We thank Dr. Pattullo and Drs. Milas and Varon for their interest and careful reading of our article on the use of naloxone in the reversal of an opioid overdose as might occur in the community setting in the United States. Individuals that overdose are commonly found in a state of unconsciousness, and these overdose victims, as recently discussed in the general media,are often positive for fentanyl as well as for other substances (e.g., methamphetamine, xylazine, cannabis, or gabapentin), that affect not only breathing but also the level of consciousness. Because illicit drugs often predominantly contain fentanyl, use of naloxone (4 to 8 mg given intranasally or 5 mg given intramuscularly) can rapidly restore rhythmic breathing activity, assuming that there is still cardiac activity. Otherwise, naloxone administration should always be combined with cardiorespiratory resuscitation.

Naloxone restores breathing activity by displacing fentanyl from the μ-opioid receptor. Consciousness may or may not be regained, which depends on many other factors. One problem is brain hypoxia that may result from the opioid overdose. In such cases, hypoxia may cause brain damage, which may impair the rapid return of consciousness. Another problem is cointoxication with tranquilizers that depress consciousness. It is frequently difficult or even impossible to determine the composition of the substances that were abused. The overdose victim and responder often have no idea what adulterants were added to the drug of abuse. Still, high-dose naloxone will often be able to restore the ventilatory component of the overdose sequelae, irrespective of the arousal state, assuming that the upper airway is patent.

Dr. Pattullo introduces the role of hypercapnia, particularly the effect of acidosis of the cerebrospinal fluid on naloxone ability to reverse opioid-induced respiratory depression. We recently studied the effect of hypercapnia on consciousness and cardiorespiratory function in rats and humans. Acutely induced hypercapnia causing severe arterial acidosis was detrimental at concentrations of more than 12% in humans, causing a state of dissociation, while the animal data indicated that levels of more than 20% reduce consciousness and increase the likelihood of mortality. Upon an opioid overdose and in contrast to opioid use in the postoperative setting, the rapid transition of the opioid to the brain compartment can silence respiratory neurons (causing apnea) before any accumulation of arterial carbon dioxide. Hence, in the acute setting, the use of naloxone can be lifesaving by restoring rhythmic breathing activity if the dose is sufficient and cardiac output is still present. When the opioid overdose causes hypoventilation for longer periods of time, hypercapnia will occur, and this may impair consciousness. However, we are not aware of data that suggest that naloxone is unable to restore breathing activity during long-term hypercapnia, particularly in the absence of hypoxia. At moderate short-term hypercapnia, naloxone is able to reverse morphine- and even buprenorphine-induced respiratory depression.  In this respect, hypoxia may be more important than hypercapnia because hypoxia may impair the naloxone activity, as shown by Haouzi et al. A nonresponse to naloxone may be related to the naloxone dose, the presence of adulterants (e.g., tranquilizers), brain hypoxia, possibly hypothermia, and/or low cardiac output; cerebral spinal fluid acidosis may play a role as well. Cerebral spinal fluid acidosis may occur when respiratory depression has lasted for longer periods of time. This is not an unrealistic scenario and many overdose victims are found hours after the overdose occurred in a state of severe hypoventilation, hypoxia, hypercapnia, and hypothermic with low cardiac output. We argue that it is still appropriate to treat these individuals with naloxone, initiate cardiorespiratory resuscitation, and arrange transport to a hospital for further treatment.

Drs. Milas and Varon give an excellent summary of our article and highlight the importance of rapid action when encountering an overdose victim. They stress the importance of adequate naloxone dosing combined with immediate cardiorespiratory resuscitation. As discussed by us, we agree whole heartedly. We thank Drs. Milas and Vernon for their support of our work.

The naloxone dose and route of administration has not been fully defined, and most studies rely on pharmacokinetic data combined with modeling the effect of naloxone on the cardiorespiratory system. We believe that such studies are important and enable the design of human studies that are safe but give sufficient data to provide dosing advice for rescue of overdose victims in the community setting. We are currently studying the effect of intranasal and intramuscular naloxone on high doses of fentanyl administered in healthy volunteers and individuals with an opioid use disorder (https://www.isrctn.com ISRCTN21068708). Other studies are evaluating agnostic respiratory stimulants, which may have a future role in improving outcomes after opioid overdoses (https://clinicaltrialregister.nl id NL9692; https://www.isrctn.com ISRCTN63027076; https://www.isrctn.com ISRCTN16683564).