidence. Even were they correct, are we to infer that these patients are disposable humans not worth this trivial cost? They should read some of the articles reviewed on this page that actually show REDUCED risky behavior in the cohort of injection users who are trained to use rescue naloxone - this knowledge elevates them within their peer community and gives them an increased sense of worth that frequently leads to reductions in opioid use.

In 2016 Fisher et al published data demonstrating that non-medical first responders (police) are fully capable or delivering IN naloxone to appropriate candidates.[54] The data is essentially identical to EMS data  - noting over 80% effective response to the drug (breathing). Only one case (out of 126 patients) led to combativeness – also confirming the low incidence of agitation following IN naloxone delivery.

Gulec et al analyzed appropriateness and effectiveness of naloxone delivery by BLS versus ALS providers over a two year period. They had 3219 cases to analyze and found no differences between the two groups. They conclude that intranasal naloxone delivered by BLS is as effective and given as appropriately as any naloxone given by ALS. They recommend the the National EMS scope of practice guidelines include BLS administration of nasal naloxone for suspected opioid overdoses.[61]

The increasing use of naloxone has allowed better analysis of single dose versus multiple dose requirements. Klebacher found that about 9% of all opiate overdoses need at least on  repeat dose while 2-3% required three or more doses. [62] Weiner et al report on 6 years experience with BLS administration of nasal naloxone to 793 patients. They  reviewed all ED charts and found that 95% had a clinical response and that 9% eventually needed an additional dose (the same percentage as seen in the 2017 Klebacher et al study reference 62).[63] They conclude that BLS administration is effective and safe.  Editorial comment: This data is important because it shows that if left alone without ALS intervention, generic nasal naloxone (which is probably a bit dilute) is effective in the same percentage of patients as the more expensive highly concentrated formulations. The point being – if your budget is limited this therapy may be more cost effective than trade name IN Narcan and just as clinically effective.

Conclusions regarding layperson and BLS administered naloxone

The evidence increasingly supports the effectiveness and safety of layperson administered naloxone. Furthermore, the USA is in the throngs of a major epidemic of opiate overdose deaths from prescription pain medications with some states death rates exceeding that of motor vehicle crashes, homicides, and many other causes of death in young adults. Hopefully we will see the FDA make this a non-prescription therapy in the very near future.

Paramedic use of intra-nasal naloxone

Nasal naloxone deliveryThe Denver Health Paramedic system investigated the efficacy and safety of atomized intranasal naloxone for the treatment of suspected opiate overdose.[14] Study patients were given 2 mg of IN naloxone (1mg/ml up each nostril) upon initial contact. After intranasal naloxone, standard protocols were followed including airway management, IV placement, and administration of IV naloxone. Ninety-five patients were enrolled. Fifty-two patients responded to naloxone: 43 (83%) to IN naloxone alone, 9 (17%) to IV following IN naloxone. Four of these "non-responders" had IV naloxone so rapidly (less than 3 minutes) that it is likely the nasal naloxone did not have time to produce a clinical effect. An additional four of the nine "non-responders" had anatomic abnormalities that may have prevented intranasal medication absorption (epistaxis, nasal trauma, nasal septal abnormalities). The median times from arrival at patient side to awakening and from administration of the IN naloxone to patient awakening were 8.0 minutes and 3.0 minutes respectively. These median times to awakening after arrival and naloxone administration are less than those reported by Wanger et al for intravenous naloxone (9.3 minutes and 3.8 minutes) or subcutaneous naloxone (9.6 minutes and 5.5 minutes).[19] Even though this was a limited study, the authors concluded that IN naloxone can be effective in the field (83% initial response rate), acts rapidly and could potentially reduce the risk of paramedic needle sticks in this population.

Kelly et al conducted a similar EMS study, comparing intranasal naloxone to intramuscular naloxone in 155 prehospital opiate overdose cases.[15] Unfortunately they did not have access to concentrated naloxone and had to use 2 mg of naloxone in 5 ml of solution – a volume that would be predicted to be less effective due to run-off into the throat (See intranasal medication delivery overview section of this web site). Nevertheless, they still found both treatments equivalent in terms of opiate reversal (74-83%) though IM naloxone worked faster. Interestingly, only 2% of patients given intranasal naloxone experienced agitation or irritation upon awakening, a difference they attributed to the gradual absorption and gradual awakening seen with intranasal naloxone. This finding was felt to be an advantage of IN naloxone, since the rapid awakening and hypoxic agitation seen with administration of IV naloxone is of considerable concern to some EMS providers. Based on this data and the considerable danger of needle stick exposure in this patient population, these authors conclude that IN naloxone should be the first line therapy for opiate overdose in the prehospital setting.

Robertson et al reviewed their EMS data on 154 opiate overdoses requiring rescue naloxone over a 17 month period.[21]  They found that the EMS providers used IV naloxone 104 times and IN naloxone 50 times.  The mean time from arrival at scene to awakening was identical for both delivery routes (about 20 minutes) though naloxone was faster in onset once an IV was established (8 minutes versus 12 minutes). 34% of patients in the naloxone grip were given a second dose, while 18% in the IV group needed a second dose. The authors conclude  "Given the difficulty and potential hazards in obtaining IV access in many patients with narcotic overdose, IN naloxone appears to be a useful and potentially safer alternative."

Merlin et al did a retrospective review of all naloxone administration in their single 6 truck EMS system over a two year period.[23] They then eliminated all cases that did not have confirmed opiate overdose (admitted by patient or family, found with paraphernalia of opiate injection, confirmed by urine toxicology screen). Using this strict inclusion criteria they found 96 cases of opiate overdose treated with naloxone. Of these cases 55 received IV naloxone, 38 intranasal and 3 intramuscular. Comparing baseline respiratory rates and change in Glasgow coma scores they found no statistical difference: IV naloxone patients had increase in respirations from 10/minute to 18/minute and GCS  increase from 4 to 15.  IN naloxone patients had increase in respirations from 10/minute to 16/minute and GCS  increase from 3 to 12. The authors conclude that "among subjects with confirmed opioid overdose, intranasal naloxone is as effective as intravenous naloxone at reversing central nervous system depressive effects caused by opioids."

A trial of concentrated intranasal naloxone [2mg Naloxone in 1mL] for suspected heroin overdose was done in the prehospital setting in Melbourne, Victoria. The findings were published in December 2009. They compared 172 patients randomized to IN versus IM naloxone. Response rates and times were the same after 1 dose (72% vs. 78%,  8.0 versus 7.9 minutes onset, p=NS). 18% of the IN patients were redosed for a total response rate of 82%. The authors conclude that intranasal naloxone is effective and safe and offers a needle-less method of treating heroin / opiate overdoses.[24] Other publications suggests that IN naloxone should move from the realm of ALS to that of BLS, allowing all first responders to administer this medication intranasally to any comatose patient at risk of opiate overdose.[17]

McDermott demonstrated that paramedics felt IN naloxone was faster to deliver, better accepted and perceived as safer than IV naloxone and that this route should be considered more frequently as first line therapy.[26]

Sabzghabaee et al conducted a prospective RCT comparing IN naloxone (0.4 mg) to IV naloxone (0.4 mg) in 100 patients who overdosed on opiates.[31] All patients were delivered the study drug and had their ventilation supported for 5 minutes. After 5 minutes those who failed to respond were administered a second dose – it is not clear from the paper how many patients required redosing. The primary outcome was level of consciousness with secondary outcomes of vital signs (primary interest was respiratory rate), time to response, oxygen saturation and side effects (agitation). They found both treatment regimens equivalent in reversing both respiratory depression and CNS depression. 100% of the IN group progressed to a state of either lethargy or full consciousness following naloxone delivery compared to only 60% of the IV group (the remaining 40% were obtunded and breathing but no longer comatose). The time to response following drug delivery was 2.56 minutes for the nasal route versus 1.48 minutes via the IV route. There was no difference in respiratory rate improvement. Mean arterial saturations increased from 71% to 94% (IN) and 73% to 94% (IV). Agitation was observed in 12 of 50 patients receiving IV naloxone but in no patients receiving IN naloxone. The authors conclude that IN naloxone is as effective as IV naloxone in reversing both opiate induced respiratory depression and CNS depression, but that the nasal form leads to less severe withdrawal symptoms following delivery and is therefore preferred.

(Free article – open access click here for PDF)

(Free article – open access click here for internet link)

Editorial note: This is a very important article for those interested in the efficacy, side effects and dosing of nasal naloxone.  All prior studies used a dose of 2 mg for nasal delivery so that was the only evidenced based recommendation possible for dosing. This study used 0.4 mg for the nasal dose and found it equivalent to the IV formulation for the primary goal of delivery – patient arousal and breathing. It would be nice to have at least one additional study to confirm this finding, but if this data is confirmed by others it opens the door to using alternate formulations of naloxone (0.4 mg/ml -  much less expensive and more readily available than the concentrated form) for nasal delivery.  I believe we need another confirmatory study prior to jumping on this concept because there are a number of missing data points (percentage of patients who required redosing) and some findings that don’t seem right (better arousal with IN than with IV drug). Until these are clarified I would be cautious on drawing firm conclusions. Another important point here is the risk of the patient becoming agitated and going into acute narcotic withdrawal. These authors demonstrate what has been reported previously: IN naloxone results in less risk of severe opiate withdrawal. I hypothesize that this is due to the absorption kinetics of the IN route being more prolonged and gentler(slow increase in breathing, oxygenation and awakening) in terms of arousal than the sudden hit and awakening (while still hypoxic) that occurs with an IV bolus.

In 2019 Dietze et al published their findings on this lower dose IN naloxone. They used a 0.8 mg in 1 ml naloxone formulation available in Australia and compared its efficacy when delivered nasally versus intramuscularly.[65] They randomized 197 patients.  They found the IM dose to work within 10 minutes in 91% of patients (most studies using IM. IV or IN find maximum efficacy in the 85-95% range so this is as good as you can generally expect). The 0.8 mg dose nasally worked in 77% of patients – a statistically and clinically important reduction in efficacy.

Comments: For 15 years or more I have been asked if it is ok to give the 0.4 mg/ml standard naloxone dose intranasally to treat opiate overdose. My answer was always to follow the literature – at the time only 2 mg/2ml had been studied so unless they were conducting a research project I felt using the 0.4 mg dose was risky as it was potentially too dilute to be effective. Admittedly Kelly et al published their results using this formulation in 2005 – but they gave 5 vials of the drug up the nose (5 ml) so surely had runoff, but did achieve a 2 mg dose. They found 74% of cases aroused compared to 83% using IM naloxone – statistically the same. Fast forward to 2014 when Sabzghabaee published their study on 100 patients where they reported 100% awakening with 0.4 mg IN naloxone – a better result than the 60% awakening with IV naloxone. This seemed too good to be true and not in line with almost ALL studies of naloxone where a 90% awakening +/- 5% is more typical (some patients just don’t wake up due to high levels of opiate or co ingestion of other sedatives). This study by Dietze is more in line with the Kelly data – they used 0.8 mg intranasally and found 77% arousal with one dose. So generic IV less concentrated naloxone is fairly effective when given nasally, but not as effective as the same dose given intramuscularily. If you ONLY have this lower dose and you cannot give it IM, then certainly if indicated you should use it nasally. However there are better nasal options including at least two commercially available IN naloxone products (2 and 4 mg in 0.1 ml prepackaged with an atomizer) and the original study drug – 2 mg/2 ml concentration.  You will need to do your due diligence and price investigation to decide, but if prices are similar the commercially available drugs are easier to use and probably very slightly more effective in situations where we are seeing more synthetic opiate (fentanyl etc) overdoses.

Study is free open access - click here for link

Zuckerman et al describe a case of failed nasal naloxone and for some reason therefore conclude that nasal naloxone is not a reliable treatment modality for opioid overdose.[44] [It is not clear why this is reportable or why they make this conclusion. IV naloxone is also ineffective after the first dose 10-15% of the time due to the quantity of opioid consumed.  As is very clear in all the provided references on this web page - there is NO 100% reliable single dose delivery method for naloxone. The providers must also support ventilation and if naloxone fails after one dose (given adequate time to be effective) they need to consider redosing, starting an IV and giving IV naloxone (only required 5-10% of the time) and seriously consider whether there is another cause for the obtundation (mixed overdose, different clinical cause such as intracranial pathology, sepsis, etc). Don't throw the baby out with the bathwater based on a single case.]

Mahonski describes the trend where increasing availability of synthetic opiates like fentanyl has led to the need to use higher doses of IN naloxone to reverse opioid toxicity. They found that effective  IN doses increased from 2.1 mg in 2015 to 3.6 mg in 2017 with a concomitant decrease in efficacy from 82% down to 76%. [69]

In 2019 US national EMS directors published their recommendations regarding prehospital use of naloxone. In a nutshell they believe nasal naloxone is first line and superior to intramuscular and if an IV is available, then IV titration is optimal.[75]

Open access link to article – click here

Take away lessons for nasal drug delivery in the emergency medical setting [10]

The information provided by these studies is important in terms of needle stick risk reduction. Accidental needle sticks resulting from a patient who is an IV drug abuser are emotionally draining for the employee as well as his family. In addition, the medications used for post-exposure prophylaxis for HIV are expensive and frequently result in major side effects.[20] By administering naloxone intranasally, needle stick risk can be reduced. This improves the safety of the work environment and eliminates the professional, personal and family turmoil that may occur should a provider incur a needle stick from an IV drug abuser.

While IN medication delivery is an exciting new method for delivering medications in the EMS setting, it is not a panacea. Being aware of limitations is an important step in appropriate utilization of this therapy. Key issues that must be addressed up front are the medication dose, volume and delivery method. Once the medication and delivery method are determined there are several other issues that will improve field experience: First, be aware of clinical situations where nasal delivery may be suboptimal. Inspect the patient’s nostrils for large amounts of mucus, blood or other problems that might inhibit absorption. If abnormalities are present, consider other routes for drug administration, as there may be an increased risk of failure. A few of the failures noted for IN naloxone administration in the Denver EMS study was due to the presence of epistaxis in the patient. [13] Second, deliver the medication without delay to allow time for effective absorption. Third, relax and reassess for a few minutes. If the clinical problem fails to resolve with the intranasal medication consider two things: The nasal route was not effective or the diagnosis is wrong. (It is fairly clear from the literature that the later is most likely the case - in every study that looked at it most patients receiving naloxone in any form did not have opiate overdoses.[14,23]) In situations where a comatose patient fails to awaken with naloxone, continue to support breathing and circulation, administer naloxone via the IM or IV route and consider alternate causes for the coma.

Personal insights from experienced clinicians

Debra Kerr, PhD Candidate, Senior Fellow – Emergency Medicine Research, Melbourne Australia ….. Rapid depression of the syringe (to atomize the drug out of the atomiser) is important and avoids respiratory administration. For paramedic use, response times may affect acceptability of IN administration as first line medication. Delay in clearance from overdose scene may reduce response times to next patient. Naloxone is not currently manufactured in a form suitable for IN administration. We had the drug manufactured by a private pharmaceutical company for the purpose of the (recent) trial. Also, the drug is not approved for IN administration by Australian legislative authorities. Anecdotally, paramedics are very keen to administer Naloxone via the IN route to reduce BBV transmission risk. Acceptability for rousable patients has not been tested. Our studies only included unrousable patients.

Erik D. Barton, MD, MS, MBA; Chief of Emergency Medicine, The University of Utah, Salt Lake City….. The biggest benefit we can offer any provider who is trying to care for IVDU’s who accidentally overdose on injected opiates is safety from blood exposure. Blood-borne exposures can be both physically and emotionally devastating to non-abusers (and their families!) who were just trying to save a life. There is often a period of several months to years in which monitoring for hepatitis and HIV seroconversion must occur. The IN route offers an immediate, noninvasive, and nearly risk-free opportunity to intervene with these patients by any first-responder: family members, police, fire, EMS, and even the ED. There is no downside to attempting such a noninvasive maneuver in a suspected IVDU FIRST as long as other resuscitative efforts are not significantly delayed, especially when the benefits to the patient and provider, as described above, significantly outweigh the risks.

Tim Wolfe, MD, emergency medicine specialist, prior academician (Associate professor, University of Utah, Salt Lake City), inventor of the MAD mucosal atomization device.... Interestingly, the mean time from heroin injection to death in fatal overdoses is 60-70 minutes. This tells us that the drug itself is only part of the issue in the final apneic cardiac arrest, otherwise they would die in 5-10 minutes. I suspect, as do others who taught me this, that opiate induced respiratory depression leads to hypercarbia (high CO2 in the blood due to reduced respiratory rate). This in turn leads to further suppression of the ventilatory drive, further hypercarbia and eventually such severe hypoxia that the patient arrests. The point of course is the importance of supportive ventilation which alone may lead to patient arousal without naloxone. As emergency providers we  can get very excited and impatient with nasal naloxone, expecting instant results from a drug we provide (we are driven by the unknown, fears of failure and adrenaline responses). My suggestion - relax, begin bag ventilation (reduces their hypercarbia), administer the nasal naloxone and be patient. It takes 3-5 minutes for any effect (note that IV naloxone takes about 3 minutes after administration - and it requires the time to start an IV) and up to 10 minutes for awakening.  Generally they are not as agitated with nasal naloxone (probably due to less hypoxia when they finally awaken) and sometimes they are not fully awake- just breathing which is really our primary goal.

NOVEMBER 2015 news flash: FDA approves intranasal naloxone for both prescription and probably OTC use:

Adapt Pharma company announced formal FDA approval of a 4 mg/0.1 ml single dose, single nostril formulation of naloxone - NARCAN Nasal spray. They also acquired the trademark brand name "Narcan." Sales are expected to begin in the USA early in 2016. They have special pricing for first responders and community based treatment programs of $37.50 per preloaded device.

Click here for the company announcement

Editorial comment: Even though  I invented the MAD nasal, began the research on nasal naloxone in the 1990s and have used this therapy for 18 years (so have a bit of a historical bent towards the original method of delivery), it seems pretty apparent to me that this new product is probably a better method for delivery of nasal naloxone than the way we have posted here on this website for the last 7 years. The new formulation is more appropriately concentrated, it has a pre-attached atomizer and because of the recent price increased in generic naloxone (single supplier cranked the price last year) this new formulation is not only better formulated, its also less expensive (in 2016). If they continue pricing it properly they should replace all generic "home made" kit formulations, if not - as of late 2017 - the research data does not show any better results than less concentrated generic formulations so the end user will need to decide which formulation to choose based on budget and convenience issues. I hope the company keeps this life saving drug at a reasonable price.

Treatment protocol

Indications: For use on patients suspected of opiate overdose
  1. Assess ABC’s – Airway, Breathing, Circulation
  2. For pulseless patients, proceed to ACLS guidelines
  3. Apnea with pulse – Establish oral airway and begin bag ventilation with 100% oxygen
  4. Load syringe with 2 mg (2 ml) of naloxone and attach nasal atomizer
  5. Place atomizer within the nostril
  6. Briskly compress syringe to administer 1 ml of atomized spray.
  7. Remove and repeat in other nostril, so all 2 ml (2 mg) of medication are administered
  8. Continue ventilating patient as needed

If no arousal occurs after 5-10 minutes, proceed down standard unconscious protocol including injectable naloxone and secure airway if necessary.

Comment: Most "failures" of IN naloxone are due to being in a hurry to see the patient wake up. IN naloxone takes 3-5 minutes to begin working. The patients often just breath but do not come up crazy so do not always expect full arousal. (The goal is breathing)

Comment 2: IN naloxone is now being used at a BLS, law enforcement and layperson level with good success.


Teaching materials:

Intranasal naloxone slide show presentations

Wolfe - Intranasal naloxone in safe injection setting

Dyer, Snuffing out the overdose: The Boston BLS nasal naloxone program (11 MB)

Lenton: Making Naloxone available to potential overdose witnesses: Evidence and policy opportunities (4.5 MB)

Gleghorn, A brief history of overdose prevention in San Francisco 2012

Intranasal Naloxone (Narcan) articles:

Kelly, A randomized trial of intranasal versus intramuscular naloxone for prehospital treatment of suspected opiate overdose, Med J Aust 2005 (click here) - PDF 0.23 MB

Doe-Simkins, Bystander Administered Naloxone, Am J Public Health 2009.pdf

Kim, Expanded access to naloxone, Am J Public Health 2009

Dasgupta, Opioid OD - a prescription for harm prevention, Am J Lifestyle Med 2009

Kerr, D., A. M. Kelly, et al. (2009). Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose. Addiction 104(12): 2067-74.

Leavitt, Intranasal naloxone for at home opioid rescue, Practical Pain Managment October 2010

New York City Intranasal Naloxone rescue kit directions

MMWR Feb 17 2012: Community based naloxone programs

McDermott, C. and N. C. Collins (2012). "Prehospital medication administration: a randomised study comparing intranasal and intravenous routes." Emerg Med Int 2012: 476161.

Open Society Foundation White paper on intranasal naloxone 2012

Community based opioid overdose prevention programs, MMWR 2012

Italian paper on the topic: Locatelli et al: Naloxone: impiego nelleurgenze per via endovenosa, intramuscolare, inalatoria ed endonasale

 Sabzghabaee, A. M., N. Eizadi-Mood, et al. (2014). "Naloxone therapy in opioid overdose patients: intranasal or intravenous? A randomized clinical trial." Arch Med Sci 10(2): 309-314.

Davis, C.S., et al., Expanded access to naloxone among firefighters, police officers, and emergency medical technicians in Massachusetts. Am J Public Health, 2014. 104(8): p. e7-9.

Doe-Simkins, M., et al., Overdose rescues by trained and untrained participants and change in opioid use among substance-using participants in overdose education and naloxone distribution programs: a retrospective cohort study. BMC Public Health, 2014. 14: p. 297.

Samuels, E., Emergency department naloxone distribution: a rhode island department of health, recovery community, and emergency department partnership to reduce opioid overdose deaths. R I Med J (2013), 2014. 97(10): p. 38-9.

Wagner, K.D., et al., "I felt like a superhero": the experience of responding to drug overdose among individuals trained in overdose prevention. Int J Drug Policy, 2014. 25(1): p. 157-65. - go to the end of the series for this document

W.H.O. (World Health Organization) 2014 recommendations regarding Community management of opioid overdose - download the PDF

Hammet, Pharmacies as providers of expanded health access for PWID, BMC Health 2014 Open access

Doyon, S., S. E. Aks, et al. (2014). "Expanding access to naloxone in the United States." J Med Toxicol 10(4): 431-434.


Acute opiate/heroin overdose: Intranasal therapy in EMS teaching document and quiz

Nasal Naloxone (Narcan) for pre-hospital opiate overdose - teaching document  (click here) (MS Word 0.12 MB)

Nasal Naloxone (Narcan) for pre-hospital opiate overdose - Quiz  (click here) (MS Word 0.05MB)

Nasal Naloxone (Narcan) for pre-hospital opiate overdose - Quiz answer key  (click here) (MS Word 0.03 MB)

Other links of interest regarding IN naloxone

Audio interview with Debra Kerr - IN naloxone researcher

Baltimore Maryland legislation approving intranasal naloxone for outpatient use to reduce heroin overdose deaths (click here) (PDF)

Project Lazarus - Home IN naloxone in North Carolina

Boston Massachusetts experience with home naloxone

Updated report on Massachusetts layperson trial (saving 755 lives to date) 2011

Boston Massachusetts experience with BLS delivered naloxone 2006

Boston Massachusetts experience with BLS naloxone 2005-2009

Legality of prescribing home naloxone in North Carolina

Leavitt, Intranasal naloxone: Overcoming opiate overdose

National public radio - Overdose rescue kits save lives

Expanding Naloxone availability in Australia (Many other links from this site)

Time Magazine - Lifesaving Overdose antidote should be made more widely available 2012 article

Newspaper article relating to a Police officer in Rural New York administering nasal naloxone as part of their BLS level naloxone delivery program

April 2012 public meeting held by the FDA to discuss approving naloxone for over the counter sales to reduce opiate overdose mortality

Open society Foundation white paper on IN naloxone 2012

National association of Drug Diversion Investigators (NADDI) statement of support for law enforcement officers to carry intranasal naloxone.

United Kingdom Advisory Council on the misuse of drugs - White paper recommending expanded access to naloxone to prevent reversible deaths.

Harm Reduction Coalition document describing how to create naloxone rescue kits for the lay person

MMWR paper on community opioid overdose prevention

Unick GJ, Rosenblum D, Mars S, Ciccarone D (2013) Intertwined Epidemics: National Demographic Trends in Hospitalizations for Heroin- and Opioid-Related Overdoses, 1993–2009. PLoS ONE 8(2): e54496. doi:10.1371/journal.pone.0054496

Today show 2014 Video interview of a mother who saved her son's life using intranasal naloxone at home.

Home naloxone treatment with intramuscular injection now FDA approved - EVIZIO - (Editor note: Expensive and still a needle stick risk, but better than no treatment)

James Roberts Emergency Medicine news article on BLS naloxone Sept 2014

Maryland toxicology report on layperson naloxone Oct 2014

Burris, Stopping an invisible epidemic - legal issues related to naloxone distribution, Temple Law 2009

Nasal Naloxone price set to Jump (Fall 2014)

Opiate rehab clinic: The Recovery Village

American addiction centers Naloxone rescue kit downloadable protocol

The PDF file downloaded from their site (click here)

Bibliography (click here for abstracts)

1. Marcus, R., et al., Risk of human immunodeficiency virus infection among emergency department workers. Am J Med, 1993. 94(4): p. 363-70.

2. Kelen, G.D., et al., Hepatitis B and hepatitis C in emergency department patients. N Engl J Med, 1992. 326(21): p. 1399-404.

3. Baker, J.L., et al., Unsuspected human immunodeficiency virus in critically ill emergency patients. Jama, 1987. 257(19): p. 2609-11.

4. Osterwalder, J.J., Patients intoxicated with heroin or heroin mixtures: how long should they be monitored? Eur J Emerg Med, 1995. 2(2): p. 97-101.

5. Vilke, G.M., et al., Are heroin overdose deaths related to patient release after prehospital treatment with naloxone? Prehosp Emerg Care, 1999. 3(3): p. 183-6.

6. Smith, D.A., et al., Is admission after intravenous heroin overdose necessary? Ann Emerg Med, 1992. 21(11): p. 1326-30.

7. Hussain, A., R. Kimura, and C.H. Huang, Nasal absorption of naloxone and buprenorphine in rats. Int J Pharm, 1984. 21: p. 233-237.

8. Loimer, N., P. Hofmann, and H.R. Chaudhry, Nasal administration of naloxone is as effective as the intravenous route in opiate addicts. Int J Addict, 1994. 29(6): p. 819-27.

9. (1999) NIOSH Alert: Preventing needlestick injuries in health care settings. National Institute for Occupational Safety and Health,

10. Wolfe, T.R. and E.D. Barton, Reducing needlestick risk: Nasal drug delivery in EMS. J Emerg Med Serv JEMS, 2003. 28(12): p. 52-63.

11. Marcus, R., et al., Occupational blood contact among prehospital providers. Ann Emerg Med, 1995. 25(6): p. 776-9.

12. Valenzuela, T.D., et al., Occupational exposure to hepatitis B in paramedics. Arch Intern Med, 1985. 145(11): p. 1976-7.

13. Pepe, P.E., et al., Viral hepatitis risk in urban emergency medical services personnel. Ann Emerg Med, 1986. 15(4): p. 454-7.

14. Barton, et al., Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting. J Emerg Med, 2005. 29(3): p. 265-71.

15. Kelly, et al., Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Med J Aust, 2005. 182(1): p. 24-7.

16. Martin, T.G., Take home naloxone: feasability, safety and efficacy. J Toxicol Clin Toxicol, 2003. 41(4): p. 415-416.

17. Belz, D., et al., Naloxone use in a tiered-response emergency medical services system. Prehosp Emerg Care, 2006. 10(4): p. 468-71.

18. Baca, C.T. and K.J. Grant, Take-home naloxone to reduce heroin death. Addiction, 2005. 100(12): p. 1823-31.

19. Wanger, K., et al., Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. Acad Emerg Med, 1998. 5(4): p. 293-9.

20. Parkin, J.M., et al., Tolerability and side-effects of post-exposure prophylaxis for HIV infection. Lancet, 2000. 355(9205): p. 722-3.

21. Robertson, T.M., et al., Intranasal naloxone is a viable alternative to intravenous naloxone for prehospital narcotic overdose. Prehosp Emerg Care, 2009. 13(4): p. 512-5.

22.  Doe-Simkins, M., et al., Saved by the nose: bystander-administered intranasal naloxone hydrochloride for opioid overdose. Am J Public Health, 2009. 99(5): p. 788-91.

23.    Merlin M.A., Saybolt M., Kapitanyan R, et al (2009) "Intranasal naloxone delivery is an alternative to intravenoius naloxone for opioid overdoses." Am J Emerg Med - published online Oct 2009, pending journal publication

24.    Kerr, D., A. M. Kelly, et al. (2009). "Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose." Addiction 104(12): 2067-74.

25. Wermeling, D. P. (2010). "Opioid harm reduction strategies: focus on expanded access to intranasal naloxone." Pharmacotherapy 30(7): 627-631.

26. McDermott, C. and N. C. Collins (2012). "Prehospital medication administration: a randomised study comparing intranasal and intravenous routes." Emerg Med Int 2012: 476161.

27. Walley, A. Y., M. Doe-Simkins, et al. (2012). "Opioid overdose prevention with intranasal naloxone among people who take methadone." J Subst Abuse Treat.

28. Unick GJ, Rosenblum D, Mars S, Ciccarone D (2013) Intertwined Epidemics: National Demographic Trends in Hospitalizations for Heroin- and Opioid- Related Overdoses, 1993–2009. PLoS ONE 8(2): e54496. doi:10.1371/journal.pone.0054496

29. Coffin, P. O. and S. D. Sullivan (2013). "Cost-effectiveness of distributing naloxone to heroin users for lay overdose reversal." Ann Intern Med 158(1): 1-9.

30.Compton, W. M., N. D. Volkow, et al. (2013). "Expanded access to opioid overdose intervention: research, practice, and policy needs." Ann Intern Med 158(1): 65-66.

31. Sabzghabaee, A. M., N. Eizadi-Mood, et al. (2014). "Naloxone therapy in opioid overdose patients: intranasal or intravenous? A randomized clinical trial." Arch Med Sci 10(2): 309-314.

32. Weiner, S.G., et al., Use of intranasal naloxone by basic life support providers. Ann Emerg Med, 2014. 64(4): p. S52 (Abstract 144).

33. Davis, C.S., et al., Expanded access to naloxone among firefighters, police officers, and emergency medical technicians in Massachusetts. Am J Public Health, 2014. 104(8): p. e7-9.

34. Doe-Simkins, M., et al., Overdose rescues by trained and untrained participants and change in opioid use among substance-using participants in overdose education and naloxone distribution programs: a retrospective cohort study. BMC Public Health, 2014. 14: p. 297.

35. Seal, K.H., 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): p. 291-301.

36. Seal, K.H., 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): p. 303-11.

37. Wagner, K.D., et al., Evaluation of an overdose prevention and response training programme for injection drug users in the Skid Row area of Los Angeles, CA. Int J Drug Policy, 2010. 21(3): p. 186-93.

38. Wagner, K.D., et al., "I felt like a superhero": the experience of responding to drug overdose among individuals trained in overdose prevention. Int J Drug Policy, 2014. 25(1): p. 157-65.

39. Galea, S., et al., Provision of naloxone to injection drug users as an overdose prevention strategy: early evidence from a pilot study in New York City. Addict Behav, 2006. 31(5): p. 907-12.

40. Bailey, A.M. and D.P. Wermeling, Naloxone for Opioid Overdose Prevention: Pharmacists' Role in Community-Based Practice Settings. Ann Pharmacother, 2014.

41. Samuels, E., Emergency department naloxone distribution: a rhode island department of health, recovery community, and emergency department partnership to reduce opioid overdose deaths. R I Med J (2013), 2014. 97(10): p. 38-9.

42. Green, T.C., et al., Two cases of intranasal naloxone self-administration in opioid overdose. Subst Abus, 2014. 35(2): p. 129-32.

43. Lenton, S., et al., Working together: Expanding the availability of naloxone for peer administration to prevent opioid overdose deaths in the Australian Capital Territory and beyond. Drug Alcohol Rev, 2014.

44. Zuckerman, M., S.N. Weisberg, and E.W. Boyer, Pitfalls of intranasal naloxone. Prehosp Emerg Care, 2014. 18(4): p. 550-4.

45. Hammett, T.M., et al., Pharmacies as providers of expanded health services for people who inject drugs: a review of laws, policies, and barriers in six countries. BMC Health Serv Res, 2014. 14: p. 261.

46. Behar E, Santos GM, Wheeler E, Rowe C, Coffin PO. Brief overdose education is sufficient for naloxone distribution to opioid users. Drug Alcohol Depend 2015;148:209-12.

47. Ray B, O'Donnell D, Kahre K. Police officer attitudes towards intranasal naloxone training. Drug Alcohol Depend 2015;146:107-10.

48. Richert T. Wasted, overdosed, or beyond saving - To act or not to act? Heroin users' views, assessments, and responses to witnessed overdoses in Malmo, Sweden. The International journal on drug policy 2015;26:92-9.

49. Wermeling DP. Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access. Therapeutic advances in drug safety 2015;6:20-31.

50. Rando, J., D. Broering, et al. (2015). "Intranasal naloxone administration by police first responders is associated with decreased opioid overdose deaths." Am J Emerg Med.

51. Fareed, A., A. M. Buchanan-Cummings, et al. (2015). "Reversal of overdose on fentanyl being illicitly sold as heroin with naloxone nasal spray: A case report." Am J Addict 24(5): 388-390.

52. Dwyer, K., A. Y. Walley, et al. (2015). "Opioid education and nasal naloxone rescue kits in the emergency department." West J Emerg Med 16(3): 381-384.

53. Dahlem, C. H., M. J. Horstman, et al. (2015). "Development and implementation of intranasal naloxone opioid overdose response protocol at a homeless health clinic." J Am Assoc Nurse Pract.

54. Fisher, R., D. O'Donnell, et al. (2016). "Police Officers Can Safely and Effectively Administer Intranasal Naloxone." Prehosp Emerg Care: 1-6.

55. Akers, J. L., R. N. Hansen, et al. (2017). "Implementing take-home naloxone in an urban community pharmacy." J Am Pharm Assoc (2003) 57(2S): S161-S167.

56. Barry, T., J. Klimas, et al. (2017). "Opiate addiction and overdose: experiences, attitudes, and appetite for community naloxone provision." Br J Gen Pract 67(657): e267-e273.

57. Chang, G., M. Davids, et al. (2017). "Overdose education and naloxone distribution for veterans with opioid use disorder: Results from a pilot initiative." J Addict Dis 36(4): 217-221.

58. Heavey, S. C., A. M. Delmerico, et al. (2017). "Descriptive Epidemiology for Community-wide Naloxone Administration by Police Officers and Firefighters Responding to Opioid Overdose." J Community Health.

59. Kobayashi, L., T. C. Green, et al. (2017). "Patient Simulation for Assessment of Layperson Management of Opioid Overdose With Intranasal Naloxone in a Recently Released Prisoner Cohort." Simul Healthc 12(1): 22-27.

60. Han, J. K., L. G. Hill, et al. (2017). "Naloxone Counseling for Harm Reduction and Patient Engagement." Fam Med 49(9): 730-733.

61. Gulec, N., J. Lahey, et al. (2017). "Basic and Advanced EMS Providers Are Equally Effective in Naloxone Administration for Opioid Overdose in Northern New England." Prehosp Emerg Care: 1-7.

62. Klebacher, R., M. I. Harris, et al. (2017). "Incidence of Naloxone Redosing in the Age of the New Opioid Epidemic." Prehosp Emerg Care: 1-6.

63. Weiner, S. G., P. M. Mitchell, et al. (2017). "Use of Intranasal Naloxone by Basic Life Support Providers." Prehosp Emerg Care 21(3): 322-326.

64. Rosenberg, M., G. Chai, et al. (2018). "Trends and economic drivers for United States naloxone pricing, January 2006 to February 2017." Addict Behav 86: 86-89.

65. Dietze, P., M. Jauncey, et al. (2019). "Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial." JAMA Netw Open 2(11): e1914977.

66. Guadamuz, J. S., G. C. Alexander, et al. (2019). "Availability and Cost of Naloxone Nasal Spray at Pharmacies in Philadelphia, Pennsylvania, 2017." JAMA Netw Open 2(6): e195388.

67. Wu, C., T. Brown, et al. (2019). "Access to naloxone at community pharmacies under the Massachusetts statewide standing order." J Am Pharm Assoc (2003).

68. Krieter, P. A., C. N. Chiang, et al. (2019). "Comparison of the Pharmacokinetic Properties of Naloxone Following the Use of FDA-Approved Intranasal and Intramuscular Devices Versus a Common Improvised Nasal Naloxone Device." J Clin Pharmacol 59(8): 1078-1084.

69. Mahonski, S. G., J. B. Leonard, et al. (2019). "Prepacked naloxone administration for suspected opioid overdose in the era of illicitly manufactured fentanyl: a retrospective study of regional poison center data." Clin Toxicol (Phila): 1-7

70. Pruyn, S., J. Frey, et al. (2019). "Quality Assessment of Expired Naloxone Products from First-Responders' Supplies." Prehosp Emerg Care 23(5): 647-653.

71. Skulberg, A. K., A. Asberg, et al. (2019). "Pharmacokinetics of a novel, approved, 1.4-mg intranasal naloxone formulation for reversal of opioid overdose-a randomized controlled trial." Addiction 114(5): 859-867.

72. Smart, R., C. K. Geiger, et al. (2019). "An Observational Study of Retail Pharmacy Naloxone Prescriptions: Differences Across Provider Specialties and Patient Populations." J Gen Intern Med.

73. Strang, J., R. McDonald, et al. (2019). "Take-Home Naloxone for the Emergency Interim Management of Opioid Overdose: The Public Health Application of an Emergency Medicine." Drugs 79(13): 1395-1418.

74. Tippey, K. G., M. Yovanoff, et al. (2019). "Comparative Human Factors Evaluation of Two Nasal Naloxone Administration Devices: NARCAN((R)) Nasal Spray and Naloxone Prefilled Syringe with Nasal Atomizer." Pain Ther 8(1): 89-98.

75. Williams, K., E. S. Lang, et al. (2019). "Evidence-Based Guidelines for EMS Administration of Naloxone." Prehosp Emerg Care 23(6): 749-763.