Newly Published
Pain Medicine  |   January 2020
Countering Opioid-induced Respiratory Depression in Male Rats with Nicotinic Acetylcholine Receptor Partial Agonists Varenicline and ABT 594
Author Notes
  • From the Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
  • Submitted for publication July 5, 2019. Accepted for publication December 17, 2019.
    Submitted for publication July 5, 2019. Accepted for publication December 17, 2019.×
  • Correspondence: Address correspondence to Dr. Greer: 3-020M Katz Building, Department of Physiology, University of Alberta, Edmonton, AB, Canada T6G 2S2. john.greer@ualberta.ca. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Pain Medicine / Pharmacology / Respiratory System / Opioid
Pain Medicine   |   January 2020
Countering Opioid-induced Respiratory Depression in Male Rats with Nicotinic Acetylcholine Receptor Partial Agonists Varenicline and ABT 594
Anesthesiology Newly Published on January 28, 2020. doi:https://doi.org/10.1097/ALN.0000000000003128
Anesthesiology Newly Published on January 28, 2020. doi:https://doi.org/10.1097/ALN.0000000000003128
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Activation of α4β2 nicotinic acetylcholine receptors by the full agonist A83580 markedly reduced opioid-induced respiratory depression in rats without compromising analgesia

  • Varenicline, which is used to treat smoking addiction, and ABT 594, which produced analgesia in trials of patients with diabetic peripheral neuropathic pain, are potent, partial agonists of α4β2 nicotinic acetylcholine receptors

What This Article Tells Us That Is New:

  • Pre- or coadministration of varenicline or ABT 594 with opioids markedly reduced the degree of respiratory depression they caused in rats

  • Varenicline and ABT 594 reversed moderate to severe respiratory depression produced by fentanyl without interfering with opioid-induced suppression of pain

  • Administration of ABT 594 and varenicline coadministered with a low dose of naloxone reversed respiratory depression and prevented death caused by a bolus lethal dose of fentanyl or the combination of fentanyl and diazepam

Background: Opioids can induce significant respiratory depression when administered as analgesics for the treatment of acute, postoperative, and chronic pain. There are currently no pharmacologic means of reversing opioid-induced respiratory depression without interfering with analgesia. Further, there is a growing epidemic of opioid overdose that could benefit from therapeutic advancements. The aim of this study was to test the ability of two partial agonists of α4β2 nicotinic acetylcholine receptors, varenicline (used clinically for smoking cessation) and ABT 594 (tebanicline, developed as an analgesic), to reduce respiratory depression induced by fentanyl, remifentanil, morphine, and a combination of fentanyl and diazepam.

Methods: Whole body plethysmographic recordings, nociception testing, and righting reflex testing were used to examine ventilation, analgesia, and sedation in adult male Sprague–Dawley rats.

Results: Pre-, co-, or postadministration of varenicline or ABT 594 did not alter baseline breathing but markedly reduced opioid-induced respiratory depression. Varenicline had no effect on fentanyl-induced analgesia and ABT 594 potentiated fentanyl-induced analgesia. Specifically, 10-min administration of fentanyl induced a decrease in respiratory rate to 43 ± 32% of control in vehicle group, which was alleviated by preadministration of varenicline (85 ± 14% of control, n = 8, P < 0.001) or ABT 594 (81 ± 36% of control, n = 8, P = 0.001). ABT 594 or varenicline with a low dose of naloxone (1 µg/kg), but not varenicline alone, partially reversed fentanyl-induced lethal apnea, but neither compound provided the very rapid and complete reversal of apnea achieved with high doses of naloxone (0.03 to 1 mg/kg). Administration of varenicline (n = 4, P = 0.034) or ABT 594 (n = 4, P = 0.034) prevented lethal apneas induced by the combination of fentanyl and diazepam.

Conclusions: Activation of α4β2 nicotinic acetylcholine receptors by varenicline and ABT 594 counters opioid-induced respiratory depression without interfering with analgesia.