LAS VEGAS — In the course of the last 20 years, medical use of opioids has increased 10-fold, according to the US Centers for Disease Control and Prevention.1

Drug poisoning deaths involving opioids nearly quadrupled between 2010 and 2013, correlating with a 4-fold increase in sales of opioids, and heroin deaths increased nearly 40% between 2012 and 2013.2

The opioid receptor antagonist naloxone can reverse overdose from both prescription opioids and heroin by canceling out the respiratory and central nervous system-depressant effects of these drugs. 

Advances in the way naloxone is administered offer more options for emergency medicine clinicians who see these patients, as well as the family members of people who use these drugs, according to a speaker here.

“Naloxone offers an important safety net for saving lives in cases of accidental or purposeful opioid overdose,” said Jeffrey Fudin, PharmD, FCCP, founder and chair of Professionals for Rational Opioid Monitoring and Pharmacotherapy (PROMPT).

“Clinicians must realize that naloxone reversal kits, regardless of administration route, are not just for substance abusers. They are for any at-risk patient receiving chronic opioid therapy.” 

Approximately 100 million patients in the United States have chronic noncancer pain and are candidates for opioid use, according to a report from the Institute of Medicine.3  

Patients at highest risk for overdose include those taking extended-release opioids, those taking more than one opioid, those taking concomitant sedative hypnotics such as benzodiazepines, those with comorbid respiratory disease and/or recent hospital admission for an opioid-related respiratory problem, and those taking antidepressants. 

“Also consider the possibility of unanticipated drug interactions with newly prescribed medications that might increase serum levels of the parent opioid or its active metabolites,” Dr. Fudin cautioned.

Naloxone is available in 3 formulations: intramuscular and intravenous injection, intranasal (off-label), and as an autoinjector (Evzio, Kaléo, Inc.). Dr. Fudin gave a comprehensive discussion of the pros and cons of each available route of administration. 

Intranasal formulation

Although not yet approved by the US Food and Drug Administration (FDA), intranasal naloxone offers the advantages of being inexpensive and easily accessible, without risk for needle-stick exposure.

“Intranasal naloxone is used ubiquitously. It is far less expensive compared with the FDA-approved auto-injector formulation,” Dr. Fudin explained.

In a 2009 study by Kerr et al in Addiction, intranasal naloxone was as effective as the intramuscular formulation in reversing heroin overdose within 10 minutes of administration (72.3% vs 77.5%).4 Despite this positive finding, more comprehensive and rigorous studies are needed regarding naloxone absorption with this route of administration.

“Although there are exciting reports of opiate overdose reversals, we do not know how many failures there were when considering attempts at reversal. It is less likely that this route will achieve comparable maximum blood concentrations within the same timeframe compared with any intramuscular formulation,” Dr. Fudin said. “It therefore may not readily and quickly reverse the more fat-soluble drugs such as fentanyl compared with its effect on heroin. In a situation where time is critical, this concerns me.”

As many substance abusers snort one or more drugs, the vasculature in their nasal mucosa could be compromised, and they may have a higher likelihood of a deviated septum, which could also affect intranasal absorption, he pointed out.

Another disadvantage of the intranasal formulation is that it may not be as easy as other options for caregivers and families because it requires users to manually assemble a syringe, plunger, and atomizer and inject half of the formulation in each nostril. Because these component pieces are not sold together as a kit, assembly requires more work on the part of the pharmacist.

Despite these disadvantages, intranasal naloxone may be well suited for use in emergency situations that involve well-trained responders such as police officers and emergency medical technicians (EMTs), specifically in states where EMTs are not permitted to administer injections, Mr. Fudin explained.

Intramuscular and intravenous injections

Naloxone administered via traditional intramuscular injection is another inexpensive and effective option for emergency responders who are well trained; however, it may be difficult to administer in an emergency situation in the home setting by someone who is unfamiliar with manipulating a syringe and vial. 

Intravenous injections are more complicated and therefore must be administered exclusively by medical professionals. If a patient who has overdosed has not been breathing for a while, venous access may be compromised; this situation may also occur with substance abusers.

Downsides to intravenous administration include the risk for needle stick and regulations in certain municipalities that restrict EMTs from injecting any drugs, whether intramuscularly or intravenously.

Auto-injector formulation

The naloxone auto-injector is the only FDA-approved formulation for in-home use in cases where there is known or suspected opioid overdose.  

A 2015 study by Edwards et al validated that all persons who received training from healthcare practitioners on naloxone use were able to give the auto-injector correctly, and 90% of those who received no training were also able to give it correctly.5 The retracting needle offers the added advantage of reducing needle-stick risk. 

“The greatest and perhaps only disadvantage of the auto-injector is the cost,” Dr. Fudin said. “The good news is that about 75% of third-party payers cover it. Nevertheless, somebody is paying for it in the long run.”

Although it is normal for insurance providers to reject claims for off-label uses of medications, they seem to support approval of intranasal naloxone kits. State regulations regarding naloxone are changing each week, but in general many are lightening up “Good Samaritan” laws to protect first responders from liability, according to Dr. Fudin. 

“Most states are easing up availability. Some allow pharmacists to dispense it without a prescription, whereas others are formulating plans for pharmacists to do this, but only after many hours of special certificate training,” Dr. Fudin said. 

Disclosures: Jeffrey Fudin, PharmD, FCCP, has worked as a consultant and is a member of speaker’s bureaus for AstraZeneca, Millennium Health, Zogenix, and Kaléo. He is also a stock shareholder for Remitigate.


  1. Centers for Disease Control and Prevention. Unintentional drug poisoning in the United States. July 2010. Available at: Accessed August 20, 2015.
  2. Centers for Disease Control and Prevention. Injury prevention & control: prescription drug overdose. Available at: Accessed August 20, 2015.
  3. Committee on Advancing Pain Research, Care, and Education. Institute of Medicine. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, DC; The National Academies Press:2011.
  4. Kerr D, Kelly A-M, Dietze P, Jolley D, Barger B. Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose. Addiction. 2009;104:2067-2074.
  5. Edwards ET, Edwards ES, Davis E, Mulcare M, Wiklund M, Kelley G. Comparative usability study of a novel auto-injector and an intranasal system for naloxone delivery. Pain Ther. 2015;4(1):89-105.