You have to be alive to enjoy the porridge: The role of Goldilocks naloxone dosing in a world of hungry bears

Gonzalez Utrilla et al. [1] argue for a ‘Goldilocks’ approach to naloxone in the era of potent synthetic opioids, seeking a dose that is not too low to reverse an overdose yet not so high as to cause unnecessary harm. The authors are right that a clear protocol on naloxone administration and potential tailoring in a clinical setting is important, especially as overdose responses typically take place in venues not overseen by emergency medicine clinicians. However, the focus on precise naloxone dosing in the context of the wider overdose epidemic risks overlooking some of our most effective tools for compassionately and effectively preventing overdoses.

First, naloxone only works if it is administered in time by a bystander. Therefore, more important than the dose of naloxone is whether there is someone present and ready to respond with naloxone or other intervention, like rescue breathing or calling for help. In the United States in 2023, drug use that resulted in fatal opioid overdose was only witnessed at 8.1% of deaths. While there was a bystander physically nearby who potentially could respond 42.6% of the time, the potential bystander provided no response usually because they were unaware that the overdose was happening [2]. The ‘crucial period before full medical care arrives’ that Gonzalez Utrilla et al. [1] describe when naloxone can be lifesaving depends on a responder recognizing the overdose. The key failure in overdose response is not naloxone's pharmacological low potency, but the absence of real-time support or monitoring at the time of use where naloxone or rescue breathing could optimally be administered within seconds to minutes of the onset of the overdose. Harm reduction strategies that are designed to address this gap, including supervised consumption sites, peer support, or hotlines, warrant more focus than the dose of naloxone.

Second, the stakes weigh differently on either side of the Goldilocks principle of ‘just right’ for naloxone administration. While too low of a dose of naloxone seems like it could be fatal, a 4 mg dose of nasal naloxone is typically sufficient to displace fentanyl from the opioid receptors [3]. Naloxone rescue kits include two doses, so that an additional dose can be administered when there is no improvement in breathing. Furthermore, responders will usually do other things while waiting for naloxone to improve respirations, like rescue breathing and verbal and physical stimulation to increase the respirations. Too much naloxone commonly results in precipitated opioid withdrawal, which means the overdose survivor is flooded with anxiety, irritability, nausea, muscle aches, vomiting and diarrhea. For the overdose survivor in precipitated withdrawal, the rescue is experienced as the trauma more than the overdose. The experience of naloxone precipitated withdrawal may establish aversive memories that fuel future solitary drug use [4] and create a barrier to future care. While Gonzalez Utrilla et al. [1] frame ‘Goldilocks’ dosing as a balance between too much and too little, the fact is that the theoretical complications of too little naloxone are very rare and more reliant on timing than dose, whereas the complications of too much naloxone are common and may undermine future overdose safety.

Finally, naloxone dosage is only a minor component of effective overdose intervention. As Gonzalez Utrilla et al. [1] state naloxone ‘should not be the first intervention’ when responding to overdose. Naloxone-sparing techniques and skills should be prioritized, including rescue breathing and oxygen administration. The focus of overdose response training should be on restoring respirations as quickly as possible to protect the brain from hypoxia. In the person who is breathing adequately but not fully responsive, the risk of additional naloxone precipitating withdrawal is high. In this case, support and time are better than more naloxone. Overdose prevention and response approaches that prevent overdose in the first place and reduce the risks of naloxone-precipitated withdrawal should be prioritized for clinical trials research [1]. Optimal naloxone dosing may be component of these trials, but should not be the anchoring focus of overdose response research. We already know that naloxone is effective when administered in time. People with lived and living experience with overdose have stated that high dose reversal products are not needed and cause harm [4] and we should listen.

In the context of an ongoing overdose crisis of an erratic and polysubstance drug supply, overdose response should focus on real-time support and monitoring during use; effective naloxone sparing techniques and support skills, and listening to those with lived and living experience telling us that there is not equipoise between too little and too much naloxone.

Jake R. Morgan: Conceptualization (equal); writing—original draft (lead). Alexander Y. Walley: Conceptualization (equal); writing—original draft (supporting).

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