Naloxone dosing: An evolving unregulated drug landscape, care setting considerations, and the need for research

Gonzalez Utrilla et al. [1] present a timely and nuanced discussion of the complexities of naloxone dosing in the era of highly potent synthetic opioids (HPSOs). They highlight the risks of both underdosing and over-antagonism, advocate for a tailored approach to naloxone administration and emphasize the importance of non-pharmacological interventions. We generally agree with the principle of titrating naloxone to clinical effect where feasible, recognizing this approach is more practicable in acute care settings than in community settings.

While minimizing adverse effects from naloxone over-antagonism is important, the foremost priority in opioid overdose management, across all settings, is preserving life. Overdose reversal hinges on prompt first aid, including airway management, ventilation and cardiopulmonary resuscitation, in tandem with timely naloxone administration [2]. That said, to mitigate the risk of precipitated withdrawal, naloxone should be reserved for restoring respiration rather than used solely in cases of decreased consciousness. Reduced consciousness may resolve as the opioid is gradually cleared, without the need for naloxone.

Despite robust evidence supporting naloxone dosing for heroin overdoses, guidance for fentanyl and other HPSOs remains limited [3, 4]. Current recommendations are largely informed from clinical experience, animal studies, in silico models, healthy volunteer studies and data on heroin-related overdoses, all of which have uncertain applicability to HPSO-related events. Moreover, polysubstance use, including benzodiazepines, xylazine and stimulants, further complicates the overdose response. These challenges highlight the need for clinical trials involving people who use synthetic opioids and polysubstance combinations to inform real-world, evidence-based practice.

Compounding these issues are the distinct pharmacological characteristics of HPSOs [3]. Fentanyl and its analogs exhibit higher receptor binding affinity and slower dissociation compared with heroin, suggesting that higher naloxone doses may be needed for effective reversal. Additionally, substantial variability in naloxone pharmacokinetics have been observed among healthy volunteers, and this variability may be even greater among people who use HPSOs. These pharmacodynamic and pharmacokinetic considerations should guide future research into dosing strategies that are effective across diverse healthcare environments.

In acute care settings, intravenous naloxone is preferred for its rapid onset and capacity for precise titration, enabling clinicians to restore respiration while minimizing severe withdrawal or rare complications, such as pulmonary edema and cardiac arrhythmias, thought to result from a catecholamine surge. Our clinical experience with intravenous naloxone, used in a different context to induce mild to moderate withdrawal for rapid buprenorphine initiation within minutes, has demonstrated how precisely the dose can be titrated to elicit the desired response without precipitating severe withdrawal [5]. When intravenous access is unavailable, intramuscular naloxone provides a relatively rapid onset of action and permits dose titration, albeit with less precision and fine control than intravenous administration.

Community settings, such as emergency medical services and take-home naloxone programs, present different challenges. Intramuscular naloxone is the recommended route in these contexts, offering a practical balance between speed and titratability. Non-clinical responders can be trained to administer and titrate intramuscular naloxone, and there are reports of community overdose responders doing so successfully.

Intranasal naloxone, though perceived as easier to administer and safer, has more limited capacity for dose titration and has shown variable efficacy compared with intramuscular naloxone. High-dose intranasal formulations, frequently introduced by pharmaceutical manufacturers, have been marketed with limited independent evidence and come at significantly higher costs, raising questions about their utility [1]. While further research is warranted, in scenarios lacking titration options or trained responders, it may be prudent to err on the side of higher initial dosing. In light of the volatility in the unregulated drug supply, the risk of inadequate reversal in overdoses involving fentanyl analogs such as carfentanil or nitazenes often outweighs the potential harms of over-antagonism.

Given these issues, nalmefene may be a promising alternative in specific contexts. With higher receptor affinity and a longer half-life than naloxone, it could reduce the risk of re-narcotization, particularly in rural and remote areas with delayed access to medical care. However, the potential for prolonged withdrawal symptoms, limited clinical data and lack of global availability warrant further investigation before broader adoption [6].

Challenges in naloxone dosing parallel those seen in opioid agonist therapy in the HPSO era [7-9]. Both domains are marked by limited evidence, an unpredictable drug supply and the need for individualized approaches. Addressing these gaps requires well-designed clinical trials and translational research. In the absence of definitive data, collaboration among clinicians, researchers, policymakers and people with lived or living experience is essential to developing pragmatic, equitable and evidence-informed naloxone strategies. A coordinated and adaptive response is needed to address the urgency of this evolving public health crisis.

James S. H. Wong: Conceptualization (lead); writing—original draft (lead). Anthony Lau: Conceptualization (supporting); writing—review and editing (supporting). Pouya Azar: Conceptualization (supporting); supervision (lead); writing—review and editing (supporting).

PA was a consultant on Indivior-led buprenorphine extended-release studies (terminated in 2023) and receives honoraria for presentations organized by Indivior, which are unrelated to this commentary. All other co-authors report no conflicts of interest.