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. 

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With respect to reversal of opioid-induced respiratory depression, the ampakines are by far the most studied drugs. We earlier reported on four ampakines, CX717, CX546, CX614, and XD-8-17C, that all reversed respiratory depression induced by a variety of opioids in rodents.[6] For example, CX717 reversed fentanyl- and DAMGO ([D-Ala, N-MePhe, Gly-ol]-enkephalin)–induced respiratory toxicity in the rat and partly prevented alfentanil-induced depression of the ventilatory response to hypercapnia in human volunteers.[34–36] Ampakines are benzamine compounds that allosterically modulate the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor–mediated synaptic response in a positive fashion.[1] The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors are ubiquitously present in the central nervous system and are expressed within the respiratory network, and their activation stimulates breathing activity under conditions of hypoventilation by increasing respiratory rate and, to a lesser extent, tidal volume. Since 2016, four new studies on ampakines in animal models of respiratory depression were published aimed at the development of a respiratory stimulant for human or veterinary medicine (CD-8-17C, LCX001, CX1739, and CX1942).[37–40] All show promising results counteracting the effect of potent opioids such as etorphine and fentanyl. Particularly compound CX1739, the precursor of LCX001, showed promising results in a phase 2 human study.[41] In a preliminary report, CX1739 reduced remifentanil-induced respiratory depression at a steady-state plasma concentration of 2 ng/ml, without affecting analgesia or pupil diameter. However, CX1739 did not counteract respiratory depression after a remifentanil 1 μg/kg bolus dose. This exemplifies the limit of ampakines in their ability to activate respiratory drive in the respiratory rhythm generator after high-dose opioid-induced respiratory depression.

Finally, the atypical antidepressant tianeptine also acts at the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor system by enhancing α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid–mediated glutamatergic neurotransmission.[42] After an animal study showed that tianeptine mitigates morphine-induced respiratory depression,[42] we tested its effect in two independent studies on alfentanil- and remifentanil-induced respiratory depression (R. van der Schrier, 2013, verbal communication; A. Dahan, 2021, verbal communication) and could not detect any respiratory stimulatory effects from oral or intravenous tianeptine. Interestingly, intravenous tianeptine worsened remifentanil-induced respiratory depression, possibly related to its agonistic activity at the μ-opioid receptor.[43]

We envision further studies on ampakines and particularly CX1739 to determine whether higher doses may overcome bolus dose–related respiratory depression, for example in combination with naloxone.