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

Serotonin Receptor Agonists

The neurotransmitter serotonin (5HT) plays an important role in inspiratory and expiratory respiratory control with actions in the opposite direction from the μ-opioid receptors. We earlier summarized data on seven different serotonin agonists aimed at receptor subtypes 1a, 4a, and 7a.[6] Irrespective of the targeted subtype, all agonists caused reversal or prevention of μ-opioid–induced respiratory depression in animal studies. In two recent studies, the effect of the 5HT4a receptor agonist BIMU8 was tested on etorphine- and sufentanil-induced respiratory depression.[26,44] In etorphine-immobilized goats, BIMU8 reduced etorphine toxicity with a reversal of the drop in respiratory rate and normalization of blood gasses.[44] In the animals, blood pressure dropped after infusion of BIMU8, and some goats developed muscle rigidity or muscle spasms. In conscious rats, however, BIMU8 failed to counter sufentanil-induced respiratory depression, although this may be dose-related.[23] This stands in contrast to 8-OH-DPAT, a 5HT1a and weak 7a receptor agonist that does reverse sufentanil-induced respiratory depression in the conscious rat by increasing respiratory rate and tidal volume.[26] The development of muscle rigidity may be an additional cause of respiratory depression. Reducing muscle rigidity by adding the α1-adrenoreceptor agonist prazosin to 8-OH-DPAT treatment further improved tidal volume and oxygenation, albeit respiratory rate decreased by about 25%.[26] This again highlights the importance of addressing muscle rigidity, the so-called wooden chest syndrome, in the light of opioid-induced respiratory depression. Importantly, and in contrast to the animal studies, in humans, the two studies that tested the effect of serotonin agonists selectively targeting the 1a- and the 4a-receptor subtypes failed to show efficacy in morphine-induced respiratory depression.[45,46] This may be related to insufficient dosing or due to insufficient exposure of the 5HT agonists at their receptor within the brainstem due to inability to pass the blood–brain barrier.[1] Further studies on selective and permeable 5HT agonists are warranted.