Opioid-induced respiratory depression: clinical aspects and pathophysiology of the respiratory network effects.

Important insights and consensus remain lacking for risk prediction of opioid-induced respiratory depression (OIRD), reversal of respiratory depression (RD), the pathophysiology of OIRD, and which sites make the most significant contribution to its induction. The ventilatory response to inhaled carbon dioxide is the most sensitive biomarker of OIRD. To accurately predict respiratory depression (RD), a multivariant RD prospective trial using continuous capnography and oximetry examining five independent variables, age ≥60, sex, opioid naivety, sleep disorders, and chronic heart failure (PRODIGY trial), were undertaken. Intermittent oximetry alone substantially underestimates the incidence of RD. Naloxone, with an elimination half-life of ∼33 min (cf. morphine 2-3 h; fentanyl and congeners only 5-15 min), has limitations for the rescue of patients with severe OIRD. Buprenorphine is potentially valuable in patients being treated long term since its high µ-receptor (MOR) affinity makes it difficult for an opioid of lower affinity (e.g., fentanyl) to displace it from the receptor. In the last decade, synthetic opioids, for example, fentanyl, its potent analogs such as carfentanil, and the benzimidazole derivative nitazene "superagonists" have contributed to the exponential growth in opioid deaths due to RD. The MOR, encoded by gene Oprm1, is widely expressed in the central and peripheral nervous systems, including centers that modulate breathing. Opioids bind to the receptors, but consensus is lacking on which site(s) makes the most significant contribution to the induction of OIRD. Both the preBötzinger complex (preBötC), the inspiratory rhythm generator, and the Kölliker-Fuse nucleus (KFN), the respiratory modulator, contribute to RD, but receptor binding is not restricted to a single site. Breathing is composed of three phases, inspiration, postinspiration, and active expiration, each generated by distinct rhythm-generating networks: the preBötC, the postinspiratory complex (PiCo), and the lateral parafacial nucleus (pF_L), respectively. Somatostatin-expressing mouse cells involved in breathing regulation are not involved in opioid-induced RD.