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

Abstract and Introduction


Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.


Opioids produce respiratory depression and are consequently potentially lethal. Activation of the μ-opioid receptors expressed within the respiratory neuronal network of the brainstem causes irregular breathing, followed by periodic breathing and eventually the cessation of rhythmic breathing activity.[1–5] Recent studies show that although μ-opioid receptors are widely expressed within the respiratory network, the pre-Bötzinger complex, the brainstem respiratory rhythm generator, and the Kölliker–Fuse nucleus are two crucial areas in the brainstem for development of opioid-induced respiratory depression but also for reversal or prevention of respiratory depression by naloxone and nonopioid respiratory stimulants (Figure 1).[1,3–5]

Figure 1.

Schematic overview of the input to the brainstem respiratory centers. In purple, the parabrachial/Kölliker–Fuse complex, located in the pons, and pre-Bötzinger complex, located in the brainstem, that show high respiratory sensitivity to exogenously administered opioids and consequently are the target of reversal of opioid-induced respiratory depression. Excitatory drives are shown from various areas within the central and peripheral nervous system (hypercapnic and hypoxic drive, arousal from activation of higher centers), receptors from the lungs and muscles or joints, hypothalamus, and administration of exogenous respiratory stimulants.

In the perioperative and emergency setting, the opioid antagonist naloxone remains the first choice of treatment of respiratory depression from an opioid overdose, mainly due to its efficacy.[1,6] In case of an emergency, all that matters is that the patient resumes rhythmic breathing, and naloxone will effectively reverse the opioid effect, although sometimes high doses are required.[1] However, there are a number of circumstances where administration of naloxone may be inadequate or undesired.[7] Such circumstances include (1) an individual overdose with potent, high-affinity, and long-acting opioids, such as carfentanil or high-dose fentanyl; (2) opioid use or abuse in combination with other depressants of the central nervous system such as alcohol, cannabis, benzodiazepines, antidepressants, or antipsychotics, which synergistically enhance respiratory depression but are not reversed by naloxone;[8] (3) conditions in which naloxone reversal will cause effects that are undesired such as loss of analgesia, precipitation of withdrawal, agitation, and sympathetic stress;[1,6,9] (4) mass accidental or intentional poisoning with opioids, where supplies of naloxone may be exhausted or where naloxone is ineffective;[7] and finally (5) in case of an opioid use disorder.[9] For these reasons, in recent years there has been an increased interest in the development of novel reversal strategies aimed at providing efficacy close to that of naloxone but without its drawbacks. One important disadvantage of naloxone is its short duration of action due to rapid metabolism (elimination half-life, 30 min) and rapid clearance from the brain compartment (blood-effect-site equilibration half-life, 5 to 8 min).[9] It may even be advantageous to combine opioid therapy with nonopioid respiratory stimulants to prevent fatal respiratory depression.

To give a narrative overview of this highly relevant topic, we systematically discuss new and predominantly experimental (immuno)pharmacotherapies, published in the last 5 yr, that are aimed at reversal of opioid-induced respiratory depression, whether successful or not, as alternatives to naloxone or related compounds. The discussion of naloxone and its analogs is beyond the scope of the current review. We do acknowledge that novel opioid-receptor antagonists are being developed with longer half-lives (e.g., methocinnamox, nalmefene, biohybrid nanoparticles-encapsulated naloxone) than naloxone,[7] but their effect is based on antagonistic activity at the opioid receptor,[3,7] which is distinct from developments that we present here.