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

[version 1; peer review: 2 approved]
PUBLISHED 07 Feb 2020
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Abstract

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, D1-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.

Keywords

opioid, respiratory depression, respiratory stimulant, ampakine, allosteric modulator, NMDA receptor antagonist, 5-HT1a, 5-HT3

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 alcohol1. 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 period2. Disturbingly, chronic opioid use accounts for an estimated 24% of central sleep apnea that can go unnoticed and be fatal without appropriate intervention3. 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 depression46. 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, D1-dopamine 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, α2-adrenoceptor antagonists, and chemoreceptor stimulants (see summary in Table 1). For a more detailed discussion, see the excellent review by Dahan and colleagues2. Herein, we have focused only on the most recent research on these experimental respiratory stimulants.

Table 1. Summary of non-opioid molecules assessed for their ability to counter opioid-induced respiratory depression.

Pharmacological
class
MoleculeDose, routeReceptor/target
interaction
Co-administered opioid
(dose)
Species (strain/sex)EffectReference
AmpakinesCX7171,500 mg, oralAMPAAlfentanil (100 ng/ml
plasma concentration)
Human (males)↑ Respiratory frequency; ↑
hemoglobin oxygenation; less
decrease of slope of the linear
relationship between expiratory
volume/minute and CO2
concentration in expired air (in
hypercapnic challenge)
18
15 mg/kg, i.v.AMPAFentanyl (60 µg/kg, i.v.)Rat (SD)↑ Respiratory frequency; ↑
oxygen saturation
19
15 mg/kg, i.v.AMPAFentanyl (60 µg/kg, i.v.)Rat (SD)↑ Respiratory frequency and
amplitude
20
CX54616 mg/kg, i.p.AMPAFentanylRat (SD)↑ Respiratory frequency; ↑ burst
amplitude; no effect on behavior
or arousal state
21
15 mg/kg, i.p.AMPAMorphine (10 mg/kg, i.p.)Rat (SD)↑ Respiratory rate; ↑ tidal volume;
↑ minute ventilation
22
CX1942AMPAEtorphine (0.1 mg/kg, i.v.)Boer goat (Capra
hircus)
↑ Tidal volume; ↑ ventilation; ↑
PaO2; ↑ SaO2; ↓ PaCO2
12
LCX00110 mg/kg, i.v.AMPAFentanyl (120 μg/kg, s.c.)Rat (SD)↑ Respiratory rate; ↑ minute
ventilation
9
XD-8-17C1–30 mg/kg, i.v.AMPATH-030418 (acute death –
15 mg/kg, s.c.; respiration
– 20 µg/kg, i.v.)
Mouse (KM), rat (SD)Protection against acute
opioid-induced death; reversal
of depression of respiratory
parameters (respiratory
frequency, minute ventilation,
pO2, sO2) to normal; no effect on
morphine antinociception
23
Tianeptine2 and 10 mg/kg, i.p.AMPAMorphine (10 mg/kg, i.p.)Rat (SD)↑ Respiratory rate; ↑ tidal volume;
↑ minute ventilation
22
5-HT agonistsBuspirone50 µg/kg, i.v.5-HT1AMorphine (21.3 ± 2.1
mg/kg, i.v.)
Rat (SD)Counteracted morphine-induced
apnea
24
Repinotan10 and 20 μg/kg, i.v.5-HT1ARemifentanil (2.5 µg/kg,
i.v.)
Rat (SD)↑ Minute ventilation25
Befiradol0.2 mg/kg5-HT1AFentanyl (60 μg/kg, i.v.)Rat (SD)↑ Respiratory frequency; ↑ tidal
volume; ↑ minute ventilation
26
BIMU81–2 mg/kg, systemic5-HT4AFentanyl (10–15 μg/kg,
systemic)
Rat (SD)↑ Respiratory minute volume27
8-OH-DPAT0.5 mg/kg, i.v.5-HT1A and 5-HT7Etorphine hydrochloride
(0.06 mg/kg, i.m.)
Boer goat (Capra
hircus)
↓ Time to recumbency; ↑
respiratory rate; ↑ PaO2; ↓ PaCO2
28
8-OH-DPAT10 or 100 µg/kg5-HT1AMorphine (21.3 ± 2.1
mg/kg, i.v.)
Rat (SD)Counteracted morphine-induced
apnea
24
Zacopride0.5 mg/kg, i.v.5-HT4Etorphine hydrochloride
(0.06 mg/kg, i.m.)
Boer goat (Capra
hircus)
↓ Time to recumbency; ↑
respiratory rate; ↑ PaO2; ↓ PaCO2
28
Phosphodiesterase-
4 inhibitors
Caffeine20 mg/kg, i.v.PDE4Morphine (0.4 mg/kg/
minute, i.v.)
Rat↑ Inspiratory time; ↓ respiratory
rate
29
3 and 10 mg/kg, i.v.PDE4Morphine (1.0 mg/kg, i.v.)Rat (WH)Recovered prolongation and
flattening effect on inspiratory
discharge in the phrenic nerve by
morphine
30
Rolipram0.1 and 0.3 mg/kg,
i.v.
PDE4Morphine (1.0 mg/kg, i.v.)Rat (WH)Recovered prolongation and
flattening effect on inspiratory
discharge in the phrenic nerve by
morphine
30
D1-dopamine
receptor agonists
6-Chloro-APB0.5–3 mg/kgD1Fentanyl citrate (15–35
µg/kg)
CatReversal of fentanyl-induced
abolition of phrenic and vagus
nerve respiratory discharges and
firing of bulbar post-inspiratory
neurons
31
Dihydrexidine0.5–2.0 mg/kgD1Fentanyl citrate (15–35
µg/kg)
CatReversal of fentanyl-induced
abolition of phrenic and vagus
nerve respiratory discharges and
firing of bulbar post-inspiratory
neurons
31
SKF-383931.5–3 mg/kgD1Fentanyl citrate (15–35
µg/kg)
CatReversal of fentanyl-induced
abolition of phrenic and vagus
nerve respiratory discharges and
firing of bulbar post-inspiratory
neurons
31
BK-channel blockerGAL021Stepped drug
infusion
Carotid bodyAlfentanil (stepped drug
infusion)
Human –healthy↑ respiratory rate; ↑ tidal volume32
GAL021(0.6, 1.5, and 6.0
mg/ml; 0.04, 0.1, and
0.4 mg/kg/minute)
Carotid bodyMorphine (10 mg/kg, i.v.)Rat (SD)↑ Minute volume; ↑ tidal volume;
↑ PaO2; ↑ pH; ↓ PaCO2
33
5-minute load of 0.2
or 0.1 mg/kg/minute
i.v. + maintenance
infusion 0.1 or 0.05
mg/kg/minute
Carotid bodyMorphine (3–4 mg/kg, i.v.)Cynomolgus monkeys↓ End-tidal carbon dioxide (ETCO2)33
Chemoreceptor
stimulant
Almitrine0.03, 0.1 mg/kg/
minute, i.v.
Peripheral
chemoreceptors
Morphine (10 mg/kg, i.v.)Rat (SD)Normoxia: ↑ respiratory
frequency; ↑ tidal volume;
Hypoxia: ↓ respiratory frequency;
↑ tidal volume (0.03 mg/kg/
minute); ↓ tidal
volume (0.1 mg/
kg/minute)
34
Doxapram1 mg/kg, i.v.Carotid bodyEtorphine (0.1 mg/kg, i.v.)Boer goat (Capra
hircus)
↑ Respiratory frequency; ↑
ventilation; ↑ PaO2; ↑ SaO2; ↓
PaCO2
12
Nicotinic
acetylcholine
receptor agonist
Nicotine0.6 mg/kg, s.c.α4β2Fentanyl (35 µg/kg, s.c.)Rat (SD)↑ respiratory frequency; ↑ tidal
volume; ↑ minute ventilation;
10
A853800.03 to 0.06 mg/kg,
s.c.
α4β2Fentanyl (35 µg/kg, s.c.)Rat (SD)↑ respiratory frequency; ↑ tidal
volume; ↑ minute ventilation
10
N-methyl-D-
aspartate
receptor antagonist
Esketamine0.57 mg/kg, i.v.,
cumulative
NMDARemifentanil (0.1–0.5
ng/ml, i.v.)
Human – healthyStimulatory effect on ventilatory
CO2 sensitivity
35
Protein kinase A
(PKA) inhibitor
H8950 µg, i.c.v.Fentanyl (60 µg/kg)Rat (SD)↑ respiratory frequency; ↑
inspiratory time; ↓ expiratory time
36
GIRK channel
blocker
Tertiapin-Q0.5–2 µg, i.c.v.Fentanyl (60 µg/kg)Rat (SD)↑ respiratory frequency; ↑
inspiratory time
36
Alpha 2-
adrenoceptor
antagonist
SK&F 864661 and 5 mg/kg, i.v.α2-adrenoceptorDermorphin (30 or 100
pmol)
Rat (SD)↑ relative ventilator minute
volume; ↑respiratory rate; ↓ CO2
production
37
AChE inhibitorDonepezil0.4 mg/kg, i.v.AcetylcholinesteraseMorphine (2 mg/kg, i.v.)Rabbit↑ Respiratory rate; ↑ respiratory
amplitude; ↑ minute phrenic
activity; ↓ phrenic nerve apnea
threshold PaCO2
38
Donepezil0.4 mg/kg, i.v.AcetylcholinesteraseBuprenorphine (0.02
mg/kg, i.v.)
Rabbit↑ Respiratory rate; ↑ respiratory
amplitude; ↑ minute phrenic
activity
39
RA61 mg i.v., 2 mg s.c.AcetylcholinesteraseMorphine (8 mg, i.v.)Rabbit↑ Respiratory rate; ↓ PaCO240
RA71 or 2 mg, i.v.AcetylcholinesteraseMorphine (8 mg, i.v.)Rabbit↑ Respiratory rate; ↓ PaCO240
RA150.25 or 0.5 mg, i.v.AcetylcholinesteraseMorphine (8 mg, i.v.)Rabbit↑ Respiratory rate; ↓ PaCO240
Physostigmine0.05 or 0.1 mg, i.v.AcetylcholinesteraseMorphine (8 mg, i.v.)Rabbit↓ PaCO240
Others4-aminopyridine0.25 mg/kg, i.v.Potassium channel
blocker
Fentanyl (0.6–0.9 mg)Human↑ Respiratory rate; ↑ tidal volume;
↑ maximum occlusion pressure;
↓ PaCO2
41
Glycyl-L-
glutamine
1–100 nmol, i.c.v.Brainstem neuronsMorphine (40 nmol, i.c.v.)Rat (SD)Inhibited hypercapnia (PaCO2),
hypoxia (PaO2), and acidosis
(blood pH) evoked by morphine
42
Thyrotropin-
releasing
hormone
2–5 mg/kg, i.v., i.t.Morphine (5–15 mg/kg,
i.v.)
Rat (SD)↑ Respiratory rate; ↑ tidal volume;
↓ PaCO2
43
Taltirelin1–2 mg/kg, i.v., i.t.Morphine (5–15 mg/kg,
i.v.)
Rat (SD)↑ Respiratory rate; ↑ tidal volume;
↓ PaCO2; ↑ PaO2
43

5-HT, 5-hydroxytryptamine; α4β2, alpha-4 beta-2 nicotinic receptor; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; D1, dopamine receptor D1; GIRK, G-protein-gated inwardly rectifying potassium; i.c.v., intracerebroventricular; i.m., intramuscular; i.p., intraperitoneal; i.t., intrathecal; i.v., intravenous; KM, Kun Ming; NMDA, N-methyl-D-aspartate; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; PDE4, phosphodiesterase 4; PKA, protein kinase A; SaO2, oxygen saturation; s.c., subcutaneous; SD, Sprague Dawley; WH, Wistar Han.

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 sites2. In both animals and humans, ampakines stimulate respiratory drive, particularly under hypoventilatory conditions2. CX717 is one of two ampakines tested in humans that have been shown to partially reverse alfentanil-induced respiratory depression7. 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 alone8. 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 analgesia9. Encouragingly, i.v. LCX001 also produced dose-dependent antinociception in rats9.

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 naloxone10. Additionally, i.v. A85380 potentiated fentanyl-induced antinociception in rats consistent with earlier work showing that agonists of the nicotinic α4β2 receptor evoke antinociception10. Furthermore, A85380 had a modest effect on fentanyl-induced sedation in rats10. 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 trial11. Thus, the finding that i.v. remifentanil-induced apnea was markedly reduced by co-administration of i.v. A85380 is of particular interest10. 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 rhythm10. Additionally, α4β2 receptors are present in the carotid bodies and so they may also potentially contribute to the respiratory stimulant effects of A8538010. The water solubility of A85380 like naloxone, together with its much longer half-life at approximately 7 hours compared with 15–30 minutes for naloxone10, 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 volume12. 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 muscle14. 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 body15,16.

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 volume17. Specifically, bilateral microinjection of 5-HT caused excitatory activity of the pre-Botzinger complex via a mechanism mediated by 5-HT1A and 5-HT3 receptors17.

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 H8936 and by the GIRK inhibitor tertiapin-Q36. 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 morphine43.

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. remifentanil35. This was underpinned by a stimulatory effect on ventilatory CO2 chemosensitivity that was otherwise reduced by remifentanil alone35. The esketamine effect had a rapid onset of action and it was driven by plasma pharmacokinetics35. 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 esketamine35.

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.

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Imam MZ, Kuo A and Smith MT. Countering opioid-induced respiratory depression by non-opioids that are respiratory stimulants [version 1; peer review: 2 approved]. F1000Research 2020, 9(F1000 Faculty Rev):91 (https://doi.org/10.12688/f1000research.21738.1)
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
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Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
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Reviewer Report 07 Feb 2020
Frances Chung, Department of Anesthesia and Pain Management, University Health Network, University of Toronto, Toronto, Canada 
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Chung F. Reviewer Report For: Countering opioid-induced respiratory depression by non-opioids that are respiratory stimulants [version 1; peer review: 2 approved]. F1000Research 2020, 9(F1000 Faculty Rev):91 (https://doi.org/10.5256/f1000research.23964.r59473)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 07 Feb 2020
Albert Dahan, Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands 
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Dahan A. Reviewer Report For: Countering opioid-induced respiratory depression by non-opioids that are respiratory stimulants [version 1; peer review: 2 approved]. F1000Research 2020, 9(F1000 Faculty Rev):91 (https://doi.org/10.5256/f1000research.23964.r59472)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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