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


Thyrotropin-releasing Hormone Receptor Agonists

Thyrotropin-releasing hormone is predominantly produced in the hypothalamus. It regulates the release of thyroid-stimulating hormone and prolactin from the pituitary gland. Thyrotropin-releasing hormone mediates its effects by binding to the G-protein–coupled thyrotropin-releasing hormone receptor that is ubiquitously expressed in the brain and in peripheral tissues, indicative of a broad functionality.[23] Thyrotropin-releasing hormone has a dose-dependent excitatory effect on breathing activity that coincides with an increase in blood pressure and heart rate and is able to overcome opioid-induced respiratory depression in various species including nonhuman primates.[24,25]

Exogenously administered thyrotropin-releasing hormone has evident neuroendocrine effects, has a short half-life of less than 5 min, and poorly passes the blood–brain barrier due its low lipophilicity. Various analogs have been developed with an improved therapeutic selectivity and a longer duration of action. One such analog is taltirelin, which is registered in Japan for treatment of spinal cerebral degeneration.[26] In a series of experiments, Cotten's research group studied the effect of thyrotropin-releasing hormone and taltirelin on opioid-induced respiratory depression in the rat.[26,27] Intravenous thyrotropin-releasing hormone and taltirelin reversed morphine-induced respiratory depression in the isoflurane-anesthetized rat. Reversal was due to an effect on respiratory rate, which exceeded premorphine respiratory rates by 200 to 300% after treatment with thyrotropin-releasing hormone or taltirelin.[26] While taltirelin normalized blood gas values, thyrotropin-releasing hormone decreased arterial carbon dioxide concentration but failed to normalize arterial oxygen concentrations; taltirelin caused lactic acidosis. Interestingly, also after intratracheal administration, thyrotropin-releasing hormone caused rapid reversal of morphine-induced respiratory depression. Overall, these data indicate that thyrotropin-releasing hormone and taltirelin cause rapid, shallow breathing after morphine administration in the anesthetized rat.[26] As stated by the investigators, this pattern of breathing is undesired because of increased dead space ventilation and a high probability of atelectasis and ensuing hypoxia. Possibly the inability to correct arterial oxygen concentration and development of lactic acidosis may be related to increased work of breathing, which causes anaerobic metabolism, reduced oxygen uptake, or both.

In a second set of experiments, Dandrea and Cotten tested the effect of intravenous taltirelin on morphine- and sufentanil-induced respiratory depression in conscious rats.[27] Similar to the experiments in anesthetized rats, taltirelin reversed respiratory depression by an increase in respiratory rate. Blood gas analysis revealed the inability to restore arterial oxygen concentration and worsening of lactic acidosis. The two studies by Cotten and coworkers suggest that the state of inhalational anesthesia allows for an improved reversal of opioid toxicity due to some muscle relaxation and reduced oxygen consumption due to anesthesia-suppressed metabolism. This is an important observation and warrants further study in awake animals and humans.

In an exploratory study, we tested the effect of a bolus and continuous infusion of thyrotropin-releasing hormone in six human volunteers after remifentanil-induced respiratory depression (A. Dahan, 2021, verbal communication). In intravenous doses ranging from 0.8 to 8 mg, which corresponds to a maximum dose of 0.1 mg/kg, thyrotropin-releasing hormone did not reverse remifentanil-induced respiratory depression. The dose range was based on earlier human studies that showed respiratory stimulation at 0.4 mg thyrotropin-releasing hormone. Further studies have to explore higher doses of thyrotropin-releasing hormone in humans. Finally, in a rat model of hemorrhagic shock, thyrotropin-releasing hormone improved circulatory and respiratory functions, but due to the release of acid metabolites, it worsened acidosis.[28] This may hamper the utility of thyrotropin-releasing hormone in patients with compromised organ perfusion.

Oxytocin Receptor Agonists

Another hypothalamic hormone, which has been studied for its ability to reverse opioid-induced respiratory depression, is the neuropeptide oxytocin.[29] In chloralose/urethane anesthetized, paralyzed, vagotomized, 100% oxygen-ventilated rats, the effect of intravenous oxytocin and the nonpeptide oxytocin receptor agonist and weak vasopressin receptor antagonist WAY-267464 were assessed on phrenic nerve activity after a fentanyl dose sufficient to silence phrenic nerve activity. Oxytocin displayed a bell-shaped response curve in its ability to reverse phrenic nerve activity with maximal reversal at low dose but absence of reversal at high dose. The return of respiratory depression was related to cross-activation of vasopressin receptors at high oxytocin levels, possibly from activation of the baroreceptor reflex by high blood pressure. Blockade of the vasopressin receptor during oxytocin exposure by the vasopressin receptor-1a receptor antagonist V1aRX resulted in reversal of opioid respiratory depression at high-dose oxytocin. Interestingly, similar to the ampakines and esketamine, oxytocin receptor activation without opioid exposure did not stimulate breathing. However, there are reports that oxytocin ameliorates respiratory rates in patients with sleep-disordered breathing.[30] The mechanism through which oxytocin stimulates opioid-depressed respiratory activity remains unknown. Oxytocin is a positive allosteric modulator of the μ-opioid receptor and enhances μ-opioid receptor signaling induced by fentanyl and other opioids.[31] While this suggests that opioid respiratory depression would be worsened by oxytocin, its respiratory excitatory effects at oxytocin receptors within the brainstem respiratory network seem to overcome such a negative effect. Whether oxytocin is able to reverse opioid-induced respiratory depression in humans overdosed on potent opioids remains unknown and may be hampered by oxytocin's bell-shaped response curve and the limited and slow passage of oxytocin across the blood–brain barrier. Further studies into WAY-267464 are warranted as this drug does not seem to have these same restrictions.

Nicotinic Acetylcholine Receptor Agonists

Nicotinic acetylcholine receptors are expressed within the respiratory network in the brainstem and are present in carotid bodies. These receptors are made up of subunits, and those present within respiratory networks contain subunits α4, α7, and β2.[1] Ren et al. studied the effect of nicotinic acetylcholine receptor agonists and partial agonists on their ability to rescue rats from opioid-induced respiratory depression.[32,33] Selective α4β2 nicotinic acetylcholine receptor agonist A85380 (but not α7 nicotinic acetylcholine receptor agonist PNU282987) did not have an effect on ventilation by itself, but countered respiratory depression induced by fentanyl in conscious adult rats; the effect was by increasing respiratory rate.[32] Additionally, A85380 reduced apnea duration and increased ventilation after remifentanil infusion. Importantly, the α4β2 nicotinic acetylcholine receptor agonist was antinociceptive and enhanced fentanyl analgesia. In an independent study by Dandrea and Cotten, A85380 was unable to reverse opioid-induced toxicity, but this may be dose-related.[27]

In a next study, Ren et al.[33] showed that using two partial α4β2 nicotinic acetylcholine receptor agonists, varenicline, which was developed for the treatment of nicotine addiction, and ABT954, which is under development for the treatment of diabetic peripheral neuropathic pain, countered fentanyl-induced respiratory depression. Similar to A85380, varenicline and ABT954 increased respiratory rate but not tidal volume. This is probably related to the muscle rigidity induced by opioids, which affects tidal volume, which is not alleviated by the nicotinic acetylcholine receptor agonists. Varenicline combined with low-dose naloxone (1 μg/kg) was able to overcome lethal apneas induced by high-dose fentanyl whereas either drug on its own, at the same doses, was unable to initiate breathing after fentanyl. This indicates a synergistic interaction between naloxone and varenicline. ABT954 on its own was able to reinitiate respiratory activity after high-dose fentanyl. Finally, both nicotinic acetylcholine receptor agonists were able to overcome lethal apneas after the combination of fentanyl and diazepam.[33]

Combined, these data provide strong evidence that α4β2 nicotinic acetylcholine receptor (partial) agonists effectively counter opioid-induced respiratory depression in conscious rats. The observation that analgesia is enhanced or not reduced and the fact that these drugs have a long half-life are advantages over naloxone. Further studies in humans using the clinically available varenicline will shed light on its efficacy in opioid overdose victims and whether the drug has a stimulatory effect on tidal volume as well as on respiratory rate. Furthermore, the combined use of naloxone and varenicline is promising and may serve as a model for the use of low-dose naloxone combined with other respiratory stimulants that show limited or partial reversal of opioid-induced respiratory depression.