Therapeutic Intranasal Drug Delivery

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.

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.

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 are investigating this method of naloxone delivery.[18] To date the published data on this concept is limited and this therapeutic strategy should likely be confined to controlled investigations until safety and efficacy can be established.

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.

A more recent publication 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] The state of New Mexico has taken this concept one step further – they already let their basic life support [BLS] providers (police and highway patrol) 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]

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. Findings are soon to be published.

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. 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.

The data supporting IN naloxone are still relatively small, leaving the door wide open to better, larger studies. Ideally these studies would utilize a concentrated form of IN naloxone that could deliver high doses in small volumes administered with a device that spreads the drug evenly over the mucosal surface (just such a study using somewhat concentrated naloxone - 2 mg/2ml - was recently completed in Melbourne Australia – we await the results). If a concentrated formulation became available, then dosing studies could also be conducted to determine the ideal dose required to routinely arouse the patient but not cause intense withdrawal symptoms. In addition, further data is needed to determine the safety and efficacy of IN naloxone in the home, law enforcement and BLS setting.

Tim Wolfe, MD (Emergency Physician, Salt Lake City) ….. I think we get in too big of a hurry and do not wait long enough for the effect of IN naloxone to occur before we advance to IV therapy. This rapid progression to using IV naloxone as soon as possible occurs despite our complaints and concerns that IV naloxone causes people to wake up agitated and combative. It is my impression that our failure to see a sudden arousal and anger response causes great anxiety (in we health care providers) and leads us to feel the nasal route has failed. In fact, IN naloxone causes more gentle awakening, less observable agitation and simply improved breathing and oxygenation without as fast a change to total awakening – which should be our true goals. I have no proof but I suspect that IV naloxone provides a huge sudden bolus of drug to the brain and the hypoxic patient is suddenly awake but still hypoxic and confused leading them to be very combative. On the other hand IN naloxone causes incremental increases in brain drug levels and more slowly arouses the patient, allowing incremental improvements in oxygenation and less agitation upon awakening. A big downside to IN naloxone is the availability of the concentrated form (2mg/2ml). It is hard to obtain and causes some systems to use the more dilute form, which is sure to reduce the efficacy of this therapy. In fact the concentrated form is still too dilute for ideal IN medication delivery – ideally we could give 2 mg of IN naloxone in about 0.5 ml of solution – half up each nostril to obtain the predicted best effect. Overall, I see IN naloxone as a bridge between no therapy and IV or IM/SQ therapy. Laypersons properly trained may be able to easily administer the medication as can law enforcement and BLS providers. If the safety of this treatment is confirmed with further research studies, it alone may prevent the need for an ALS response, or at least reverse the respiratory depression occurring following a narcotic overdose and preclude overly aggressive treatments such as intubation. ALS providers can utilize IN naloxone as their first therapeutic intervention and then make a decision whether IV access is indeed needed. Often times, as proven in the two trials discussed above, no access is needed and the extra resource consumption and needle stick risk can be avoided. In the case of short acting narcotics such as heroin, that may be all that is needed. With longer acting narcotics such as methadone and OxyContin, it gives the provider time to assess and more carefully establish IV access.

Debra Kerr, PhD Candidate, Senior Fellow – Emergency Medicine Research, Melbourne Australia ….. Rapid depression of the syringe 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.

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.

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, 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.

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.