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


Ventilatory drive is modulated by redox-sensitive pathways. For example, the hypoxic ventilatory response, originating at the carotid bodies, is modulated by changes in redox state. Oral intake of the antioxidant N-acetyl-cysteine, which elevates intracellular cysteine levels, enhances the magnitude of the hypoxic ventilatory response, suggestive of a role for the thiol redux state in hypoxic chemosensitivity.[47] A combination of the antioxidants ascorbic acid and α-tocopherol effectively reversed the blunted hypoxic response due to a low dose of inhalational anesthetics.[48] Hence, it seems attractive to determine the ability of antioxidants to counter opioid-induced respiratory depression. In a first study, Lewis's research group showed that L-cysteine-ethyl ester reverses respiratory acidosis and arterial hypoxemia after morphine administration, but only in tracheotomized rats, not in nontracheotomized animals.[49] This is possibly related to an increase in upper airway resistance and subsequent occurrence of negative intrathoracic pressure in the latter group of animals. L-cysteine and L-serine-ethyl ester were ineffective, which highlights the importance of ability to penetrate relevant neurons and the essential role for the sulfur moiety in causing the respiratory stimulatory effects. In a subsequent study, Lewis's group showed that D-cysteine-diethyl and D-cysteine-dimethyl ester offset moderate morphine-induced respiratory depression in freely moving, nontracheotomized rats due to increases in respiratory rate and tidal volume, while enhancing morphine analgesia.[50] D-cysteine was without effect. In a third study, in awake rats, the investigators show that pretreatment with glutathione ethyl ester offsets fentanyl-induced respiratory depression through effects on respiratory rate and tidal volume, and consequently stabilized breathing and enhanced analgesia.[51] In summary, these studies show that ethyl esters increase respiratory rate and sometimes also tidal volume, and that the increase is sustained during moderate opioid-induced respiratory depression, offsetting the opioid effect on respiratory rate. Finally, in awake and isoflurane-anesthetized rats, pretreatment with the antioxidant Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) prevented fentanyl-induced respiratory depression, while the potent antioxidant N-acetyl-L-cysteine methyl ester was without effect.[52] In all of these studies, the sedative opioid effects remained unaffected by the antioxidants.

Various mechanisms have been postulated to explain the ability of these antioxidants to reverse or prevent opioid-induced respiratory depression, including reduction of enhanced production of reactive oxygen species by opioids, enhancement of nitrosyl derivatives in the carotid body and nucleus tractus solitarius, enhancement of skeletal muscle contractility, or alterations in opioid bias toward the G-coupled transduction pathway. All can theoretically increase respiratory drive after opioid exposure. However, the absence of efficacy of the potent antioxidant N-acetyl-L-cysteine methyl ester on opioid toxicity suggests that an effect on reductive processes seems less plausible.[52] We are probably observing specific redox-independent actions of these agents outside of the opioid transduction pathway as no effects were observed on opioid-induced sedation and analgesia remained uncompromised. Further studies are warranted both mechanistically and clinically to determine whether such agents have a role in preventing opioid overdose toxicity in humans.