Countering opioid-induced respiratory depression by non-opioids that are respiratory stimulants

Strong opioid analgesics are the mainstay of therapy for the relief of moderate to severe acute nociceptive pain that may occur post-operatively or following major trauma, as well as for the management of chronic cancer-related pain. Opioid-related adverse effects include nausea and vomiting, sedation, respiratory depression, constipation, tolerance, and addiction/abuse liability. Of these, respiratory depression is of the most concern to clinicians owing to the potential for fatal consequences. In the broader community, opioid overdose due to either prescription or illicit opioids or co-administration with central nervous system depressants may evoke respiratory depression. To address this problem, there is ongoing interest in the identification of non-opioid respiratory stimulants to reverse opioid-induced respiratory depression but without reversing opioid analgesia. Promising compound classes evaluated to date include those that act on a diverse array of receptors including 5-hydroxytryptamine, D 1-dopamine, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) receptor antagonists, and nicotinic acetylcholine as well as phosphodiesterase inhibitors and molecules that act on potassium channels on oxygen-sensing cells in the carotid body. The aim of this article is to review recent advances in the development potential of these compounds for countering opioid-induced respiratory depression.


Introduction
Although the incidence of opioid-induced respiratory depression in the post-operative setting is low, it is of major concern to clinicians because of the potential for fatal consequences when clinical monitoring is inadequate. Of additional concern is the large increase in opioid-related deaths over the past decade due to respiratory depression, particularly in overdose and in individuals consuming other central nervous system depressants such as sedatives and alcohol 1 . The opioids may have been prescribed for the management of chronic pain or they may have been obtained through diversion of prescribed opioids or by illicit means. Opioid-related deaths due to respiratory depression have risen in parallel with the marked increase in opioid consumption, particularly in the United States of America, over this period 2 . Disturbingly, chronic opioid use accounts for an estimated 24% of central sleep apnea that can go unnoticed and be fatal without appropriate intervention 3 . Apart from strategies aimed at risk mitigation by reducing clinical opioid administration, drug discovery programs have been aimed at discovering a new generation of opioids that retain potent analgesic activity but with less respiratory depression 4-6 . Another strategy, which is the subject of this review, is to identify respiratory stimulant molecules for potential co-administration with an opioid analgesic to counter opioid-related respiratory depression whilst sparing opioid analgesia.

Recent advances in countering opioid-induced respiratory depression
Classes of molecules showing promising preclinical and/or clinical results to date include ampakines, 5-hydroxytryptamine (5-HT) receptor agonists, phosphodiesterase-4 inhibitors, D 1dopamine receptor agonists, nicotinic acetylcholine receptor agonists, acetylcholine esterase inhibitors, bradykinin receptor antagonists, N-methyl-D-aspartate (NMDA) receptor antagonists, protein kinase A inhibitors, G-protein-gated inwardly rectifying potassium channel (GIRK) blockers, α 2 -adrenoceptor antagonists, and chemoreceptor stimulants (see summary in Table 1). For a more detailed discussion, see the excellent review by Dahan and colleagues 2 . Herein, we have focused only on the most recent research on these experimental respiratory stimulants.
Ampakines are positive allosteric modulators of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, which has a key role in the maintenance of respiratory drive in the pre-Botzinger complex and other central nervous system sites 2 . In both animals and humans, ampakines stimulate respiratory drive, particularly under hypoventilatory conditions 2 . CX717 is one of two ampakines tested in humans that have been shown to partially reverse alfentanil-induced respiratory depression 7 . The other, CX1739, has been assessed in a phase 2 clinical trial for its capacity to antagonize remifentanil-induced respiratory depression; however, the results are not published as yet (ClinicalTrials.gov; Identifier: NCT02735629). Apart from evoking respiratory stimulation, ampakines augment morphine-induced antinociception in rats, showing the utility of combining an opioid with an ampakine to produce potent pain relief but with a superior respiratory safety profile compared with an equi-analgesic dose of morphine alone 8 . More recently, single intravenous (i.v.) bolus doses of the ampakine LCX001 prevented and reversed fentanyl-induced respiratory depression in rats by strengthening respiratory frequency and minute ventilation whilst maintaining opioid analgesia 9 . Encouragingly, i.v. LCX001 also produced dose-dependent antinociception in rats 9 .
In other work, i.v. administration of either nicotine or the α4β2 nicotinic acetylcholine receptor agonist A85380, but not the α7 nicotinic acetylcholine receptor agonist PNU282987, rapidly reversed fentanyl-induced respiratory depression and apnea in rats in a manner comparable to i.v. dosing with the opioid receptor antagonist naloxone 10 . Additionally, i.v. A85380 potentiated fentanyl-induced antinociception in rats consistent with earlier work showing that agonists of the nicotinic α4β2 receptor evoke antinociception 10 . Furthermore, A85380 had a modest effect on fentanyl-induced sedation in rats 10 . Remifentanil is a highly potent respiratory depressant that is particularly difficult to reverse by either a low dose of naloxone or an ampakine in a recent clinical trial 11 . Thus, the finding that i.v. remifentanil-induced apnea was markedly reduced by co-administration of i.v. A85380 is of particular interest 10 . The respiratory protective effects of A85380 appear to be underpinned by the fact that the nicotinic acetylcholine receptor subunits α4 and β2 are expressed by the medullary respiratory network and activation of α4β2 receptors increases respiratory rhythm 10 . Additionally, α4β2 receptors are present in the carotid bodies and so they may also potentially contribute to the respiratory stimulant effects of A85380 10 . The water solubility of A85380 like naloxone, together with its much longer half-life at approximately 7 hours compared with 15-30 minutes for naloxone 10 , support the progression of this compound towards clinical trials.
Doxapram is widely used in veterinary practice to reverse opioid-induced respiratory depression. In goats, i.v. doxapram reduced etorphine-induced respiratory depression by rapid reversal of all respiratory parameters except tidal volume 12 . In adult humans, doxapram is used to reverse respiratory depression post-anesthesia by direct input on brainstem centers with differential effects on the pre-Botzinger complex and the downstream motor output (XII) 13 . In preterm infants with apnea of prematurity insensitive to caffeine treatment, doxapram infusion significantly reduced apnea episodes primarily by its effect on respiratory drive rather than on respiratory muscle 14 . Interestingly, the molecular mechanism underpinning the respiratory stimulant effects of doxapram is restricted to the positive enantiomer and involves inhibition of human TWIK-related acid-sensitive K + -channels (TASK), in particular TASK-1 and TASK-3 channels that are expressed in the carotid body 15,16 .
Recent work in anaesthetized rabbits has shed new light on the mechanism by which 5-HT receptor agonists stimulate respiratory parameters, including minute ventilation, respiratory rate, and tidal volume 17 . Specifically, bilateral microinjection of 5-HT caused excitatory activity of the pre-Botzinger complex via a mechanism mediated by 5-HT 1A and 5-HT 3 receptors 17 . Other pharmacological classes assessed for their ability to blunt opioid-induced respiratory depression include PKA inhibitors, GIRK inhibitors, and thyrotropin-releasing hormone (TRH) analogs. Specifically, fentanyl-induced respiratory depression was attenuated in unrestrained rats by intracerebroventricular (i.c.v.) bolus doses of the PKA inhibitor H89 36 and by the GIRK inhibitor tertiapin-Q 36 . In anaesthetized rats, TRH and its long-acting analog, taltirelin, evoked a marked increase in respiratory rate, tidal volume, and blood oxygenation after i.v. co-administration with morphine 43 .
In a proof-of-concept clinical study in healthy human subjects, i.v. infusion of the NMDA receptor antagonist esketamine at a subanesthetic dose dose-dependently reversed respiratory depression induced by i.v. remifentanil 35 . This was underpinned by a stimulatory effect on ventilatory CO 2 chemosensitivity that was otherwise reduced by remifentanil alone 35 . The esketamine effect had a rapid onset of action and it was driven by plasma pharmacokinetics 35 . By contrast, esketamine had little or no effect on resting ventilation. Of concern, however, is that two of 14 subjects withdrew from the study owing to the psychotomimetic side-effects of esketamine 35 .

Conclusions
The US opioid epidemic has focused attention on the discovery of respiratory stimulants to reverse opioid-induced respiratory depression whilst sparing opioid analgesia. Although progress has been made, most studies have been confined to the preclinical setting. Very few molecules have entered clinical development, and there are currently no ongoing clinical trials of respiratory stimulants registered on ClinicalTrials.gov (accessed 5 December 2019). Hence, considerable work remains before respiratory stimulant molecules with promising preclinical and/or human data become available for use in clinical practice. apnea in the anesthetized rat by drugs that activate 5-hydroxytryptamine 1A receptors. J Pharmacol Exp Ther. 2000; 292(2): 704-13. PubMed Abstract