Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
Anesthesiology. 2010 Jun;112(6):1417-27. doi: 10.1097/ALN.0b013e3181d5e29d.
Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist-antagonist interaction, the effects of various naloxone doses on morphine and morphine-6-glucuronide (M6G)-induced respiratory depression were studied in healthy volunteers.
Twenty-four subjects received 0.15 mg/kg morphine intravenously at t = 0 followed by placebo, 200 or 400 microg naloxone at t = 30 min. Thirty-two subjects received 0.3 mg/kg M6G intravenously at t = 0 followed by placebo, 25, 100, or 400 microg naloxone at t = 55 min. There were a total of 8 subjects per treatment group. Respiration was measured on a breath-to-breath basis at constant end-tidal Pco2. A mechanism-based pharmacokinetic-pharmacodynamic model consisting of a part describing biophase equilibration and a part describing receptor association-dissociation kinetics was used to analyze the data.
Naloxone reversal of M6G-induced respiratory depression developed more slowly than reversal of the respiratory effect of morphine. A simulation study revealed that this was related to the slower receptor association-dissociation kinetics of M6G (koff M6G = 0.0327 +/- 0.00455 min versus morphine 0.138 +/- 0.0148 min; values are typical +/-SE). Duration of naloxone reversal was longer for M6G. This was related to the three- to fourfold greater potency of naloxone as an antagonist against M6G compared with morphine. Increasing the naloxone dose had no effect on the speed of reversal, but it did extend reversal duration.
Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration.
阿片类药物引起的呼吸抑制可被竞争性阿片受体拮抗剂纳洛酮有效拮抗。然而，为了充分了解复杂的阿片类激动剂-拮抗剂相互作用，研究了在健康志愿者中，纳洛酮的不同剂量对吗啡和吗啡-6-葡萄糖醛酸（M6G）引起的呼吸抑制的影响。
24 名受试者在 t=0 时静脉注射 0.15mg/kg 吗啡，然后在 t=30 分钟时给予安慰剂、200 或 400μg 纳洛酮。32 名受试者在 t=0 时静脉注射 0.3mg/kg M6G，然后在 t=55 分钟时给予安慰剂、25、100 或 400μg 纳洛酮。每个治疗组共有 8 名受试者。在恒定的终末 Pco2 下，通过呼吸到呼吸的方式测量呼吸。使用包含描述生物相平衡和描述受体结合-解离动力学的部分的基于机制的药代动力学-药效学模型来分析数据。
纳洛酮逆转 M6G 引起的呼吸抑制的速度比逆转吗啡呼吸作用的速度慢。一项模拟研究表明，这与 M6G 较慢的受体结合-解离动力学有关（koff M6G=0.0327+/-0.00455min 与吗啡 0.138+/-0.0148min；值为典型+/-SE）。纳洛酮逆转 M6G 的持续时间更长。这与纳洛酮作为拮抗剂对 M6G 的效力比吗啡大三到四倍有关。增加纳洛酮剂量对逆转速度没有影响，但确实延长了逆转持续时间。
纳洛酮逆转阿片类药物效应取决于需要逆转的阿片类药物的受体结合-解离动力学与逆转速度的关系。纳洛酮的药效学决定了逆转的幅度和持续时间。
