Understanding Re-Narcotization Is Key To Battling Opioids Like Fentanyl
By Tom Jenkins, Ph.D.
As the fentanyl epidemic rages on, opioid antagonist rescue agents like Narcan, Kloxxado, and Opvee have become omnipresent. Like defibrillators and EpiPens, advocates insist they should be available virtually everywhere, from schools to concert events to the home. No doubt the monumental effort to have rescue medications on-hand has saved tens of thousands of lives. In urgent settings, like a police officer arriving at the scene of an overdose, a teacher finding an overdosing student, or a parent finding an overdosing child, a single dose of a short-acting opioid antagonist can reverse the effects of an opioid overdose, buying time for individuals to get to the emergency room where more can be done to prevent extensive damage or death.
Today, illicit synthetic opioids are commonly used as adulterants to other street drugs, and they are widely used in pill form as well. Opioid overdose remains the leading cause of death for individuals between 25 and 64 years old, and by some estimates, 50% of illicit fentanyl-containing pills that have been flooding into the U.S. contain a fatal dose.
Rescue Medication Mismatch
What is the mismatch between current rescue medications and synthetic opioids? Rescue medications currently in use are well suited to effectively reverse less potent short-acting, semi-synthetic opioids especially when abused via non-oral routes of administration (e.g., injection or smoking). However, orally ingested fentanyl can lead to dangerously persistent respiratory depression.
Current short-acting rescue medications often do not maintain effective exposures in the body long enough to fully mitigate the risks attending an oral fentanyl overdose. The protective effects of the rescue medication can wear off before the more persistent fentanyl exposure decreases to a safe level. This can lead to a “fentanyl rebound” for an individual who has been revived with a short-acting countermeasure, and produce a rapid recurrence of symptoms, termed “re-narcotization," including respiratory depression that may lead to hypoxic brain injury or death. As a result, repeated doses of short-acting opioid antagonists are often needed to effect a successful rescue. In fact, in managing synthetic opioid overdoses, 20% to 45% of overdose victims initially rescued with naloxone experience a re-narcotization event. Families, schools and other venues that take the proactive step to have a rescue medication on-hand need to be ready with multiple doses, especially if the ambulance is slow to arrive. Even a brief period of anoxia (~ 5 mins) during a re-narcotization episode can induce neuron death, potentially resulting in enduring damage or death.
In response to this concern, several higher naloxone dose strength formulations and a more potent nalmefene-containing product have been introduced, in an effort to decrease onset time and modestly extend their duration of action. As these formulations are designed to produce a more rapid and higher exposure of naloxone or a more potent antagonist than that delivered by Narcan, an undesirable consequence is a higher incidence and severity of withdrawal symptoms during reversal.
Understand The Risks
As we work to reduce opioid overdose deaths, we need greater access to rescue medications, while understanding the risks these treatments may present to individuals in the midst of an overdose, especially those who refuse or do not have immediate access to follow-up medical care.
To meet the challenge of this evolving problem now dominated by synthetic opioids like fentanyl, we must push for and fund innovative solutions. Various levels of government, law enforcement, the medical community, and advocacy groups continue to work together to stem the tide of this epidemic. Just as the current iteration of opioid rescue medications represented incredible innovations offering hope, we look to the biopharma industry to innovate next generation rescue medications to combat the current and evolving dangers of synthetic opioids.
About The Author:
Tom Jenkins, Ph.D., is the Co-Founder and Chief Science Officer of Elysium Therapeutics, with 30 years of experience in the pharmaceutical industry with a focus on the development of therapeutics for pain, anesthesia, and opioid use disorders. He previously cofounded Theravance, Inc., and he also led the team at Axys Pharmaceuticals, whose discoveries led to several multi-million dollar strategic collaborations and a successful IPO.