TAK-925 (Danavorexton), an Orexin Receptor 2 Agonist, Reduces Opioid-induced Respiratory Depression and Sedation without Affecting Analgesia in Healthy Men.

Summary

In a double-blind crossover phase 1 study in 13 healthy men under remifentanil-induced respiratory depression, danavorexton (orexin-2 agonist) significantly increased minute ventilation, tidal volume, and respiratory rate, and reduced sedation without altering pain tolerance. Effects persisted beyond infusion with only mild adverse events (one transient insomnia).

Key Findings

• Danavorexton significantly increased minute ventilation by 8.2 and 13.0 L/min at low and high doses versus placebo (P < 0.001).
• Sedation was reduced (VAS −29.7 mm; RASS +0.4) without changes in pain tolerance compared to placebo.
• Respiratory improvements persisted post-infusion; adverse events were mild, including one transient insomnia.

Clinical Implications

If validated in patients (e.g., surgical, obstructive sleep apnea, chronic opioid users), orexin-2 agonists could augment ventilation without reversing analgesia or precipitating acute withdrawal, serving as targeted rescue or prophylaxis for opioid-induced respiratory depression.

Limitations

• Small sample size (n=13) of healthy men limits generalizability to clinical populations.
• Phase 1 study with short-term outcomes; no comparison to standard reversal agents (e.g., naloxone).

Future Directions

Randomized trials in perioperative and high-risk patients (OSA, elderly, opioid-tolerant) comparing orexin agonists to standard care, dose optimization, safety (arrhythmia, arousal), and evaluation in opioid overdose scenarios.