Keywords
opioid, respiratory depression, respiratory stimulant, ampakine, allosteric modulator, NMDA receptor antagonist, 5-HT1a, 5-HT3
opioid, respiratory depression, respiratory stimulant, ampakine, allosteric modulator, NMDA receptor antagonist, 5-HT1a, 5-HT3
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 depression4–6. 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.
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.
Pharmacological class | Molecule | Dose, route | Receptor/target interaction | Co-administered opioid (dose) | Species (strain/sex) | Effect | Reference |
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Ampakines | CX717 | 1,500 mg, oral | AMPA | Alfentanil (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. | AMPA | Fentanyl (60 µg/kg, i.v.) | Rat (SD) | ↑ Respiratory frequency; ↑ oxygen saturation | 19 | ||
15 mg/kg, i.v. | AMPA | Fentanyl (60 µg/kg, i.v.) | Rat (SD) | ↑ Respiratory frequency and amplitude | 20 | ||
CX546 | 16 mg/kg, i.p. | AMPA | Fentanyl | Rat (SD) | ↑ Respiratory frequency; ↑ burst amplitude; no effect on behavior or arousal state | 21 | |
15 mg/kg, i.p. | AMPA | Morphine (10 mg/kg, i.p.) | Rat (SD) | ↑ Respiratory rate; ↑ tidal volume; ↑ minute ventilation | 22 | ||
CX1942 | AMPA | Etorphine (0.1 mg/kg, i.v.) | Boer goat (Capra hircus) | ↑ Tidal volume; ↑ ventilation; ↑ PaO2; ↑ SaO2; ↓ PaCO2 | 12 | ||
LCX001 | 10 mg/kg, i.v. | AMPA | Fentanyl (120 μg/kg, s.c.) | Rat (SD) | ↑ Respiratory rate; ↑ minute ventilation | 9 | |
XD-8-17C | 1–30 mg/kg, i.v. | AMPA | TH-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 | |
Tianeptine | 2 and 10 mg/kg, i.p. | AMPA | Morphine (10 mg/kg, i.p.) | Rat (SD) | ↑ Respiratory rate; ↑ tidal volume; ↑ minute ventilation | 22 | |
5-HT agonists | Buspirone | 50 µg/kg, i.v. | 5-HT1A | Morphine (21.3 ± 2.1 mg/kg, i.v.) | Rat (SD) | Counteracted morphine-induced apnea | 24 |
Repinotan | 10 and 20 μg/kg, i.v. | 5-HT1A | Remifentanil (2.5 µg/kg, i.v.) | Rat (SD) | ↑ Minute ventilation | 25 | |
Befiradol | 0.2 mg/kg | 5-HT1A | Fentanyl (60 μg/kg, i.v.) | Rat (SD) | ↑ Respiratory frequency; ↑ tidal volume; ↑ minute ventilation | 26 | |
BIMU8 | 1–2 mg/kg, systemic | 5-HT4A | Fentanyl (10–15 μg/kg, systemic) | Rat (SD) | ↑ Respiratory minute volume | 27 | |
8-OH-DPAT | 0.5 mg/kg, i.v. | 5-HT1A and 5-HT7 | Etorphine hydrochloride (0.06 mg/kg, i.m.) | Boer goat (Capra hircus) | ↓ Time to recumbency; ↑ respiratory rate; ↑ PaO2; ↓ PaCO2 | 28 | |
8-OH-DPAT | 10 or 100 µg/kg | 5-HT1A | Morphine (21.3 ± 2.1 mg/kg, i.v.) | Rat (SD) | Counteracted morphine-induced apnea | 24 | |
Zacopride | 0.5 mg/kg, i.v. | 5-HT4 | Etorphine hydrochloride (0.06 mg/kg, i.m.) | Boer goat (Capra hircus) | ↓ Time to recumbency; ↑ respiratory rate; ↑ PaO2; ↓ PaCO2 | 28 | |
Phosphodiesterase- 4 inhibitors | Caffeine | 20 mg/kg, i.v. | PDE4 | Morphine (0.4 mg/kg/ minute, i.v.) | Rat | ↑ Inspiratory time; ↓ respiratory rate | 29 |
3 and 10 mg/kg, i.v. | PDE4 | Morphine (1.0 mg/kg, i.v.) | Rat (WH) | Recovered prolongation and flattening effect on inspiratory discharge in the phrenic nerve by morphine | 30 | ||
Rolipram | 0.1 and 0.3 mg/kg, i.v. | PDE4 | Morphine (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-APB | 0.5–3 mg/kg | D1 | Fentanyl citrate (15–35 µg/kg) | Cat | Reversal of fentanyl-induced abolition of phrenic and vagus nerve respiratory discharges and firing of bulbar post-inspiratory neurons | 31 |
Dihydrexidine | 0.5–2.0 mg/kg | D1 | Fentanyl citrate (15–35 µg/kg) | Cat | Reversal of fentanyl-induced abolition of phrenic and vagus nerve respiratory discharges and firing of bulbar post-inspiratory neurons | 31 | |
SKF-38393 | 1.5–3 mg/kg | D1 | Fentanyl citrate (15–35 µg/kg) | Cat | Reversal of fentanyl-induced abolition of phrenic and vagus nerve respiratory discharges and firing of bulbar post-inspiratory neurons | 31 | |
BK-channel blocker | GAL021 | Stepped drug infusion | Carotid body | Alfentanil (stepped drug infusion) | Human –healthy | ↑ respiratory rate; ↑ tidal volume | 32 |
GAL021 | (0.6, 1.5, and 6.0 mg/ml; 0.04, 0.1, and 0.4 mg/kg/minute) | Carotid body | Morphine (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 body | Morphine (3–4 mg/kg, i.v.) | Cynomolgus monkeys | ↓ End-tidal carbon dioxide (ETCO2) | 33 | ||
Chemoreceptor stimulant | Almitrine | 0.03, 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 |
Doxapram | 1 mg/kg, i.v. | Carotid body | Etorphine (0.1 mg/kg, i.v.) | Boer goat (Capra hircus) | ↑ Respiratory frequency; ↑ ventilation; ↑ PaO2; ↑ SaO2; ↓ PaCO2 | 12 | |
Nicotinic acetylcholine receptor agonist | Nicotine | 0.6 mg/kg, s.c. | α4β2 | Fentanyl (35 µg/kg, s.c.) | Rat (SD) | ↑ respiratory frequency; ↑ tidal volume; ↑ minute ventilation; | 10 |
A85380 | 0.03 to 0.06 mg/kg, s.c. | α4β2 | Fentanyl (35 µg/kg, s.c.) | Rat (SD) | ↑ respiratory frequency; ↑ tidal volume; ↑ minute ventilation | 10 | |
N-methyl-D- aspartate receptor antagonist | Esketamine | 0.57 mg/kg, i.v., cumulative | NMDA | Remifentanil (0.1–0.5 ng/ml, i.v.) | Human – healthy | Stimulatory effect on ventilatory CO2 sensitivity | 35 |
Protein kinase A (PKA) inhibitor | H89 | 50 µg, i.c.v. | – | Fentanyl (60 µg/kg) | Rat (SD) | ↑ respiratory frequency; ↑ inspiratory time; ↓ expiratory time | 36 |
GIRK channel blocker | Tertiapin-Q | 0.5–2 µg, i.c.v. | – | Fentanyl (60 µg/kg) | Rat (SD) | ↑ respiratory frequency; ↑ inspiratory time | 36 |
Alpha 2- adrenoceptor antagonist | SK&F 86466 | 1 and 5 mg/kg, i.v. | α2-adrenoceptor | Dermorphin (30 or 100 pmol) | Rat (SD) | ↑ relative ventilator minute volume; ↑respiratory rate; ↓ CO2 production | 37 |
AChE inhibitor | Donepezil | 0.4 mg/kg, i.v. | Acetylcholinesterase | Morphine (2 mg/kg, i.v.) | Rabbit | ↑ Respiratory rate; ↑ respiratory amplitude; ↑ minute phrenic activity; ↓ phrenic nerve apnea threshold PaCO2 | 38 |
Donepezil | 0.4 mg/kg, i.v. | Acetylcholinesterase | Buprenorphine (0.02 mg/kg, i.v.) | Rabbit | ↑ Respiratory rate; ↑ respiratory amplitude; ↑ minute phrenic activity | 39 | |
RA6 | 1 mg i.v., 2 mg s.c. | Acetylcholinesterase | Morphine (8 mg, i.v.) | Rabbit | ↑ Respiratory rate; ↓ PaCO2 | 40 | |
RA7 | 1 or 2 mg, i.v. | Acetylcholinesterase | Morphine (8 mg, i.v.) | Rabbit | ↑ Respiratory rate; ↓ PaCO2 | 40 | |
RA15 | 0.25 or 0.5 mg, i.v. | Acetylcholinesterase | Morphine (8 mg, i.v.) | Rabbit | ↑ Respiratory rate; ↓ PaCO2 | 40 | |
Physostigmine | 0.05 or 0.1 mg, i.v. | Acetylcholinesterase | Morphine (8 mg, i.v.) | Rabbit | ↓ PaCO2 | 40 | |
Others | 4-aminopyridine | 0.25 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 neurons | Morphine (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 | |
Taltirelin | 1–2 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.
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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Competing Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
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