Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity

Rutger van der Schrier, M.D.; Jack D. C. Dahan, B.Sc.; Martijn Boon, M.D., Ph.D.; Elise Sarton, M.D., Ph.D.; Monique van Velzen, Ph.D.; Marieke Niesters, M.D., Ph.D.; Albert Dahan, M.D., Ph.D.


Anesthesiology. 2022;136(4):618-632. 

In This Article

Miscellaneous Peptides

Neuropeptide FF is a mammalian amidated peptide with antiopioid analgesic activity.[46] Since it modifies opioid analgesia, Wojciechoski et al.[53] tested its effect on respiratory depression induced by endomorphin-1 in urethane-anesthetized rats. Before any opioid challenge, at a high intravenous dose, neuropeptide FF reduced minute ventilation. Lower doses were unable to systematically reduce the number and duration of endomorphin-1–induced apneas, possibly related to poor permeability across the blood–brain barrier. In contrast, intracerebroventricular administration caused a dose-dependent reduction of apneic events, an effect that was blocked by the neuropeptide FF antagonist RF9. The mechanisms of these effects on opioid-induced respiratory depression remain unknown, but are possibly related to reversal of vagal-mediated opioid-induced apneas via neuropeptide FF receptor activation in the nucleus tractus solitarius.

Another approach to influence opioid-induced respiratory depression has been to focus on peptides that directly interact with the signaling pathway(s) of the opioid receptor. Liang et al.[54] show that intracerebroventricular pretreatment with protein kinase A inhibitor H89 slowly reversed fentanyl-induced respiratory depression by increasing respiratory rate. Similarly, G-protein gated inwardly rectifying potassium channel blocker Tertiapin-Q dose-dependently reversed fentanyl effects through increasing respiratory rate but without affecting minute ventilation.[54] Somewhat surprisingly, phosphodiesterase-4 inhibitor rolipram and cAMP analogs were ineffective in this model.[54] These data suggest that H89 interacts with the ventilatory control system in a cAMP-independent fashion.

These observations that various peptides, including, for example, the endogenous dipeptide glycyl-L-glutamine,[55] may counter opioid-induced respiratory depression increase our knowledge on the mechanisms of opioid-induced respiratory depression. The viability of such targets in the reversal and prevention of a lethal opioid overdose is still far off, but merits further study.