van der Schier Rutger, Roozekrans Margot, van Velzen Monique, Dahan Albert, Niesters Marieke
Department of Anesthesiology, Anesthesia & Pain Research Unit, Leiden University Medical Center Building 1, Postzone P05-Q, P.O. Box 9600, 2300 RC Leiden The Netherlands.
F1000Prime Rep. 2014 Sep 4;6:79. doi: 10.12703/P6-79. eCollection 2014.
The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality. One possible way of prevention of OIRD is by adding a respiratory stimulant to the opioid treatment, which through activation of non-opioidergic pathways will excite breathing and consequently will offset OIRD and should not affect analgesia. Various new respiratory stimulants are currently under investigation including (a) potassium channel blockers acting at the carotid bodies, and (b) ampakines and (c) serotonin receptor agonists acting within the brainstem. (a) GAL-021 targets BKCa-channels. Initial animal and human experimental evidence indicates that this potassium channel blocker is a potent respiratory stimulant that reverses OIRD without affecting antinociception. GAL021 is safe and better tolerated than the older K(+)-channel blocker doxapram and more efficacious in its effect on respiration. (b) Ampakines modulate glutamatergic respiratory neurons in brainstem respiratory centers. Various ampakines have been studied showing their ability to increase respiratory drive during OIRD by increasing respiratory rate. Currently, CX717 is the most promising ampakine for use in humans as it is safe and does not affect opioid analgesia. (c) While animal studies show that serotonin receptor agonists increase respiratory drive via activation of serotonin receptors in brainstem respiratory centers, human studies are without success. Further clinical studies are required to improve our care of patients that are treated with potent opioid analgesics. The use of non-opioid adjuvants may reduce the probability of OIRD but does never relieve us of our duty to continuously monitor these patients, irrespective whether they are treated in-house or in an ambulatory setting.
人体严重依赖通气控制系统来充分摄取氧气和排出二氧化碳（CO2）。强效阿片类镇痛药通过作用于脑干呼吸神经元上表达的μ-阿片受体（MOR）来抑制通气。阿片类药物引起的呼吸抑制（OIRD）有潜在生命危险，是导致大量发病和死亡的原因。预防OIRD的一种可能方法是在阿片类药物治疗中添加呼吸兴奋剂，该兴奋剂通过激活非阿片能途径来兴奋呼吸，从而抵消OIRD，并且不应影响镇痛效果。目前正在研究各种新型呼吸兴奋剂，包括（a）作用于颈动脉体的钾通道阻滞剂，（b）安帕金，以及（c）作用于脑干内的5-羟色胺受体激动剂。（a）GAL-021作用于大电导钙激活钾通道（BKCa通道）。最初的动物和人体实验证据表明，这种钾通道阻滞剂是一种强效呼吸兴奋剂，可逆转OIRD而不影响镇痛作用。GAL021比旧的钾通道阻滞剂多沙普仑更安全、耐受性更好，对呼吸的作用更有效。（b）安帕金调节脑干呼吸中枢中的谷氨酸能呼吸神经元。已经研究了多种安帕金，显示它们在OIRD期间通过增加呼吸频率来增加呼吸驱动力的能力。目前，CX717是用于人体最有前景的安帕金，因为它安全且不影响阿片类药物镇痛。（c）虽然动物研究表明5-羟色胺受体激动剂通过激活脑干呼吸中枢中的5-羟色胺受体来增加呼吸驱动力，但人体研究未取得成功。需要进一步的临床研究来改善我们对接受强效阿片类镇痛药治疗患者的护理。使用非阿片类佐剂可能会降低OIRD的可能性，但无论患者是在住院还是门诊环境中接受治疗，我们都绝不能免除持续监测这些患者的责任。
