From the Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington (M.J.E., C.C.G., T.N.K., C.S., G.W.T.); and Pulmonary and Critical Care Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (M.J.E.).
Anesthesiology. 2016 Apr;124(4):945-57. doi: 10.1097/ALN.0000000000000997.
Opioid-related deaths are a leading cause of accidental death, with most occurring in patients receiving chronic pain therapy. Respiratory arrest is the usual cause of death, but mechanisms increasing that risk with increased length of treatment remain unclear. Repeated administration produces tolerance to opioid analgesia, prompting increased dosing, but depression of ventilation may not gain tolerance to the same degree. This study addresses differences in the degree to which chronic morphine (1) produces tolerance to ventilatory depression versus analgesia and (2) alters the magnitude and time course of ventilatory depression.
Juvenile rats received subcutaneous morphine for 3 days (n = 116) or vehicle control (n = 119) and were then tested on day 4 following one of a range of morphine doses for (a) analgesia by paw withdraw from heat or (b) respiratory parameters by plethysmography-respirometry.
Rats receiving chronic morphine showed significant tolerance to morphine sedation and analgesia (five times increased ED50). When sedation was achieved for all animals in a dose group (lowest effective doses: opioid-tolerant, 15 mg/kg; opioid-naive, 3 mg/kg), the opioid-tolerant showed similar magnitudes of depressed ventilation (-41.4 ± 7.0%, mean ± SD) and hypercapnic response (-80.9 ± 15.7%) as found for morphine-naive (-35.5 ± 16.9% and -67.7 ± 15.1%, respectively). Ventilation recovered due to tidal volume without recovery of respiratory rate or hypercapnic sensitivity and more slowly in morphine-tolerant.
In rats, gaining tolerance to morphine analgesia does not reduce ventilatory depression effects when sedated and may inhibit recovery of ventilation.
阿片类药物相关死亡是意外死亡的主要原因，大多数发生在接受慢性疼痛治疗的患者中。呼吸骤停通常是死亡的原因，但增加治疗时间会增加这种风险的机制尚不清楚。重复给药会产生阿片类镇痛药的耐受，促使增加剂量，但通气抑制可能不会产生相同程度的耐受。这项研究探讨了慢性吗啡（1）产生通气抑制耐受与镇痛耐受的程度差异，以及（2）改变通气抑制的程度和时间过程。
幼年大鼠接受皮下吗啡治疗 3 天（n = 116）或载体对照（n = 119），然后在第 4 天接受一系列吗啡剂量中的一种，通过（a）热爪退缩测试来评估镇痛，或（b）通过体积描记-呼吸描记术来评估呼吸参数。
接受慢性吗啡治疗的大鼠表现出对吗啡镇静和镇痛的显著耐受（五倍增加 ED50）。当在一个剂量组中所有动物都达到镇静状态时（最低有效剂量：阿片类药物耐受，15mg/kg；阿片类药物未耐受，3mg/kg），阿片类药物耐受组表现出类似的通气抑制程度（-41.4 ± 7.0%，平均值 ± SD）和高碳酸血症反应（-80.9 ± 15.7%），与阿片类药物未耐受组（-35.5 ± 16.9%和-67.7 ± 15.1%）相似。通气恢复由于潮气量而没有恢复呼吸频率或高碳酸血症敏感性，并且在吗啡耐受组中恢复更慢。
在大鼠中，获得吗啡镇痛耐受不会降低镇静时的通气抑制作用，并且可能抑制通气的恢复。
