Why Intranasal Naloxone is a Safe Antidote for Anyone to Administer
Mike McEvoy // May 31, 2014
Opioid abuse is a major international health problem that is worsening each year, causing increased 911 call volume for opioid induced respiratory depression, altered levels of consciousness and deaths.
The opioid heroin spiked in use in the United States from 373,000 yearly users in 2007 to 669,000 users in 2012 according to SAMSHA (Substance Abuse and Mental Health Services Administration).
Not surprisingly, fatal heroin overdoses also increased by 45 percent between 2006 and 2010, according to the U.S. Drug Enforcement Administration. Drug overdoses have surpassed motor vehicles crashes as a cause of death in the U.S. for the past several years.
In March, U.S. Attorney General Eric Holder deemed rise in heroin overdoses a public health crisis, and vowed to increase law enforcement actions.
He urged law enforcement agencies and first responders to carry naloxone, an opioid reversal agent1. This caused a surge and in some cases, local competition between law enforcement, fire and EMS to carry and use intranasal (IN) naloxone.
Heroin is on the rise
Opioids are natural or synthetic substances with morphine-like activity. They depress the central nervous system, provide analgesia (pain control) and can cause feelings of euphoria. Both prescription and nonprescription opioids are involved in recreational misuse, abuse, addiction, dependence, and overdoses.
Prescription opioids include: morphine, fentanyl, codeine, buprenorphine, hydrocodone, hydromorphone, tramadol, meperidine, methadone, oxycodone, oxymorphone, loperamide, and others. Heroin is a derivative of morphine and garners considerable media attention.
“Designer” opioids are created in makeshift laboratories and change frequently in attempts to evade legislation and law enforcement. Examples include 3-methylfentanyl (aerosolized during the Moscow theater hostage situation in 2002) and α-fentanyl (also known as China White).
Factors fueling the rise in heroin use include increased supply, decreased cost, and greater purity2. Latin American drug cartels have vastly increased their heroin production, significantly increasing supply throughout the United States despite efforts to curtail shipments.
A bag of street heroin in Chicago sells today for $20 and is 7 to 10 percent pure. Ten years ago, the same heroin (if a potential buyer could even find it) would have cost up to $150 and been only 2 to 3 percent pure.
Today’s purity means the drug can be snorted rather than injected, as was necessary with less pure heroin. Needleless administration and cheaper cost have made heroin more accessible and cheaper than prescription opioids such as oxycodone (Percocett, Oxycontin) and hydrocodone (Vicodin), which are increasingly difficult to obtain on the black market. Greater numbers of prescription opioid users are turning to heroin, which is also leading to a great number of overdoses.
How to recognize a heroin overdose
Most overdoses fall into the following categories:
- Recreational use.
- Attempt to hide drugs from law enforcement by stuffing them into a body orifice.
- Deliberate attempt to cause self-harm.
- Accidental overdose — a child chews on a discarded fentanyl patch or ingests an adult’s prescription opioid, or a post surgical patient takes excessive amounts of a prescribed opioid.
- Swallowing large packages of opioids to transport them across borders (body packing).
In some of the previous instances, a high index of suspicion is necessary. Physical exam findings in opioid overdose classically include pinpoint pupils (miosis), respiratory and CNS depression, and often flushing, hypotension and decreased bowel sounds.
Miosis typically lasts about six hours but may not be present if the patient co-ingests a stimulant or if respiratory depression was prolonged and profound enough that a hypoxic brain injury occurred. Other, less common findings associated with opioid overdose include non-cardiogenic pulmonary edema, bradycardia, and rhabdomyolysis.
Death from opioid overdose is rare and uncommonly immediate. Surveys of heroin users indicate that upwards of 38 percent have overdosed at least once. Fortunately, mortality associated with heroin overdoses is very low, in the range of 3 to 6 percent.
The common cause of death is hypoxia resulting from respiratory depression, with about 15 percent of deaths occurring immediately after drug use. This offers a typical window of 40 to 50 minutes during which interventions are likely to be successful3. We continue to have a very minimal understanding of the actual pathophysiology associated with death from opioid overdose.
Who’s qualified to administer naloxone?
Naloxone is a synthetic derivative of oxymorphone that competes to bind with opioid receptors and is the antagonist of choice for opioid overdoses. While originally given intravenously (IV) or intramuscularly (IM), naloxone is increasingly being administered intranasally.
First reported in 1984 as effective for opioid reversal in rats, IN naloxone has been studied repeatedly in humans since 19924. When administered IV, naloxone is effective within three to five minutes (mean 3.7 minutes) and typically has a short duration of action, lasting for 30 minutes to an hour. Given IM or IN, naloxone’s effects are usually evident within three to seven minutes (mean 4.2 minutes) and the duration of action longer, lasting up to 90 minutes IN and up to 2 hours IM3.
Actual pharmacokinetic studies comparing IM to IN naloxone in human volunteers show peak concentrations of IN naloxone occur in six to nine minutes and IM peaks in 12 minutes5.
Early studies of alternative routes for administration of naloxone met some stumbling blocks. There was considerable uncertainty about IN dosing of naloxone, coupled with the only strength available being 0.4 milligrams per mL, yielding a concentration significantly greater than the maximum 1 mL volume recommended for intranasal medications4.
One prehospital study used nebulized naloxone with good success, but only in patients with spontaneous respirations (not requiring bag-valve-mask assistance)6. Subsequent studies using IN naloxone manufactured or compounded at 1 or 2 milligram per mL found that a total dose of 2 milligrams, administering 1 milligram into each nostril (nare) with an atomizing device designed for intranasal drug administration (MAD™ Nasal, Wolfe Tory Medical, Inc.) had the best effect. Most protocols currently in effect utilize this dosing strategy, with naloxone concentrations that limit the total volume to 1 mL or less per nostril7.
Between 1996 and 2010, community prevention programs reported training 53,032 people in naloxone administration, with 10,171 overdose reversals8. The vast majority of these were citizens, either family members or friends of known opioid drug users. The success of these programs speaks for itself and suggests that, like AEDs and epinephrine auto-injectors, anyone can be trained to administer naloxone in the prehospital environment.
Published studies on EMS use of intranasal naloxone cite numerous advantages over other routes of administration. Chief among these are scene safety issues.
Eighty percent of intravenous drug users (IVDU) in major metropolitan areas are HIV or hepatitis C positive7. Given the ongoing incidence of needle stick injuries to prehospital providers, IN administration of naloxone seems an intuitive provider safety advantage.
Although often cited as a disadvantage, IN administration has been repeatedly shown to be more rapid than IV dosing. Multiple studies comparing median time from arrival to clinical response demonstrate an eight minute time for IN and 10 minute time for IV when factoring in the equipment set-up and IV placement delays7.
Despite the less invasive nature of IN naloxone, another advantage is an equal efficacy when compared to IV administration. Numerous studies of IN naloxone have demonstrated an overall response rate of 83 percent, matching that seen with IV naloxone7.
Intranasal administration is best for basic care
IN administration of naloxone is a hot topic, but not a new concept in prehospital medicine. Optimal outcomes can be achieved if we make it our mission to equip as many friends and family members of IV drug users, law enforcement officers, firefighters, EMS providers and other first responders with the only antidote needed to save a life: intranasal naloxone.
This should not be a turf battle; patients are dying before we can arrive to treat them. It’s time to put a harmless life-saving tool into the hands of everyone and anyone who might be there or get there before we show up on scene. That would be caring for our community.
While poorly documented with any large studies, IN naloxone clearly results in a slower, more gradual distribution resulting in a much more gradual emergence from opioid effects and considerably less prehospital violence and aggression. A small number of studies have highlighted this additional scene safety advantage7 and a search of paramedic and EMS blogs yields dozens of anecdotal reports confirming gradual awakening is the norm with IN naloxone.
Every time I read an editorial or blog post from a physician or paramedic touting the grievous risk of violent awakenings associated with “inexperienced” rescuers administering IN naloxone, I immediately recognize an author who has no experience in actual use of IN naloxone.
In my experience and the studies I have participated in, not once have I seen an abrupt or untoward awakening following IN naloxone administration. I have, however, witnessed (and caused) innumerable unpleasant awakenings with IV naloxone.
A Seattle study of IN naloxone administered by BLS providers cited a 15 percent rate of “naloxone associated violence” which was probably exaggerated as the authors included agitation and vomiting as violent behavior when, in fact, these were probably withdrawal symptoms9.
Also consider the odd locations where opioid overdoses often occur. In the absence of ALS, and the inability of BLS or law enforcement responders to administer an opioid antidote, it is quite likely that overdose victims would need to be carried significant distances to a waiting ambulance or ALS unit.
Such patient movements, especially over difficult terrain, have tremendous potential to result in back or other musculoskeletal injuries to the care providers. Patient compromise is also possible should the rescuers not be able to support respirations throughout patient movement. With the availability of IN naloxone, many overdose patients recover their ability to ambulate from the scene, thus limiting potential injury to responders.
Disadvantages of naloxone include the initiation of withdrawal symptoms (regardless of how it’s administered). Unlike other agents, opioid withdrawal signs and symptoms, which include tremors, sweating, agitation, nausea, vomiting, and anxiety are non-life threatening and resolve relatively quickly (30 to 60 minutes) due to the short half-life of naloxone7.
Shortages of naloxone have occurred and the recent surge in use may result in additional shortages. Originally sold by Endo Pharmaceuticals under their brand name, Narcan, the surge in community naloxone programs unfortunately coincided with Endo’s discontinuation of their naloxone products in July 2013 after 41 years of sales. The resulting shortage has since been alleviated by the two remaining manufacturers, Amphastar and Hospira.
On the fast track for approval, expected by March 2015, is a naloxone nasal spray from AntiOp. Naloxone is not currently approved by the U.S. Food and Drug Administration for intranasal use hence, manufacturers cannot sell naloxone prepackaged for IN use.
EMS services can order naloxone IN kits, but such use is considered “off label” by the FDA. The end result increases the price of IN naloxone kits used by civilians, law enforcement and first responders to the $50 range whereas the naloxone itself retails for only $20 per dose.
We have a problem and a solution. Opioid overdoses are increasing worldwide. While heroin is a common culprit today, even in rural areas,, patients may overdose on any variety of both prescription and non-prescription opioids. Recognizing the circumstances and classic signs and symptoms of opioid overdose can save a life.
1. U.S. Department of Justice, Public Affairs. News Release: Attorney General Holder, Calling Rise in Heroin Overdoses ‘Urgent Public Health Crisis,’ Vows Mix of Enforcement, Treatment. March 10, 2014. On-line, available at: www.justice.gov/opa/pr/2014/March/14-ag-246.html.
2. Gray E. Heroin gains popularity as cheap doses flood the U.S. Time. 2014 (Feb 4);183. On-line, available at: http://time.com/#4505/heroin-gains-popularity-as-cheap-doses-flood-the-u-s/.
3. Kerr D, Dietze P, Kelly A. Intranasal naloxone for the treatment of suspected heroin overdose. Addiction. 2008; 103:379-386.
4. Ashton H, Hassan Z. Intranasal naloxone in suspected opioid overdose. Emerg Med J. 2006;23:221-223.
5. Dowling J, Isbister GK, Kirkpatrick CM, Naidoo D, Graudins A. Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers. Ther Drug Monit. 2008;30:490-496.
6. Weber JM, Tataris KL, Hoffman JD, Aks, SE, Mycyk MB. Can nebulized naloxone be used safely and effectively by emergency medical services for suspected opioid overdose? Prehosp Emerg Care. 2012;16:289-292.
7. Wermeling DP. A response to the opioid overdose epidemic: naloxone nasal spray. Drug Deliv Transl Res. 2013;3:63-74.
8. Centers for Disease Control and Prevention. Community-Based Opioid Overdose Prevention Programs Providing Naloxone — United States, 2010. MMWR. 2012;61:101-105. On-line, available at: www.cdc.gov/mmwr/preview/mmwrhtml/mm6106a1.htm.
9. Belz D, Lieb J, Rea T, Eisenberg MS. Naloxone use in tiered-response emergency medical services system. Prehosp Emerg Care. 2006;10:468-471.