Abstract
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 preBötzinger complex (preBötC) in the ventrolateral medulla. Other important brainstem respiratory centres include the pontine Kölliker-Fuse and adjacent parabrachial nuclei (KF/PBN) in the dorsal lateral pons, and the dorsal respiratory group in the medulla. Deletion of μ opioid receptors from neurons showed that the preBötC and KF/PBN contribute to OIRD with the KF as a respiratory modulator and the preBötC 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.
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The authors thank Nghia H. Pham for help in the preparation of Fig. 1.
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BAB conceived the study, undertook the literature review, researched and wrote the pathophysiology section and drafted the paper. MAR contributed to the literature review, clinical detail, and helped draft the review. Both authors approved the final draft of the review and agree to be accountable for all aspects of the work.
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Baldo, B.A., Rose, M.A. Mechanisms of opioid-induced respiratory depression. Arch Toxicol 96, 2247–2260 (2022). https://doi.org/10.1007/s00204-022-03300-7
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DOI: https://doi.org/10.1007/s00204-022-03300-7
Keywords
- Opioid-induced respiratory depression
- Brainstem centers and respiration
- Pathophysiology of opioid-induced respiratory depression
- Pre-Bötzinger complex and opioid-induced respiratory depression
- Kölliker-Fuse nucleus and opioid-induced respiratory depression
- Neural mediation of opioid-induced respiratory depression