Authors: van Lemmen MA et al.
Anesthesiology, February 5, 2026
Summary
With opioid overdose deaths increasingly driven by potent synthetic opioids such as fentanyl and carfentanil, understanding the real-world effectiveness of intranasal naloxone is critical. This prospective crossover trial evaluated whether a single 4 mg dose of intranasal naloxone (Narcan®) effectively reverses moderate respiratory depression induced by fentanyl and sufentanil in both opioid-naïve individuals and self-reported daily opioid users.
Thirty participants were studied: 12 opioid-naïve individuals and 18 daily opioid users (median morphine milligram equivalent 291 mg/day). Subjects received controlled fentanyl or sufentanil infusions titrated to reduce minute ventilation (V̇E) by 30–40%. At steady-state respiratory depression, 4 mg intranasal naloxone was administered.
Primary outcomes included:
• Time to recovery of minute ventilation (V̇E)
• Time to normalization of end-tidal CO₂ (pCO₂)
Key findings:
• V̇E recovered rapidly (within 2–4 minutes) across all participants after naloxone administration.
• End-tidal pCO₂ recovery was delayed (11–17 minutes) and incomplete in some participants.
• During sufentanil exposure (higher μ-opioid receptor affinity), full pCO₂ recovery occurred in only 8 opioid-naïve individuals and 10 daily opioid users.
• Hysteresis analysis demonstrated near-immediate V̇E effect-site equilibration (0–1 min), whereas pCO₂ normalization lagged significantly (2–11 min half-life).
• Seven of eighteen daily opioid users only completed one study arm due to withdrawal symptoms after naloxone administration.
Notably, this study modeled continuous opioid infusion rather than bolus overdose scenarios, limiting direct extrapolation to street overdoses. However, it provides important pharmacodynamic insight into naloxone’s physiologic effects under controlled conditions.
The authors conclude that a single 4 mg intranasal dose effectively reverses moderate fentanyl- and sufentanil-induced ventilatory depression as measured by minute ventilation, but reversal of hypercapnia is slower and sometimes incomplete — particularly with higher-affinity opioids like sufentanil. This raises concern about persistent respiratory instability even after apparent clinical reversal.
Key Points
• 4 mg intranasal naloxone rapidly restores minute ventilation after fentanyl and sufentanil exposure.
• CO₂ normalization lags behind ventilatory improvement.
• Reversal is less complete during high-affinity opioid (sufentanil) exposure.
• Withdrawal symptoms may limit tolerability in chronic opioid users.
• Higher doses or alternative formulations may be needed for high-potency opioid overdoses.
What You Should Know
For anesthesiologists, pain specialists, and perioperative leaders, this study reinforces several important realities:
• Visible respiratory effort does not guarantee complete physiologic reversal.
• Hypercapnia may persist even after ventilation appears clinically improved.
• High-affinity opioids may require repeat naloxone dosing or higher initial doses.
• In opioid-tolerant patients, naloxone-induced withdrawal remains a significant management challenge.
From a systems standpoint — particularly for those overseeing perioperative opioid stewardship or community naloxone distribution programs — this paper suggests that standard 4 mg intranasal naloxone may not be uniformly sufficient against next-generation synthetic opioids.
Further pharmacologic optimization of naloxone dosing strategies may be necessary as high-potency opioid exposure continues to evolve.
Thank you to Anesthesiology for allowing us to summarize and share this important article.