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11 Articles in Volume 16, Issue #7
A Perspective on Tapentadol Therapy
Acupuncture to Treat Brachial Plexopathy and CRPS
Behavioral Medicine: How to Incorporate CBT Into Pain Management
EpiPens and Opioids: Common Ground
Fibromyalgia and Coexisting Chronic Pain Syndromes
Life-Saving Naloxone: Review of Currently Approved Products
Medical Foods Hold Promise In Chronic Pain Patients
Moving Beyond Pain Scales: Building Better Assessment Tools for Today’s Pain Practitioner
Moving Toward an (Almost) Opioid-Free Emergency Department
No Perfect Medicine—What You Need to Know About NSAIDs and Opioids
Prescribing Opioids: How New Policies Are Affecting Medical Specialties

Life-Saving Naloxone: Review of Currently Approved Products

Aimed at reducing the frequency of unintentional opioid-induced deaths, 3 recently FDA approved naloxone products are reviewed to compare their attributes and pitfalls for reversing life-threatening respiratory depression.

In 2015, the Centers for Disease Control and Prevention (CDC) reported that 44 people die from prescription opioid-related toxicity in the United States every day.1 This figure equates to almost 2 deaths every hour. Moreover, 83% of these opioid deaths were unintentional, or at least unanticipated.2 From 2013 to 2014, the CDC also noted a 14% increase in age-adjusted drug overdose deaths.An age-adjusted death rate was calculated by applying age-specific death rates to the US standard population age distribution.3

With acute and chronic pain management issues touching almost all aspects of healthcare, opioid medications are prescribed frequently to help manage these patients. Physicians who prescribe opioids maintain an important role and are tasked with opioid safety initiatives that include monitoring, which involves risk-mitigation strategies to help combat the rising death toll associated with unintentional opioid-induced respiratory depression.  

To help prevent accidental drug overdoses, the Food and Drug Administration has approved a number of new naloxone-containing products. Naloxone is a non-scheduled opioid antagonist that has been proven to rapidly reverse life-threatening respiratory depression and other opioid depressant effects.4 Naloxone (in any formulation) is not intended to replace emergency medical care. It works by displacing opioid agonists at the mu receptor-binding site in the central nervous system.4 There are currently three different naloxone products available to providers and patients, and this overview examines the attributes and pitfalls of each formulation.

Handheld Auto Injector

In April of 2014, the FDA approved a handheld auto-injector with unique technology that includes auditory stepwise instructions for naloxone delivery.5 This new product, Evzio, is approved for in-home use to reverse opioid-induced respiratory depression. Each injection delivers a dose of 0.4 mg, up to 0.4 mL.6

The product is designed with ease of use in mind for patients, their caregivers or acquaintances, and providers to enable an intramuscular (IM) injection with little or no training. While the majority of patients will receive a dose from a caregiver or healthcare professional, there have been documented cases of patients self-injecting with naloxone.  

The auto-injector features an electronic voice system that directs the administrator, as well as red and green light activation, which is helpful for patients with poor eyesight or hearing. In addition, the auto-injector does not require manipulation of a vial or syringe, which might otherwise be difficult for anyone with poor dexterity or in a panicked state of mind.  

The needle inside the auto-injector is engaged only after consistent pressure is placed on a 3-second timer, and immediately retracts after injection. This feature minimizes and virtually eliminates the risk of an accidental needle stick. Another benefit to the public is that certain states bar emergency medical technicians (EMTs) from giving injections in the field; the auto-injector is a feasible solution that may be carried and legally used by those individuals.7

The most obvious drawback of the auto-injector is price, which has been at least in part attributable to the advanced technology. The most recent average wholesale price (AWP) for the auto-injector is $4500 per kit.8 Each kit includes a trainer and 2 naloxone auto-injectors. The trainer does not contain naloxone and is needleless for teaching and training purposes. Patient assistance programs and coupons for reimbursement are available from the manufacturer, Kaléo Pharma. The product coverage has expanded since its approval and is now covered by all private insurance payers and Medicaid in most states. 

Nasal Spray

Narcan, which has been available for many years as an injectable, recently has been rebranded as a nasal spray by Adapt Pharma and was approved by the FDA in November 2015.9 It is available as a prefilled, single-dose nasal spray. It is approved for in-home use for the reversal of opioid overdose. Each unit contains and delivers 4 mg, up to 0.1 mL of naloxone HCl. Narcan is dispensed as a kit containing 2 units.10 No assembly is required prior to administration. As intranasal (IN) administration does not require a needle, there is no risk of a needle stick with this formulation.  

Although Narcan nasal spray arguably may require more dexterity than Evzio, it is still more user-friendly than a vial and syringe. Prior medical training is not required in order to administer Narcan nasal spray. Nevertheless, there is a NARCAN Now smartphone app that provides access to training and safety information. Per these instructions, administration is relatively simple and straightforward—although use of just an app would require familiarity in advance. Review on such a platform would not be conducive to use in an emergency situation. (Patients and caregivers should be advised by the pharmacist to review the app or instruction when they first fill the prescription.) The instructions are fairly straightforward, and similar to other intranasal devices. According to the manufacturer, “First, peel back the package and remove the device, second place the tip of the nozzle in either nostril until your fingers touch the bottom of the patient’s nose, and finally press the plunger firmly to release the dose into the patient’s nose.”10

More information about this product, including directions, an instructional video on how to use it, and information on how purchase it, are available on Adapt Pharma’s website. The most recent AWP for each individual Narcan nasal spray is $150 per kit.10 Each kit is dispensed as previously stated with 2 prepared nasal spray devices; however, no trainer is included.

The premise for both the nasal spray and the auto-injector in dispensing 2 units is to allow caregivers or healthcare professionals to give a second dose after 3 to 5 minutes if help has not arrived and the patient becomes or remains unresponsive.6,8  

Other Options

Prior to the release of the previously discussed intranasal formulation of naloxone, naloxone kits have been available as a generic formulation for both IM and (a makeshift) IN administration of naloxone. The IN product itself carries no FDA approval for in-home use. Federal law requires drugs covered by Medicaid to carry FDA indications in order to be covered for payment.11 Presently the AWP for the naloxone IM kit is $19.80.8 Compared with the nasal spray and the auto-injector, this product is less expensive to both patients and third-party payers; however, there are questions regarding dispensing, education, and billing.

Presently the kit is dispensed with a naloxone vial, a syringe, and an atomizer. The administrator must first draw the naloxone dose into the plunger from a vial using a needle. Next, they must attach an atomizer and deliver 1 mL into each nostril of the patient. This presents difficulties for administrators with dexterity concerns or poor eyesight, and also carries a greater risk of a needle stick. In addition to more manipulation required, the administrator must also recall training on how to use all 3 dispensed kit components appropriately.  

For a dispensing pharmacist, this formulation also raises questions of product billing and time for training the patient and caregiver. Is each component a separate drug requiring a separate prescription and billing piece? Or is the kit dispensed as one entity? Is the teaching done by the dispensing pharmacist or the prescriber, or both? This formulation has been used by EMS providers and emergency department (ED) providers for years; however, untrained patients or caregivers require additional training and reinforcement. Plus, although evidence is available for opioid reversal by this technique, there is no data on failures for any number of reasons, as outlined above.

Too Soon for Comparative Studies

There have been no published studies that compare absorption and efficacy of the new Narcan nasal spray with the naloxone auto-injector. The use of the naloxone kit for IN administration as compared with  IM administration  was studied prior to approval of the Narcan nasal spray formulation.12 In 2009, Kerr et al reported that an IM administration was just as effective as intranasal administration for reversal of heroin overdose within 10 minutes—72.3% versus 77.5%, respectively.13

In 2005, Kelly et al conducted a prospective trial comparing IM to IN naloxone in 155 patients to determine if there was any difference in response time to opioid reversal. Not surprisingly, IM patients responded faster than the IN group (time until respirations >10/minute)—6 minutes versus 8 minutes, respectively (P<0.0006). Secondary outcomes included time to Glasgow Coma Scale that showed no difference between the groups; however, need for ‘rescue’ naloxone was in favor of IM use, 13% versus 26% in the IN group.14    

In a usability study conducted in 2015 by Edwards et al, the authors compared the auto-injector to the off-label makeshift kit for IN administration.15 A total of 42 patients were enrolled in the study and were asked to deliver a dose of naloxone by either auto-injector or intranasal kit: first without training and then following a training session. Prior to a training session, 90.5% of participants were able to successfully administer the auto-injector versus 0% of the intranasal kit (P<0.0001). Following a training session reviewing the use of each product, 100% of participants were able to successfully administer the auto-injector versus 57.1% of the IN kit (P<0.0001). It is important to note that this study was funded by the manufacturer of the auto-injector, Kaléo.  

The authors also looked at secondary endpoints of shorter time to administration and administration in accordance with the instructions-for-use in favor of the auto-injector. The authors also discussed concerns for concentrations absorbed in the nasal cavity as well as the effects on patients with deviated septa.15,16

There is 1 small study listed in the Narcan Nasal Spray prescribing information that compares IN Narcan with traditional unbranded IM naloxone in the gluteus maximus muscle. The study examined 30 healthy inpatients and compared 1 dose of Narcan IN (4 mg/0.1 mL), 2 doses of Narcan IN (8 mg/0.2 mL), and 1 dose of naloxone IM injection (0.4 mg/1 mL). There was no statistically significant difference between the times to maximum concentration achieved by any of the naloxone formulations—meaning that they are all equally fast acting. In addition, the bioavailability of 1 and 2 doses of the IN Narcan was 46.7% compared with 43.9% for the IM naloxone. This explains the need to administer higher doses of IN naloxone versus IM naloxone (4 or 8 mg versus 0.4 mg) to achieve adequate patient response.10

The prescribing information contains no direct comparison of the difference (or lack thereof) in efficacy between the different doses and routes of administration. Therefore, the information provided from this source must be used in combination with the other studies discussed previously when making clinical decisions and choices regarding which formulation to recommend for any given patient.

Access to Naloxone

In general, there are 2 different types of regulations regarding naloxone: those that increase access and the Good Samaritan regulations that mitigate personal and professional liability. The aims of increased prescribing and access are to enhance naloxone availability when prescribed in good faith. These regulations allow for naloxone administration without fear of legal consequences for the prescriber or for the person administering the drug. The goal is to reduce barriers to both the prescribing and the administration of naloxone. Forty-two states (including the District of Columbia) have passed a law allowing a layperson to have access to naloxone.17 The states that still have not passed this type of law are AZ, IA, KS, MO, MT, SD, and WY.  

The goal of Good Samaritan laws is to encourage bystanders to take action and help someone who overdosed by calling for emergency responders without fear of legal consequences and/or arrest. Thirty-five states have passed a Good Samaritan law regarding laypeople.17 Unfortunately, not all Good Samaritan laws are expanded to cover professional responders such as EMS, police, and firefighters. Figure 1 is a color-coded map based on which law(s) were active in each state as of September 14, 2015.17 States colored in white had no naloxone legislation in place.


Opioid use and misuse are on the rise in the United States. While prescribers are faced with new guidelines to ensure appropriate assessment, screening, and evaluation of opioid-purchasing patients, they also must arm appropriate patients with naloxone. In 2015, the AMA created a task force specifically to reduce opioid abuse. This task force, which included a number of professional medical associations and healthcare providers, supports improved naloxone access.18 The Indian Health Service, the Substance Abuse and Mental Health Services Administration (SAMSHA), and the World Health Organization (WHO) have also made public statements of support regarding the importance of access to naloxone for patients and caregivers.19,20,21

On November 5, 2015, a bill was introduced in the Senate called the Co-Prescribing Saves Lives Act of 2016, sponsored by Sen. Tim Kaine (D-VA), the current democratic vice-presidential candidate.22 Among this bill’s aims are to create federal co-prescribing guidelines and to establish a grant program with respect to naloxone. It is slated to be reviewed sometime in 2016.  

Patients who have been on the same chronic opioid therapy for years could and perhaps should justifiably be provided with in-home naloxone. Patients can have a change in renal function, hepatic function, fluid or weight shifts, drug-drug interactions, drug-food interactions, or pharmacogenetic factors that could increase a stable patient’s risk for opioid induced respiratory depression.  

While there are pros and cons to each available naloxone formulation, as discussed previously, it is important to first acknowledge that chronic opioid patients should be evaluated for the need of in-home naloxone. Zedler et al
have developed a risk index score for both Veterans Affairs (VA) and non-VA patients that stratifies patients for a risk of opioid-induced respiratory depression based on history, active diagnoses, and current medications.23 Once identified, the patient, family, and/or caregivers should then be properly trained on the use of the product and re-
educated when needed. If a reversal by naloxone is needed, that patient then needs to have their pain management regimen re-evaluated immediately.

The newer naloxone formulations do provide practitioners with a way to safely and effectively arm their patients with naloxone in the home, where a difference in minutes could be the difference between life and death. It is important for all medical personnel to understand the benefits and pitfalls of each formulation and to advocate for all patients at risk for known or suspected opioid overdose in order for patients to gain safe, appropriate access to this potentially lifesaving medication.

Last updated on: June 15, 2017
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