The latest data from the US Centers for Disease Control and Prevention for opioid overdose deaths puts the number at 84,600 for 2023 with 90% of those deaths being linked to fentanyl (https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm). Until recently, naloxone (N-allyl-noroxymorphone), discovered in 1960 by Harold Blumberg, was the only opioid antagonist approved for reversal of opioid overdose (Kolbe and Fins, 2021). A research team comprised of Harold Blumberg, Mozes Lewenstein, and Jack Fishman synthesized naloxone and reported the first testing of naloxone in rodents in 1961 (Blumberg et al., 1961). In these early animal studies, naloxone was shown to be ten times more effective than levallorphan in reversing the adverse respiratory effects of opioids in rabbits (Blumberg et al., 1961). Naloxone was also effective in reversing respiratory depression after oxymorphone in healthy human volunteers (Sadove et al., 1963). Yet, even in 1963, Sadove et al. (1963) remarked on the short-lived ability of naloxone to reverse opioid-induced respiratory depression. For example, while the ability of intramuscular oxymorphone to reduce minute volume lasted 60 minutes in healthy volunteers, the antagonism of this response by naloxone only lasted 40 minutes (Sadove et al., 1963). Despite this imperfection, naloxone was approved by the US Food and Drug Administration for intravenous use by licensed healthcare professionals in 1971 (US Food and Drug Administration, NDA 016,636) and as an over-the-counter intranasal spray in March 2023.

The debate continues about the utility of naloxone to reverse respiratory depression caused by fentanyl and high potency analogs (Britch and Walsh, 2022; France et al., 2021; Kim et al., 2019; Rzasa Lynn and Galinkin, 2018). Elimination of naloxone from the body (t1/2 ∼2 hours) (Tylleskar et al., 2017) is much quicker than fentanyl (4.4–9.7 hours) (Bentley et al., 1982), meaning that multiple naloxone doses must be administered to mitigate an overdose caused by fentanyl. The lipophilicity of naloxone, while greater than for morphine, is lower than that of fentanyl. Thus, fentanyl is distributed through the body more quickly (1–3 minutes after intravenous injection and ∼ 7 minutes after intranasal administration) than naloxone (15–30 minutes). As a longer-acting alternative to naloxone, nalmefene hydrochloride nasal spray was approved by the US Food and Drug Administration in May 2023 for reversal of opioid overdose (https://www.fda.gov/news-events/press-announcements/fda-approves-prescription-nasal-spray-reverse-opioid-overdose). Nalmefene has a more rapid onset (Ellison et al., 2024) and longer t1/2 (10–11 hours) than naloxone (Crystal et al., 2024).

The use of synthetic opiates such as carfentanil and 3-methylfentanyl has increased since 2016 (Noble et al., 2021). The opioid receptor antagonist methocinnamox (MCAM) is a promising antagonist for mitigating the reinforcing effects of synthetic fentanyl analogs (Gerak and France, 2023). In this issue of the Journal of Pharmacology and Experimental Therapeutics, Hiranita et al. (2024) report that MCAM can reverse the effects of ultra-potent fentanyl analogs, carfentanil and 3-methylfentanyl, as well as fentanyl and heroin, on respiratory depressant effects in rats using whole-body plethysmography. First, they performed side-by-side dose-response comparisons of heroin, fentanyl, and the fentanyl analogs alone to reduce minute volume after intravenous administration in male rats. Second, they tested the abilities of naloxone and MCAM to reverse the respiratory depressant effects of heroin, fentanyl, and the fentanyl analogs by administering the antagonists 5 minutes after agonist treatment. Finally, the authors examined the ability of prior MCAM and naloxone administration to prevent the depressive effects of the heroin, fentanyl, and the fentanyl analogs on ventilation by administering the antagonists 22, 46, and 70 hours before the agonists. Hiranita et al. (2024) report a rank order potency of the opioid agonists to decrease tidal volume that was 3-methylfentanyl > carfentanil > fentanyl > heroin. At the highest doses, both antagonists reversed respiratory depression caused by the opioid agonists, including the ultra-potent fentanyl analogs. However, at lower doses, the effects of naloxone were notably shorter in duration than MCAM. In experiments assessing the ability of antagonist pre-treatment to prevent respiratory depression, the highest dose of MCAM, but not naloxone, administered 22 or 44 hours prior effectively prevented respiratory depression caused by the opioid agonists, including the ultra-potent fentanyl analogs. This work is a rigorous analysis of the ability of MCAM to effectively reverse and prevent respiratory depression by heroin, fentanyl, and other high-potency fentanyl-derived synthetic opioids (Hiranita et al., 2024).

Treatment with Narcan, the trade name for intranasal naloxone, can reverse opioid-induced hypoventilation, which is the predominant cause of death in overdose victims. However, the relatively short duration of action for naloxone relative to the longer-lasting ability of opioids to cause respiratory depression is a significant limitation to the use of this drug for treating opioid overdose victims. For this reason, overdose victims frequently require multiple doses of naloxone, a process anecdotally referred to as “re-narcanization”. Another significant limitation to the use of naloxone to reverse opioid overdose is that 4 mg Narcan doses typically carried by first responders are not always effective at fully reversing the effects of high potency and high affinity synthetic fentanyl-derived synthetic opioids (Skolnick, 2022). As a consequence, there is still a significant risk of overdose death due to respiratory depression, even when naloxone is administered. The current work directly addresses this important medical need, and the use of MCAM has the potential to save numerous lives from opioid overdose (Hiranita et al., 2024). The work accomplishes this goal with an experimental approach and design that is rigorous in assessing the ability of naloxone and MCAM to reverse multiple parameters of opioid-induced hypoventilation at several doses and time points after treatment. However, there are several important limitations regarding the current study that are important for readers to bear in mind.

First, the work performed by Hiranita et al. in 2024 was performed exclusively in male rodents (Hiranita et al., 2024). While men make up a large majority (70%) of opioid overdose deaths, 23,654 females also died from opioid overdose in 2021. Thus, the risk of opioid overdose is also a significant human health problem for women as well. Future preclinical and clinical work assessing the ability of MCAM to reverse or prevent opioid-induced respiratory depression in females will provide critical additional information about the broad utility of MCAM in both sexes. Second, the current study was performed in rodent models, which is an excellent starting point for assessing the ability of MCAM to rescue opioid-induced respiratory depression in patients. Previous work from this group has demonstrated that MCAM can reverse the effects of heroin in rhesus monkeys (Gerak et al., 2019) and attenuate the reinforcing effects and self-administration of opioids, including fentanyl in rhesus monkeys (Gerak and France, 2023; Maguire and France, 2022, 2024; Maguire et al., 2019). Presumably, MCAM would also be able to prevent the hypo-ventilatory effects of high potency synthetic opioids such as fentanyl in non-human primates and humans but this needs to be tested in future work. Third, although the ability of MCAM to reverse opioid-induced antinociception and respiratory depression for much longer durations than naloxone is a major strength of the current work, there are also possible drawbacks to long-term antagonism of opioid receptors. The current study by Hiranita et al. in 2024 finds that pretreatment with MCAM can prevent the opioid effects for up to 46 hours at the highest doses tested (Hiranita et al., 2024). Previous works showed that MCAM can antagonize opioid effects for up to 14 days (Jimenez et al., 2021; Zamora et al., 2021). The rapid reversal of opioid effects in overdose victims using naloxone is known to precipitate an acute withdrawal syndrome. The use of a pseudo-irreversible opioid antagonist has the potential to increase the duration of opioid withdrawal syndrome. Preclinical research in rodents did not necessarily find longer or more severe withdrawal symptoms for MCAM but this important question requires assessment in human subjects. Long-term antagonism of opioid receptors by MCAM is likely to render medical-assisted therapies such as methadone and buprenorphine ineffective. Finally, current formulations of MCAM are administered to animal models via intravenous and/or subcutaneous injection. An important facet to the widespread use of Narcan is that it can be easily administered intranasally with relatively little training by non-medical personnel. Thus, for MCAM to reach its full potential as an opioid overdose rescue agent, production of formulations that can be more easily administered via oral or intranasal routes will be important to develop (Jordan et al., 2022).

Taken together, the current work assessing the ability of MCAM to reverse and prevent antinociception and respiratory depression by high potency opioid agonists is an impactful and novel finding that addresses an important medical problem in a way that has the potential to improve the current standard of care. There are some possible limitations to the therapeutic use of MCAM as an opioid overdose rescue agent that need to be addressed by future clinical studies in human subjects. However, the possible advantages of MCAM, including a longer duration of action than naloxone and its ability to reverse high potency synthetic opioids such as fentanyl, far outweigh any modest drawbacks.

Wrote or contributed to the writing of the manuscript: Carr, Morgan.

This work was supported by National Institutes of Health National Institute on Drug Abuse (NIDA) [Grant DA044999].

No author has an actual or perceived conflict of interest with the contents of this article.

dx.doi.org/10.1124/jpet.124.002205.