Opioid overdoses have reached epidemic proportions—fatalities due to opioid overdose have risen from 4,030 deaths reported in 1999 to 16,651 in 2010 (Jones CM et al, JAMA 2013;309(7):657–659). Some 80% of these deaths are unintentional, according to the US Centers for Disease Control and Prevention (CDC).

While the best solution would be to prevent opioid overdoses in the first place, an important piece in the effort to reduce these fatalities is to have a good way of preventing overdoses from leading to death. That’s where the opioid antagonist naloxone (Narcan) comes in.

Naloxone, which has been available for over 40 years, rapidly reverses opioid-induced respiratory depression by displacing most opioids from their receptors. While effective for those who receive timely treatment, a several minute delay in naloxone rescue can be fatal (respiratory depression can lead to brain damage or death within a few minutes in severe overdose).

A new intranasal (IN) form of naloxone administration is available and if broadly distributed it could ensure that opioid-addicted patients live long enough to get into effective long-term treatment. As a clinician, you need to know how the formulation works, which patients need it, and the logistics of how to prescribe it.

History of Intranasal Naloxone

Until recently, naloxone use was limited to medical personnel, such as emergency medical technicians (EMTs) in the field or emergency department (ED) staff, who would give the drug as intramuscular (IM) or intravenous (IV) injections. Limiting its use to medical professionals is a problem because it causes an inevitable delay in administration. One review of North Carolina data reported that over half of accidental drug overdoses ended in death before emergency medical services could arrive on the scene (http://bit.ly/163Ofzl). Aside from the possibility of delays, another disadvantage of injectable naloxone is the risk of needle sticks, which exposes emergency personnel to hepatitis C, HIV, or other blood borne pathogens.

IM/IV Naloxone vs. IN Naloxone

Currently, only injectable naloxone is approved by the US Food and Drug Administration (FDA). But over the past few years, crafty healthcare professionals have figured out a way to transform the injectable form into an intranasal form.  It works by taking a syringe filled with naloxone, and instead of capping it with a needle it uses a fitted tip, which is attached to a Mucosal Atomization Device, or MAD. Though not a household name, the MAD is an approved medical device, which can render liquid drug into a fine mist that is delivered to the nasal mucosa, where it is absorbed directly into the bloodstream. When used with naloxone, the whole set-up is called intranasal naloxone.

It’s an interesting delivery system, but does it actually work? Two randomized, controlled trials have compared IN versus IM naloxone in a total of 327 people who had suspected opiate overdoses (Kerr D et al, Addiction 2009;104(12):2067–2074; Kelly AM et al, Med J Aust 2005;182(1):24–27). The main outcome variable in such studies is the percentage of patients who respond to naloxone (usually defined as having spontaneous respirations) within eight to 10 minutes. A meta-analysis of the two studies, done by the World Health Organization (WHO), found no significant difference in response rate between the two methods (http://bit.ly/1tWqkLa).

The IN naloxone formulation has been fast-tracked for approval by the FDA. The company manufacturing it, AntiOp, has partnered with Reckitt Benckiser Pharmaceuticals (of Suboxone fame), and approval is expected sometime this year. Insurance coverage will likely follow soon after that.

Bystander Administration

Given the positive data, various emergency response programs in cities such as Boston, Denver, and San Francisco, have already been using IN naloxone off-label for a number of years as their standard response to opioid overdose. Several cities and states also are allowing non-professionals to administer IN naloxone through a program termed “bystander-administered rescue.” For example, Project Lazarus in North Carolina developed a protocol that allows providers who prescribe opiate analgesics to also prescribe IN naloxone (made available at a local pharmacy) to a broad group of patients who may be at risk for overdose (Leavitt SB, Practical Pain Management 2010;10(8):42–46). In Rhode Island, all Walgreens and CVS Pharmacies have made both IM and IN naloxone available without a prescription. Studies have shown that providing naloxone to bystanders is associated with an opioid overdose mortality rate of 1% versus mortality rates of 2% to 4% in areas without such programs.

Issues Impacting More Widespread IN Naloxone Use

While expanding access of IN naloxone to bystanders would appear to be an obvious solution to reducing opioid deaths, there are several factors impeding broader acceptance. These include the following:

• Absence of FDA-approval and difficulties obtaining the product. While off-label use of drugs is both legal and common, IN naloxone presents some logistical and financial challenges. There is currently only one manufacturer (Amphastar) that provides naloxone suitable for IN administration even though the generic product has been on the market for decades. The IN version needs to be a higher 2mg/2ml concentration compared to the injectable 0.4mg/ml concentration to get comparable effects. In December, most likely in response to surging demand, Amphastar more than doubled its price for the drug from $13 to $30, making it difficult for many of the nonprofit programs that now provide IN naloxone. The drug must be provided along with an atomizer, which is sometimes difficult to get, not inexpensive ($10-$25 for one disposable unit), and for the most part is not covered by insurance. Nonetheless, this cobbled together IN version is still cheaper than the most recent formulation of injectable naloxone which came to market in April of 2014—Evzio, naloxone packaged in an auto-injector which retails for about $700 per dose (http://www.goodrx.com/evzio/price).


• Legal issues. In an overdose situation, your patient will not be self-administering IN naloxone. Instead, he or she will rely on a bystander, most likely a family member or friend. Most state pharmacy and medicine practice regulations will require exemption to allow a layperson to administer naloxone. There is already precedence for such layperson exemptions—for example, administering epinephrine for anaphylaxis or glucagon for insulin shock—and some states have already passed laws protecting clinicians from malpractice lawsuits related to prescribing naloxone for layperson use; others are sure to follow. You can check here (http://bit.ly/1BEMHr2) to see if your state permits third party prescribing. If not, you must prescribe the rescue naloxone to the individual at risk for overdose and the bystander will rely on Good Samaritan laws that provide some immunity from drug-related charges and from civil liability to those who call 911 in overdose situations (Network for Public Health Law, http://bit.ly/NqV8Bw).


• Fear of encouraging drug use. Some opposition to bystander-administered IN naloxone is based on the concern that a readily available rescue option might encourage drug use because users will be less worried that an overdose will kill them. The data thus far (two European studies, as well as studies from San Francisco, Boston, and New York) don’t support this notion (Maxwell S et al, J Addict Dis 2006;25(3):89–96; Seal KH et al, J Urban Health 2005;82(2):303–311; Wagner KD et al, Int J Drug Policy 2010;21(3):186–193; Burris S et al, Int J Drug Policy 2001;12:237–248; http://www.drugpolicy.org/docUploads/OverdoseReportMarch2009.pdf). In these various studies, no differences in heroin use were seen after enrollment in naloxone rescue program compared to baseline use.

How Should You Implement IN Naloxone in Your Practice?

Both the American Medical Association (AMA) and the American Public Health Association (APHA) have established policies supporting take-home naloxone. The WHO released guidelines in November 2014 calling for wide access to naloxone for non-medically trained individuals to help reduce fatal overdoses (http://bit.ly/1tWqkLa).

Here are some practical guidelines for prescribing IN naloxone in your practice:

1. Identify your opioid abusing patients who are at particularly high risk for overdose: those with a history of overdose; those in high-risk periods such as soon after abstinence; those who inject opiates or use high dose prescription opiates; and those who use opiates in combination with sedatives, such as benzodiazepines.


2. Identify potential bystander rescuers such as partners, family members, or roommates of your patient.


3. Make sure bystanders are trained to recognize opioid overdose symptoms and know how to use IN naloxone. You can do this training yourself in the office, or you can refer people to more formal programs, such as online videos or group teaching sessions (video training: http://prescribetoprevent.org/video; finding a prevention program by zip code: http://bit.ly/1DYC2XZ).


4. Check out the Prescribe to Prevent website (http://prescribetoprevent.org) for prescriber resources such as webinars, toolkits, patient education material, and medical-legal resources. This website also provides guidance to the physician on writing the prescription for IN naloxone as well as to the pharmacist for obtaining the MAD.

To actually prescribe IN naloxone, see a suggestion for what to write (see “A Sample Prescription for Intranasal Naloxone” below). Note that the prescription is more detailed than a typical prescription because not all pharmacists will be familiar with the product.

TCPR's Verdict: IN naloxone saves lives. Prescribe it.