Discussion and Future Perspectives
We systematically reviewed three dozen often still experimental approaches to reduce or prevent opioid-induced respiratory depression (Figure 2). We envision even more potential targets that stimulate breathing and may overcome respiratory depression from opioids or any other cause, derived from existing drugs, such as the carbonic anhydrase inhibitor acetazolamide, the antioxidants ascorbic acid and α-tocopherol, the cholinesterase inhibitor physostigmine, and the hormones progesterone or orexin.[6,89] We subdivided the countermeasures by mode of action or molecule characteristics to give a clear insight into their mechanism of action and side effect profile. Some drugs, such as the majority of controlled substances, have a limited indication, mostly due to their adverse effects such as high probability of abuse and addiction and development of schizotypal adverse events.
List of agents used to treat or prevent opioid-induced respiratory depression. Green circles indicate effective reversal/prevention or ability to reverse an apneic event; red circles indicate ineffective reversal/prevention or inability to reverse an apneic event; gray circles indicate that no studies have been published.
Irrespective of mechanism, all countermeasures, apart from sequestration techniques, have in common that their goal is the pharmacologic strengthening or reactivation of rhythmogenesis within the respiratory neuronal network by providing tonic input to the respiratory neurons that remain depressed by the opioids due to their enduring presence within the network. The main conclusion of our scoping review is that, compared to naloxone, most if not all of these medical countermeasures are insufficiently viable to be used in daily clinical practice to treat an acute high-dose (synthetic) opioid-induced respiratory depression that causes apnea, let alone to successfully address mass casualties from public health or military events due to the release of potent high-affinity opioids such as carfentanil in the environment. There are various reasons why these therapeutic or preventive interventions fail. The main reason lies within the respiratory neuronal network itself in that, as long as respiratory drive is depressed due to activation of the μ-opioid receptor system, the degree of activity that is being generated by nonopioid stimulants is insufficient to overcome depression of respiratory neurons in, for example, the pre-Bötzinger and parabrachial/Kölliker–Fuse complexes, two small brain areas with high respiratory sensitivity to opioids.[3–5,90] Baertsch et al. showed that opioids have a dual mechanism of opioid-induced respiratory depression at the pre-Bötzinger complex within the inspiratory rhythm-generating network (Figure 1). While stimulants such as ampakines may compensate one mechanism, i.e., opioid-induced impairment of excitatory presynaptic neurotransmission, they are unable to compensate the second mechanism, i.e., opioid-induced intrinsic hyperpolarization of respiratory neurons. Consequently, the overall efficacy of ampakines may be limited and only be useful in case of low-dose opioid-induced mild to moderate respiratory depression. Additionally, due to their specific mechanism of action, some drugs act at the Kölliker–Fuse complex, while others target the pre-Bötzinger complex, with a net insufficient effect on severe respiratory depression leading to apnea. This applies to most stimulants with possibly the exception of the nicotinic acetylcholine receptor agonists, which are able to overcome opioid-induced apnea, at least in rodents.[32,33] Stimulants that act at the carotid bodies are limited in their ability to reverse opioid-induced apnea due to a ceiling in afferent input from the carotid body to the respiratory network in the brainstem. In summary, it is evident from recent experimental data and our systematic review that at higher opioid doses, the level at which the disruption of the respiratory rhythmogenesis is restored by reversal agents or respiratory stimulants is limited.[3–5] An additional reason for therapy failure may be that an insufficient amount of drug reaches the brainstem respiratory neurons. While the mechanism of action may be appropriate, this pharmacokinetic drawback may be overcome by designing more lipophilic reversal agents that readily cross the blood–brain barrier. This may, for example, apply to serotonin receptor agonists. Approaches that sequester opioid molecules within the bloodstream will effectively lower the opioid load within the brainstem respiratory network. While this is a desired mechanism under some circumstances, these countermeasures are still insufficiently tested with respect to efficacy, speed of onset and offset, and safety.
Considering these limitations, we suggest altering current research approaches and initiating research programs that specifically test drug combinations. Ren et al. already showed that combining the nicotinic acetylcholine receptor agonist varenicline with low-dose naloxone overcomes fentanyl-induced apnea. As stated earlier, this interaction of two drugs with different modes of action may serve as a model for other drug combinations that separately show limited or partial reversal of opioid respiratory depression but in combination might be highly potent with synergistic excitatory effects on respiration. Several combinations come to mind such as low-dose naloxone in combination with nicotinic acetylcholine receptor agonists, ampakines, or drugs acting at the carotid bodies. Particularly when opioids are overdosed in combination with other depressants, the combination of stimulants may be more effective. Whether low-dose naloxone needs to be part of such drug combinations requires further study, as possibly other combinations are viable as well.
Given the immediate need for alternatives to current therapy, the U.S. National Institute of Allergy and Infectious Diseases/National Institutes of Health (Bethesda, Maryland) recently (August 2019) organized a 2-day transagency scientific meeting and discussed the development of novel medical countermeasures and treatment strategies to mitigate opioid-induced respiratory toxicity. One of the goals of the meeting was to provide a forum for networking and collaborative partnership. We encourage such collaborations aimed at optimizing treatment in the reversal and prevention of opioid-induced respiratory depression.
Support was provided from institutional and/or departmental sources. This work is part of the research project Tackling and Preventing the Opioid Epidemic (TAPTOE). This research received funding from the Dutch Research Council (NWO; The Hague, The Netherlands) in the framework of the NWA-ORC Call (NWA.1160.18.300).
Anesthesiology. 2022;136(4):618-632. © 2022 American Society of Anesthesiologists | Lippincott Williams & Wilkins