Therapeutic Intranasal Drug Delivery

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

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.

http://www.theverge.com/2015/9/25/9398823/naloxone-heroin-overdose-cvs-stores-over-the-counter

http://www.huffingtonpost.com/entry/cvs-naloxone-overdose-reversal_5602dba2e4b0fde8b0d0d189

New York City nasal 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:

https://www.statnews.com/2018/11/08/costs-heroin-naloxone-tragic-snapshot-opioid-crisis/

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.

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."