Mechanisms of opioid-induced respiratory depression

Opioid-induced respiratory depression (OIRD), the primary cause of opioid-induced death, is the neural depression of respiratory drive which, together with a decreased level of consciousness and obstructive sleep apnea, cause ventilatory insufficiency. Variability of responses to opioids and individual differences in physiological and neurological states (e.g., anesthesia, sleep-disordered breathing, concurrent drug administration) add to the risk. Multiple sites can independently exert a depressive effect on breathing, making it unclear which sites are necessary for the induction of OIRD. The generator of inspiratory rhythm is the preBotzinger complex (preBotC) in the ventrolateral medulla. Other important brainstem respiratory centres include the pontine Kolliker-Fuse and adjacent parabrachial nuclei (KF/PBN) in the dorsal lateral pons, and the dorsal respiratory group in the medulla. Deletion of mu opioid receptors from neurons showed that the preBotC and KF/PBN contribute to OIRD with the KF as a respiratory modulator and the preBotC as inspiratory rhythm generator. Glutamatergic neurons expressing NK-1R and somatostatin involved in the autonomic function of breathing, and modulatory signal pathways involving GIRK and KCNQ potassium channels, remain poorly understood. Reversal of OIRD has relied heavily on naloxone which also reverses analgesia but mismatches between the half-lives of naloxone and opioids can make it difficult to clinically safely avoid OIRD. Maternal opioid use, which is rising, increases apneas and destabilizes neonatal breathing but opioid effects on maternal and neonatal respiratory circuits in neonatal abstinence syndrome (NAS) are not well understood. Methadone, administered to alleviate symptoms of NAS in humans, desensitizes rats to RD.

Automated summary

Opioid-induced respiratory depression is the main cause of opioid-induced death, affected by factors such as variability in responses to opioids and individual differences. Multiple brain regions can independently exert depressive effects on breathing, including the preBotzinger complex and Kolliker-Fuse, but some signal pathways remain poorly understood. Naloxone is the main medication used to reverse opioid-induced respiratory depression.