From the Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
Anesthesiology. 2020 May;132(5):1197-1211. doi: 10.1097/ALN.0000000000003128.
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.
Whole body plethysmographic recordings, nociception testing, and righting reflex testing were used to examine ventilation, analgesia, and sedation in adult male Sprague-Dawley rats.
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.
Activation of α4β2 nicotinic acetylcholine receptors by varenicline and ABT 594 counters opioid-induced respiratory depression without interfering with analgesia.
阿片类药物在治疗急性、术后和慢性疼痛时作为镇痛药使用时，可引起明显的呼吸抑制。目前，还没有在不干扰镇痛作用的情况下逆转阿片类药物引起的呼吸抑制的药物治疗方法。此外，阿片类药物过量的流行呈上升趋势，这可能得益于治疗方法的进步。本研究旨在测试两种α4β2 烟碱型乙酰胆碱受体部分激动剂伐伦克林（用于临床戒烟）和 ABT-594（替巴尼克林，开发为一种镇痛药）减少芬太尼、瑞芬太尼、吗啡和芬太尼与地西泮联合引起的呼吸抑制的能力。
使用全身 plethysmographic 记录、伤害感受测试和翻正反射测试来检查成年雄性 Sprague-Dawley 大鼠的通气、镇痛和镇静作用。
伐伦克林或 ABT-594 的预、共或后给药均不改变基础呼吸，但明显减轻了阿片类药物引起的呼吸抑制。伐伦克林对芬太尼引起的镇痛没有影响，而 ABT-594 增强了芬太尼引起的镇痛作用。具体来说，10 分钟给予芬太尼可使对照组呼吸频率降低至 43 ± 32%，预先给予伐伦克林（85 ± 14%对照组，n = 8，P < 0.001）或 ABT-594（81 ± 36%对照组，n = 8，P = 0.001）可缓解。ABT-594 或伐伦克林与低剂量纳洛酮（1μg/kg）联合使用，但单独使用伐伦克林，部分逆转了芬太尼引起的致死性呼吸暂停，但这两种化合物都没有达到高剂量纳洛酮（0.03 至 1mg/kg）实现的非常快速和完全的呼吸暂停逆转。给予伐伦克林（n = 4，P = 0.034）或 ABT-594（n = 4，P = 0.034）可预防芬太尼与地西泮联合引起的致死性呼吸暂停。
伐伦克林和 ABT-594 激活α4β2 烟碱型乙酰胆碱受体可对抗阿片类药物引起的呼吸抑制，而不干扰镇痛作用。
