As ASA members spearheading the initiative, we appreciate the thorough review of naloxone’s pharmacokinetics and dynamics by Lemmen et al. and the focus it brings to our Journal’s readers. It is clear that further study of opioid overdose reversal of respiratory depression and prevention of cardiac arrest is warranted, and novel µ-receptor antagonists or combinations with agnostic respiratory stimulants represent promising developments.

There are three crucial takeaway points from the information presented in the review that require emphasis. First, because the Koff value for naloxone is greater than that of fentanyl, sufentanil, and carfentanil, one needs to be aware that a minimum of 4 mg naloxone should be given, that repeated doses may be needed to reverse respiratory depression, and that renarcotization can occur. Rescuers should always be instructed not to leave a victim unattended after giving naloxone even if breathing and consciousness are restored. It should be noted that the illicit drug supply in the United States predominantly contains fentanyl, not sufentanil, and a much lower percentage contains carfentanil.

Second, naloxone reversal of opioid-induced apnea becomes irreversible at low inspired oxygen fractions but can return to regular breathing at room air concentrations of oxygen. However, full reversal of respiratory depression is not needed to sustain or reinitiate gas exchange, because the authors suggest that only 60% or less of µ-receptor occupancy is adequate to allow for sufficient oxygen uptake. Ventilatory support (rescue breathing) is crucial in a naloxone rescue attempt of a hypoventilating or apneic overdose victim. It provides the conditions for naloxone to fully restore normal breathing and protects the brain from potential irreversible injury.

Last, survival after an opioid-related out-of-hospital cardiac arrest is greater than after arrest from other causes, therefore attempts at resuscitation should be undertaken. As indicated above, ventilation plays a critical role in resuscitation and is the standard of care per the American Heart Association algorithm in a primary respiratory arrest regardless of the underlying cause. If the pulse is eventually lost, then chest compressions should be instituted. According to data from the U.S. transplant registry, the single greatest percentage increase in mechanism leading to organ donation during the past 25 yr is drug overdose. The heart may be resuscitated, but the brain is not tolerant of anoxia. The relationship of the opioid crisis to irreversible brain injury or death due to overdose cannot be overstated.

There is a multitude of variables in the success of rescue from opioid overdose that cannot be controlled as in clinical studies, such as the drug, dose, tolerance, combined intoxication, patient’s comorbidities, timing of rescue, or experience of the rescuers. As opposed to a simulated model, an actual opioid overdose victim is a vast unknown entity. All that can be identified on the scene are signs of likely drug overdose, breathing adequacy or absence, and pulse presence or absence. That is all that any rescuer has to act upon.

Calling 911, naloxone, rescue breathing, and chest compressions as indicated are the mainstays of overdose resuscitation. Naloxone 4 mg nasal spray is user friendly and proven safe; basic life support is a skill any layperson can learn. It is not the medication that ultimately limits survival, instead it is the conditions on the scene, which includes our personal biases and the willingness to be an immediate responder to an overdose victim.