Kong Wong, PharmD

Opioid analgesics have a useful place in the management of moderate to severe pain. However, in the past few years, the use and abuse of these agents have increased exponentially. Along with the upward trend in the utilization of opioids, there has been a massive increase in opioid overdoses. In 2014, drug overdose was the third leading cause of injury deaths, with opioid prescriptions causing a majority of these deaths.

Naloxone, an opioid antagonist, is currently the drug of choice for the treatment of overdose-induced respiratory depression. When opioid overdose occurs, naloxone—if administered quickly enough&mdash;will effectively reverse opioid-induced respiratory depression and therefore decrease the risk of complications and mortality. Because the effectiveness of naloxone is so time-dependent, community administration may lead to greater opportunities to reverse overdose symptoms.

At this time, there are 2 FDA-approved naloxone delivery devices intended for community administration: Evzio auto-injector and Narcan nasal spray. By providing easy-to-use naloxone delivery devices to high-risk opioid users and their families and friends, naloxone devices can shorten the time to overdose rescue, limit damage to the brain and other organs, and reduce the probability of overdose death.

Although the use of naloxone delivery devices has proven benefits, many qualms still exist about supporting these devices in the community setting. By dispelling misconceptions, we can educate the community and save lives nationwide.

Opioid analgesics have a useful place in the management of moderate to severe pain. However, in recent years, there has been a significant increase in the utilization of both illicit and prescription opioids. In 2013, the CDC reported a 4-fold increase in the amount of prescription opioids dispensed from 1999 to 2013.

 Along with this trend, the number of Americans who have used heroin in the past year steadily increased from 2002 to 2014.

The considerable increase in opioid utilization has resulted in an upward trend of mortality due to overdose. Drug overdose was the leading cause of injury death in 2014, causing more deaths than either car accidents or homicide.

 Prescription opioid drugs and heroin were the cause of a majority of these overdose deaths.

 In 2014, 18,893 Americans died from prescription opioid overdose, while 10,574 Americans died from heroin overdoses.

Opioids exert their action by binding to 3 main opioid receptors: the mu, delta, and kappa receptors. The mu opioid receptor is responsible for the majority of the clinical and adverse effects associated with opioids, such as analgesia, euphoria, constipation, respiratory depression, and dependence.

Severe opioid intoxication can be fatal. The classic clinical features of opioid intoxication are unconsciousness, miosis, bradycardia, and respiratory depression (Table 111). If left untreated, opioid overdose can lead to pulmonary, neurological, cardiovascular, and infectious complications, and ultimately death.

Naloxone: Pharmacology and Delivery Devices 

The drug of choice for the reversal of respiratory and central nervous system depression in the presence of an opioid overdose is naloxone.

 Developed in 1960, naloxone was the first pure competitive mu opioid receptor antagonist to be synthesized.

 Due to its high affinity for the mu opioid receptor, naloxone competes with and displaces other opioids at opioid receptor sites, reversing their effect.

The onset of action of naloxone ranges from 1 to 13 minutes, depending on the route of administration (Table 2

). The approved routes for naloxone are intravenous (IV), intramuscular (IM), subcutaneous (subQ), and more recently, intranasal (IN). The IV route provides the most rapid and predictable effects. However, for overdoses occurring in the community, obtaining IV access may be difficult, leading to a delay in administration.

Once naloxone is administered, it has a relatively short half-life, and depending upon the route of administration, its duration of action ranges from 20 to 90 minutes.

 As a result, the duration of most opioids may exceed that of naloxone. Because of this, medical personnel should always be contacted and repeated naloxone doses may be necessary to prevent the return of respiratory depression.

Although the onset of action of the IV naloxone is more rapid than that of other routes of administration, the IV route is not recommended for bystanders to use when encountering a person who has overdosed on opioids.

 The subQ, IM, and IN routes are more suitable for administration in the community.

 Currently, 3 naloxone delivery devices have proven beneficial in the treatment of opioid-induced respiratory depression: the naloxone auto-injector (Evzio), the naloxone nasal spray (Narcan), and the off-label IN naloxone kit, which consists of a naloxone vial with a nasal atomizer. Only Evzio and Narcan are FDA-approved for the treatment of opioid overdose, with the latter receiving FDA approval in November 2015. Table 322-25 outlines additional factors, such as cost, for each formulation.

Evzio, the first FDA-approved naloxone delivery device, is a take-home naloxone auto-injector that will administer naloxone either intramuscularly or subcutaneously, depending on the patient’s body fat percentage.

 This device provides voice instructions to assist and guide the user through the administration of the naloxone dose.

Evzio should be injected into the anterolateral aspect of the thigh, and it can be administered through clothing, if necessary. Additionally, it contains a retractable needle system that conceals the needle before, during, and after administration.

IN administration may be more user-friendly in a community setting. The IN route eliminates the need for needles and thus the risk of needle sticks in settings where HIV and difficult IV access are common.

Prior to the FDA approval of IN naloxone, this delivery device came as an off-label kit that contained a parenteral vial of naloxone, a plastic delivery syringe, an intranasal atomizer, personal protective equipment, and instructions for use. Due to the multiple steps required to assemble this kit, it has been shown to have lower administration success and a longer time of administration.

The major benefit of Narcan nasal spray is that it comes as a single-spray device that requires no assembly or priming prior to use, which decreases the potential lag time for administration. Pre-marketing trials found that the time to reach maximum plasma concentration was comparable with that of the IM naloxone formulation.

Patients Who May Benefit From Naloxone Distribution 

Access to naloxone delivery devices is beneficial to high-risk opioid users who are in a substance-use treatment program, those leaving prison, and those receiving high-dose opioid prescriptions.

 The CDC’s 2016 Guidelines on Prescribing Opioids for Chronic Pain recommend that patients receiving ≥50 mg of morphine per day should be co-prescribed naloxone.

Other high-risk users who may benefit from naloxone include patients who are prescribed opioids and have a diagnosis of sleep apnea and/or pulmonary disease, patients who are concurrently on opioids and benzodiazepines, and patients who have recently abstained from heroin, particularly the injectable form.

 By distributing naloxone to high-risk opioid/heroin users and their family and friends, naloxone can shorten the time to overdose rescue, limit potential complications, and reduce the probability of overdose death and overall mortality.

Naloxone Delivery Devices in the Community: Efficacy and Benefits 

In an attempt to address the higher rates of prescription opioid and heroin overdose deaths in the United States, recent legislation and many organizations, such as the American Medical Association, have endorsed the use of naloxone distribution to laypersons. As of June 2016, the District of Columbia and 47 states have passed laws to increase naloxone access to laypersons.

In March 2016, President Obama announced that his administration is working to provide additional initiatives to increase community strategies to prevent overdose deaths. Several pharmacy chains have also followed suit, proposing initiatives to increase the access of naloxone in the community. By the end of 2016, Walgreens and CVS Pharmacy plan to be able to dispense naloxone to patients without an individual prescription in 35 states and Washington, DC.

These efforts have proven beneficial and effective in decreasing the amount of overdose-related deaths. A study conducted in Massachusetts observed 27% to 46% decreases in opioid overdose-related deaths in communities that distributed naloxone devices.

Another study found that naloxone distribution would prevent approximately 2000 overdose deaths in a population of 200,000 heroin users.

 This analysis also estimated that 1 overdose death would be prevented for every 164 naloxone kits distributed.

In addition to its proven effectiveness in decreasing overdose deaths, naloxone distribution has been found to be a cost-effective way to prevent opioid overdose death. Coffin and Sullivan found that naloxone distribution increased lifetime cost by just $53 and the incremental cost of $438 per quality-adjusted life-years (QALYs) gained.

 This estimated incremental cost per QALY is well below $50,000, which is traditionally considered cost effective by policymakers.

Since 1996, the number of laypersons who have been provided naloxone kits has significantly increased.

 Traditionally, the distribution of naloxone has been provided by community-based naloxone programs; however, there has been an increased focus on naloxone distribution in the outpatient setting through retail pharmacies.

A 2016 study analyzing national trends of naloxone prescriptions—including all available naloxone formulations except Narcan&mdash;found that the number of naloxone prescriptions dispensed from US retail pharmacies was low between 2010 and 2013, ranging from 241 to 463 prescriptions per quarter.

This number has dramatically increased in the past few years, however, with 4291 prescriptions dispensed in the second quarter of 2015.

 Evzio represented 29.3% of these prescriptions. This study also found that primary care physicians accounted for the majority of naloxone prescriptions, suggesting that naloxone prescriptions in the outpatient setting can be a complementary approach (Figure).

Although naloxone delivery devices have proven benefits, there remains some hesitation to support these devices in the community setting. A common argument is that these devices will encourage opioid abusers to increase their use,

 but no published studies support this argument.

Indeed, studies suggest that an increase in the training programs that accompany naloxone distribution reduces the use of opioids and increases the desire of users to seek addiction treatment. Moreover, researchers found this did not encourage users to increase their heroin use.

 Additional barriers are addressed in Table 4.

As opioid utilization continues to rise, we will likely see a rise in opioid-related mortality and overdose. Therefore, it should be a priority of managed care organizations, public health advocates, and healthcare professionals to collaborate and provide harm-reduction options, such as naloxone distribution for high-risk members in the community.

By addressing many of the misconceptions related to providing naloxone in the community, our hope is to increase support of naloxone delivery devices nationwide, potentially saving many lives.

: Department of Mental Health (JEC) and Department of Pharmacy (JEC, KW, PN), Veterans Affairs Medical Center, Washington, DC; College of Pharmacy, Howard University (UIE), Washington, DC.

: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

: Concept and design (JC,KW,UE,PN); acquisition of data (JC,KW,UE,PN); analysis and interpretation of data (JC,KW,UE,PN); drafting of the manuscript (JC,KW,UE,PN); critical revision of the manuscript for important intellectual content (JC,KW,UE,PN); statistical analysis (JC,KW,UE,PN); provision of patients or study materials (JC,KW,UE,PN); and supervision (JC).

: Jasmine E. Carpenter, PharmD, BCPS, BCPP, 219 S St NE, Washington, DC 20002. E-mail: 

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Articles

Although naloxone delivery devices are proven to reduce opioid overdoses, challenges persist in increasing the use of these devices in the community setting.