Understanding and countering opioid-induced respiratory depression

Abstract

Respiratory depression is the proximal cause of death in opioid overdose, yet the mechanisms underlying this potentially fatal outcome are not well understood. The goal of this review is to provide a comprehensive understanding of the pharmacological mechanisms of opioid-induced respiratory depression, which could lead to improved therapeutic options to counter opioid overdose, as well as other detrimental effects of opioids on breathing. The development of tolerance in the respiratory system is also discussed, as are differences in the degree of respiratory depression caused by various opioid agonists. Finally, potential future therapeutic agents aimed at reversing or avoiding opioid-induced respiratory depression through non-opioid receptor targets are in development and could provide certain advantages over naloxone. By providing an overview of mechanisms and effects of opioids in the respiratory network, this review will benefit future research on countering opioid-induced respiratory depression. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Keywords: addiction; brainstem; control of breathing; electrophysiology; mu opioid receptor; opioids; respiratory pharmacology.

Figure 1.

Summary diagram of breathing-related effects of opioids observed in humans. Opioids cause sedation, sleep disruption, sleep-disordered breathing, obstructed breathing and muscle rigidity. Opioids decrease respiratory rate, chemoreflexes, and diaphragm activity. Description of these effects and potential underlying mechanisms are reviewed in the text (section 2. Opioid effects on respiration).

Figure 2.

Mu opioid receptor distribution in the pontomedullary respiratory network. Dorsal view of a rodent brainstem with bilateral pontomedullary respiratory structures is depicted. Mu opioid receptor expression is indicated as postsynaptic (somatodendritic, left side of brainstem, filled symbols) or presynaptic (axon terminals, right side of brainstem, outlined symbols). In each area, mu opioid receptors are expressed (+, orange), highly expressed (++, dark orange), not expressed (-, black) or not determined (ND, gray). Details are in the text (section 3. Brainstem mechanisms of opioid-induced respiratory depression). Abbreviations and references: MOR, mu opioid receptor; KF, Kölliker-Fuse (Levitt et al., 2015); LPB, lateral parabrachial area (Chamberlin et al., 1999); LC, locus coeruleus (Bradaia et al., 2005; Levitt and Williams, 2012); RTN/pFRG, retrotrapezoid nucleus/parafacial respiratory group (Mulkey et al., 2004); BötC, Bötzinger complex (Lonergan et al., 2003); preBötC, preBötzinger complex (Lonergan et al., 2003; Gray et al., 1999; Sun et al., 2019; Bachmutsky et al., 2020b); rVRG, rostral ventral respiratory group (Lonergan et al., 2003); cVRG, caudal ventral respiratory group; NTS, nucleus of the solitary tract (Aicher et al., 2000; Poole et al., 2007); XII, hypoglossal motor nucleus (Lorier et al., 2010); NA, nucleus ambiguous (Erbs et al., 2015); Phrenic, phrenic motor neurons.

Figure 3.

Schematic of molecular mechanisms of opioid-induced respiratory depression and potential strategies to counter respiratory depression. Fentanyl activates G protein-coupled MORs and GIRK to hyperpolarize neurons and depress breathing. Strategies to counter fentanyl-induced depression of breathing include 1) naloxone (NLX), 2) monoclonal antibodies (mAB), 3) positive allosteric modulators of AMPA receptors (AMPAkines), 4) 5-HT1a and 5-HT4 receptor agonists, 5) orexin receptor agonists. These strategies are further reviewed in the text (sections 6 and 7).