Reducing Respiratory Depression Due to Opioids in Anesthesia

Opioid-induced respiratory depression remains a major limitation in the perioperative use of opioids for analgesia. While opioids are indispensable for controlling moderate to severe pain, particularly in surgical settings, their interaction with μ-opioid receptors in the brainstem suppresses central respiratory drive, often in a dose-dependent and patient-specific manner. This suppression can lead to life-threatening hypoventilation, hypercapnia, and in severe cases, respiratory arrest. Consequently, a central challenge in anesthesiology is how to preserve the potent analgesic properties of opioids while reducing the risk of respiratory depression (1).

Historically, the only pharmacological counter to opioid-induced respiratory depression has been opioid antagonists like naloxone. While naloxone is effective at rapidly reversing the respiratory side effects of opioids, it also eliminates opioid-mediated analgesia, can trigger acute withdrawal in opioid-tolerant individuals, and may lead to rebound pain. These significant limitations have spurred efforts to develop alternative therapies that counteract respiratory depression caused by opioids without reducing with pain control. Among the most promising of these are orexin receptor 2 (OX2R) agonists—such as danavorexton (TAK-925)—which activate endogenous arousal pathways that are independent of opioid signaling, thereby preserving analgesia while improving ventilation (1).

Mechanistically, danavorexton works by stimulating orexin-2 receptors (OX2Rs) in the brain, particularly in the lateral hypothalamus—an area that plays a key role in the regulation of alertness and breathing. By activating this system, danavorexton enhances signals that travel to brainstem centers responsible for generating breathing rhythms, such as the pre-Bötzinger complex. These signals help maintain regular, effective breathing. In animal studies, danavorexton increased the activity of muscles critical to breathing, such as the diaphragm and the genioglossus (a muscle that keeps the airway open), suggesting that it may support both respiratory drive and upper airway tone—two areas commonly suppressed by opioids (2).

In preclinical models, danavorexton not only sped up recovery from general anesthesia with isoflurane but also reversed the typical respiratory side effects associated with opioid use. Specifically, it improved oxygen saturation levels and lowered carbon dioxide levels (3). Notably, danavorexton achieved these benefits without triggering major cardiovascular side effects such as increased heart rate or blood pressure. This sets it apart from older respiratory stimulants like doxapram, which are limited by their tendency to cause tachycardia and hypertension.

Beyond danavorexton, there is growing interest in so-called “mechanism-agnostic” respiratory stimulants—agents that enhance respiratory drive by acting directly on central neural circuits rather than interfering with opioid pathways. This approach allows clinicians to reverse respiratory depression without compromising pain control. In a recent review, van Lemmen and van der Schrier examined several such compounds, including ampakines and serotonin receptor agonists. While each class showed potential, orexin receptor agonists stood out for their unique ability to restore wakefulness, stabilize ventilation, and preserve analgesia simultaneously, making them especially well-suited for use in the perioperative setting (4).

Despite these promising results, danavorexton remains investigational and is not yet FDA-approved. However, its safety profile and targeted action make it an appealing alternative to opioid antagonism. As surgical populations become more complex—older, heavier, and with more comorbidities—the need for safer perioperative opioid strategies becomes more urgent. OX2R agonists like danavorexton may become key components of multimodal anesthesia regimens that aim to preserve analgesia while reducing the risk of respiratory depression caused by opioids.

References

1. van Lemmen M, Dahan A, Hang Y, et al. TAK-925 (Danavorexton), an Orexin Receptor 2 Agonist, Reduces Opioid-induced Respiratory Depression and Sedation without Affecting Analgesia in Healthy Men. Anesthesiology. 2025;142(4):628-638. doi:10.1097/ALN.0000000000005375
2. Yamada R, Koike T, Nakakariya M, Kimura H. Orexin receptor 2 agonist activates diaphragm and genioglossus muscle through stimulating inspiratory neurons in the pre-Bötzinger complex, and phrenic and hypoglossal motoneurons in rodents. PLoS One. 2024;19(6):e0306099. Published 2024 Jun 25. doi:10.1371/journal.pone.0306099
3. Suzuki M, Shiraishi E, Cronican J, Kimura H. Effects of the orexin receptor 2 agonist danavorexton on emergence from general anaesthesia and opioid-induced sedation, respiratory depression, and analgesia in rats and monkeys. Br J Anaesth. 2024;132(3):541-552. doi:10.1016/j.bja.2023.12.032
4. van Lemmen M, van der Schrier R, Dahan A, van Velzen M, Sarton E, Niesters M. Pharmacology of viable mechanism agnostic respiratory stimulants for the reversal of drug-induced respiratory depression in humans. Expert Opin Drug Metab Toxicol. 2023;19(10):671-679. doi:10.1080/17425255.2023.2262386