Project 5: Novel strategies to prevent opioid-induced hypoventilation during sleep and identification of underlying mechanisms

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY/ABSTRACT The current opioid epidemic presents a significant public health crisis, with opioid-induced respiratory depression (OIRD) being a major cause of morbidity and mortality. This project aims to address this critical issue by elucidating the effects of opioids on respiratory function during sleep, a period of heightened risk due to natural reductions in breathing. Another objective of this grant is to identify non-opioid respiratory stimulants to counteract OIRD without negating the analgesic benefits of opioids. Our central hypothesis posits that opioids exacerbate sleep-related hypoventilation by significantly dampening both diaphragm and pharyngeal muscle activity, and diminishing ventilatory and arousal responses to hypercapnia, thus compounding the natural reduction in breathing that occurs during sleep. This project will investigate the mechanisms of OIRD during sleep and test pharmacological agents like danavorexton and taltirelin, which have shown potential in stimulating breathing without reversing opioid analgesia. The first specific aim is to explore the mechanisms of opioid-induced hypoventilation during sleep in healthy controls and patients with Obstructive Sleep Apnea taking 50 mg or extended-release morphine. Preliminary data suggest a synergistic interplay involving reduced central respiratory drive, decreased responsiveness of respiratory pump and pharyngeal dilator muscles to CO2, and potentially delayed arousal response to hypercapnia. The second aim focuses on the pharmacological reversal of OIRD during sleep using danavorexton, an orexin agonist. Initial evidence indicates that danavorexton stimulates breathing without impacting sleep architecture or the analgesic effects of opioids, showing promise as a therapeutic agent. The third aim investigates the use of taltirelin, a thyrotropin-releasing hormone receptor agonist, in reversing OIRD during sleep. We aim to quantify its efficacy in stimulating breathing during opioid-induced hypoventilation. In addition to exploring the efficacy of danavorexton and taltirelin, this project will also investigate other promising pharmacological agents identified in Projects 1-4 of this P01, targeting key mechanisms implicated in opioid- induced respiratory depression. This research is expected to provide a comprehensive understanding of how opioids affect breathing during sleep and to offer novel strategies for safer opioid use in pain management. The successful completion of this project could significantly impact public health by reducing the morbidity and mortality associated with opioid use, especially during sleep.