Intranasal Naloxone

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

Introduction

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)

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 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. Several states such as New Mexico, Massachusetts and North Carolina have adapted home layperson administered intranasal naloxone into their state regulations.[18, 22]

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)

Sites in Massachusetts to obtain IN naloxone training (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 o f 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)

2010 Wermeling editorial article discussing value of home intranasal naloxone - (click here) OR (Here)

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 life worth $438-$14,000 to you? Is it worth saving a human 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. Have they forgotten why we have entered the practice of medicine, have they really lost their human compassion for the value of someone else’s life? Do they truly believe they can judge a life worth saving (for a few hundred dollars per year no less) versus one that is not?

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

The 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 has just been finished 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]

December 2009: Abstracted results of now completed prospective Australian intranasal naloxone trial (Click here)

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]

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.

Treatment protocol

Indications: For use on patients suspected of opiate overdose

Procedure:

Assess ABC’s – Airway, Breathing, Circulation
For pulseless patients, proceed to ACLS guidelines
Apnea with pulse – Establish oral airway and begin bag ventilation with 100% oxygen
Load syringe with 2 mg (2 ml) of naloxone and attach nasal atomizer
Place atomizer within the nostril
Briskly compress syringe to administer 1 ml of atomized spray.
Remove and repeat in other nostril, so all 2 ml (2 mg) of medication are administered
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:

Barton, Intranasal naloxone as a needleless alternative for treatment of opiate overdose in the prehospital setting, J Emerg Med 2005 (Click here for web site link)

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. Addiction104(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

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)

Bibliography (click here for abstracts)

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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.

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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 Med158(1): 65-66.

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