Kozer Eran, Levichek Zina, Hoshino Noriko, Kapur Bhushan, Leombruno John, Taguchi Nobuko, Garcia-Bournissen Facundo, Koren Gideon, Ito Shinya
Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
Anesth Analg. 2008 Oct;107(4):1216-22. doi: 10.1213/ane.0b013e31817e6e53.
Severe exacerbation of chronic neuropathic pain often requires morphine in patients already treated with drugs such as tricyclic antidepressants, carbamazepine and gabapentin. However, it is unclear if a combination of these drugs intensifies the effects of morphine on the respiratory system and, if so, whether these effects are due to pharmacokinetic or pharmacodynamic interaction.
We gave rabbits (n=6 per group) the following drugs daily for 4 days: subcutaneous normal saline 1 mL (control); amitriptyline subcutaneously 7 mg/kg; carbamazepine orally 100 mg/kg; gabapentin subcutaneously 25 mg/kg; and all three drugs concurrently (combination). On the fifth day, morphine 5 mg/kg was given IV, and Paco2, Pao2 and pH were measured. Morphine, morphine 3-glucoronide and morphine 6-glucoronide concentrations were measured in the plasma over the 4 h period after morphine injection.
Compared with controls, premorphine baseline Paco2 was significantly higher (P<0.05) in the amitriptyline group. Postmorphine Paco2 was significantly higher in the amitriptyline and combination groups at all time points over the 240 min, and in the gabapentin group at 10 and 30 min after morphine injection (P<0.05). Peak Paco2 was significantly higher in the amitriptyline group (58.4+/-1.6 mm Hg; mean SD, P<0.005) and in the combination group (57.4+/-1.0 mm Hg, P<0.02) than in the control group (50.2+/-5.2 mm Hg). Similarly, the area under the curve of Paco2 from zero to 240 min was significantly higher in the amitriptyline and combination groups than in the control (P<0.001). There were no significant differences among the groups in plasma concentrations of morphine and its metabolites.
We conclude that pretreatment with amitriptyline increases morphine- induced hypercarbia through pharmacodynamic processes. The effects of carbamazepine or gabapentin were not obvious in this model.
慢性神经性疼痛的严重加剧通常需要对已经接受过三环类抗抑郁药、卡马西平和加巴喷丁等药物治疗的患者使用吗啡。然而，尚不清楚这些药物的联合使用是否会增强吗啡对呼吸系统的作用，如果是，这些作用是否归因于药代动力学或药效学相互作用。
我们每天给兔子（每组6只）服用以下药物，持续4天：皮下注射1 mL生理盐水（对照组）；皮下注射阿米替林7 mg/kg；口服卡马西平100 mg/kg；皮下注射加巴喷丁25 mg/kg；以及同时给予所有三种药物（联合用药组）。在第5天，静脉注射5 mg/kg吗啡，并测量动脉血二氧化碳分压（Paco2）、动脉血氧分压（Pao2）和pH值。在注射吗啡后的4小时内测量血浆中吗啡、吗啡-3-葡萄糖醛酸苷和吗啡-6-葡萄糖醛酸苷的浓度。
与对照组相比，阿米替林组吗啡注射前的基线Paco2显著更高（P<0.05）。在注射吗啡后的240分钟内，阿米替林组和联合用药组的吗啡注射后Paco2在所有时间点均显著更高，加巴喷丁组在注射吗啡后10分钟和30分钟时Paco2显著更高（P<0.05）。阿米替林组（58.4±1.6 mmHg；均值±标准差，P<0.005）和联合用药组（57.4±1.0 mmHg，P<0.02）的Paco2峰值显著高于对照组（50.2±5.2 mmHg）。同样，从0到240分钟的Paco2曲线下面积在阿米替林组和联合用药组中显著高于对照组（P<0.001）。各组之间吗啡及其代谢物的血浆浓度无显著差异。
我们得出结论，阿米替林预处理通过药效学过程增加了吗啡诱导的高碳酸血症。在该模型中，卡马西平或加巴喷丁的作用不明显。
