Is Evzio (naloxone HCL injection auto-injector) the answer for preventing death from opioid overdose? Can it turn caregivers into heroes and save lives?

Evzio is a new formulation of naloxone administered using a user friendly auto-injector device. It is marketed by Kaléo and was recently approved for the emergency treatment of suspected opioid overdose. Physicians in operating and emergency rooms have used naloxone, an opioid antagonist, for almost half a century for the treatment of opioid overdose. Evzio is designed for non-medical professionals to administer naloxone.

The FDA and physicians see Evzio as a new “tool” to combat opioid abuse, misuse, and related deaths. It will work in a manner similar to the epinephrine pen which is marketed for acute treatment of anaphylaxis. Evzio contains a speaker that provides voice instructions to guide the user through each step of the injection. When activated, an automatically inserted needle delivers 0.4 mg of naloxone hydrochloride injection intramuscularly or subcutaneously and afterwards fully retracts the needle into its housing. 

Caregivers can use Evzio to administer naloxone after an observation of possible symptoms of opioid overdose. Vague symptoms such as extreme sleepiness, breathing problems, or even “pinpoint” pupils may prompt a family member or close friend to whip out this life-saving device and spring into action!

Evzio cost about $650 with a prescription. For Evzio to be successful, it will have to be paid for by either the patient or the prescription insurance company. Prescribers may be willing to prescribe Evzio to some of their patients on high-dose opioids or maybe just those with known substance abuse or those with a history of addiction, including past stays in detox programs. However, these are not the only group of opioid users at risk for overdose. The numbers of “opioid consumers” who acquire these pain killers from friends, relatives and illegal “dealers” is unknown but surely an enormous and unacceptable number that clearly has overwhelmed the ability of law enforcement to manage.

Medical communities and the media are proclaiming that providing this antidote to family members and caregivers of chronic pain patients will prevent the epidemic of opioid medication related deaths in the US. 

Expectations and exuberance for Evzio may be too high. Consider that unintentional overdose is a common term used by physicians and medical examiners after patients consume dozens of medications not even prescribed or acquired legally. Patients may combine prescription opioids with non-prescription substances like marijuana, cocaine, and alcohol without the consent of their physicians. Any death that involves opioids is reported as “accidental” and continue to be counted the same way as a car accident or falling off a ladder, Evzio may not be effective in these situations. 

Prescribers believe that giving Evzio to all chronic pain patients on high-dose opioids or with a history of drug abuse alone would be very beneficial in preventing misuse and overdose. There still needs to be adequate patient education about the risk of respiratory depression and death from consuming too much or even therapeutic doses of opioids by patients who are not prescribed high doses or are not suspected drug abusers.

Reports of Evzio not having risk or side effects have suggested that it will be used by good samaritans who happen to be bystanders positioned around the country, like superheroes, ready to assist doctors and reduce society’s concerns about opioid deaths. Caregivers must be educated about what to expect AFTER giving naloxone. Side effects of naloxone include: 

• Sweating
• Goose-bumps
• Increased heart rate
• Agitation
• Severe anxiety
• Palpitations,
• Withdrawal symptoms
• Increased in blood pressure 
• Increased heart rate (HR)

Myocardial infarction and stroke complications can and will occur, especially in patients with risk factors such as smoking history, obesity, sedentary lifestyle (from their chronic pain), hypertension, hyperlipidemia, and tachycardia. 

The development of a severe hypertensive response after the administration of the opiate antagonist naloxone was evaluated in one study that characterized the risks of giving opioid antagonists. One individual studied showed significant mean arterial pressure changes with a rise from a baseline of 107 mmHg to 147 mmHg 145 min after naloxone injection and infusion. After stopping naloxone, his blood pressure rapidly returned to baseline. Thus, endogenous opioids appear to regulate blood pressure in some hypertensive patients and opiate antagonists must be administered with caution to these individuals.

It is shocking that despite evidence of cardiovascular side effects in studies, few warnings have been provided about untoward side effects that could manifest as dramatic changes in vital signs following administration by lay people.

Moreover naloxone does not work for overdoses of none opioid medications, for example benzodiazepines, that may have also been used. It is also very important to consider that most opioids will last longer in the body than naloxone and persuading patients to go to the emergency room for additional doses of naloxone and further care, including management of withdrawal symptoms, would be difficult after their first exposure to naloxone. These side effects and challenges associated with Evzio, which is marketed as safe and an easy treatment, creates a very difficult and even potentially dangerous situation for these non-medical professional who are only trying to help revive someone who in their untrained opinion may be unresponsive.

Stopping overdoses is obviously not enough to combat the significant and multifactorial problem of opioid misuse, abuse, and overdose. Recent regulatory efforts have focused on rescheduling hydrocodone combination products to the more restrictive Drug Enforcement Administration (DEA) schedule II in an effort to reduce the quantities available for illegal or even legally prescribed use. Refills and telephone prescriptions are available for the less restrictive class III-V opioid-based medications. With rescheduling to class II, refills and telephoned prescriptions will no longer be allowed for hydrocodone combination products. This will not reduce the amount of opioids prescribed, abused or diverted. Rather, prescribers, pharmacists, and other healthcare providers will face more hurdles in furnishing hydrocodone combination products.  

Some pharmacist and physicians do not support these rescheduling measures due to the proposed increase in record keeping requirements and additional roadblocks to filling what has been considered useful and first-line for the treatment of mild, moderate and moderately severe pain. With a potential switch from its long-time position as a class III controlled substance to the class II location, there are concerns that physicians will more likely prescribe morphine, methadone, hydromorphone, oxymorphone, or even oxycodone products.

What else can be done by physicians and the US Food and Drug Administration (FDA) to reduce the unbelievable statistic of a death every 36 minutes from an opioid overdose in the United States? Over 17,000 Americans die yearly from prescription opioid overdose, accidentally or intentionally for suicide. The million dollar question remaining to be answered is will a new drug formulation device in the hands of laypeople really make a dent in this crisis that in recent years has actually surpassed car accidents as the leading cause of accidental death? 

Pharmacy manufactures and researchers designing and creating more abuse-deterrent opioid formulations is another strategy suggested by the medical community and government theorist. Risk Evaluation and Mitigation Strategies (REMS) which include FDA Mandated med-guides together with Prescription Drug Monitoring Programs (PDMP) have done very little to combat abuse and misuse. This may be due to little cohesiveness between prescribers and pharmacists in addressing this problem and working toward the creation of a successful strategy

Nature gave man opioid agonists and pharmaceutical companies created antagonists to reduce the mortality associated with overdoses. Pharmaceutical companies now want the public to believe that an opioid antagonist can actually reduce the incidence of opioid induced overdoses. With current trends in pain management and utilization of benzodiazepines, muscle relaxants, anticonvulsants to manage pain, an unconscious person would need to be revived by utilizing several different antidotes by trained medical professionals to ensure that transportation to a hospital takes place and additional care is provided.  

References

Alcorn T (2014). America embraces treatment for opioid drug overdose. Lancet 383: 1957-1958.

Evzio Prescribing Information

Levin ER, Sharp B, Drayer JI, Weber MA (1985). Severe hypertension induced by naloxone. Am J Med Sci 290: 70-72.

About the Author

Adam M. Kaye Pharm.D. , FASCP, FCPhA and Jessica Sarah Kaye
Clinical Professor of Pharmacy,
Department of Pharmacy Practice,
Thomas J. Long School of Pharmacy and Health Sciences