Therapeutic
Intranasal Drug DeliveryIntranasal 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)
Delivering intranasal naloxone to a patient suffering from an opiate overdose
Introduction
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 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 hepatis 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, 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) New York City also reports approximately 300 opiate reversals 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)
New York City nasal naloxone device:
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 verus 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]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 ato
miser) 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-bourne 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.
Treatment protocol
Indications:
For use on patients suspected of opiate overdoseProcedure:
If no arousal occurs after 5-10 minutes, proceed down standard unconscious protocol including injectable naloxone and secure airway if necessary.
Teaching materials:
Intranasal Naloxone (Narcan) articles:
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
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
Interview with Debra Kerr - IN naloxone researcher (click here)
Audio interview with Debra Kerr - IN naloxone researcher
Project Lazarus - Home IN naloxone in North Carolina
Newspaper discussion of project Lazarus -Wilkes Journal Patriot
Boston Massachusetts experience with home naloxone
Legality of prescribing home naloxone in North Carolina
Leavitt, Intranasal naloxone: Overcoming opiate overdose
Bibliography (click here for abstracts)
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9. (1999) NIOSH Alert: Preventing needlestick injuries in health care settings. National Institute for Occupational Safety and Health, http://www.cdc.gov/niosh/2000-108.html#1
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.
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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.