Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol
Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol
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DOI：
10.1016/j.clpt.2004.11.002
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发表时间：
2005-04-01
影响因子：
6.7
通讯作者：
Brosen, K
中科院分区：
文献类型：
--
作者：
Laugesen, S;Enggaard, TP;Brosen, K
目的：盐酸曲马多（Tramadol hydrochloride， INN, Tramadol）主要通过母体化合物介导的单胺能作用和o -去甲基化代谢物(+)-M1介导的阿片效应发挥其抗伤性作用。o -去甲基化由细胞色素P450 (CYP) 2D6催化。帕罗西汀是一种有效的CYP2D6抑制剂。本研究旨在探讨帕罗西汀预处理对曲马多生物转化及镇痛作用的影响。采用实验性疼痛模型，采用随机、双盲、安慰剂对照、四向交叉研究的方法，研究了在有和没有帕罗西汀预处理（每天20 mg，连续3天）的情况下，16例健康的斯帕汀广泛代谢物的M1的形成和150 mg曲马多的镇痛作用。经帕罗西汀预处理后，曲马多和(-)-曲马多的血浆浓度-时间曲线下面积（AUC）分别增加37% [P = .001]和32% [P = .002]。（+）-和(-)- m1对应的auc分别降低67% [P = .0004]和40% [P = .0008]。在整个研究期间，无论是否进行帕罗西汀预处理，所有受试者均可测定(+)- m1和(-)- m1。在安慰剂/曲马多组和安慰剂/安慰剂联合组中，用药后和用药前疼痛测量值的差异值的总数不同，中位数如下：压力疼痛耐受阈值为390 kPa(95%置信区间[CI]， 211 ~ 637 kPa) vs -84 kPa (95% CI, - 492 ~ -32 kPa) (P = .001)；单腓肠神经刺激疼痛耐受阈值，25.8 m-A (95% CI， 15.3至29.8 mA) vs 9.0 mA (95% CI， 1.5至14.8 mA) (P = 0.005)；疼痛累积阈值，10.7 mA (95% CI， 5.2至17.6 mA) vs 5.0 mA (95% CI， 2.8至11.2 mA) (P = 0.066)；冷压迫疼痛，-4.2 cm.s (95% CI, -6.8 ~ - 1.9 cm.s) vs -0.4 cm.s (-1.4 ~ 1.4 cm.s) (P = 0.002)；和不适，-4.7 cm (95% CI, -10.6至-2.8 cm) vs . 0.5 cm(-0.1至1.4 cm) （P = 0.002）。帕罗西汀/曲马多联合组与安慰剂/曲马多组在某些指标上的差异值也不同，中位数如下：冷压疼痛，-2.2 cm.s (95% CI, -3.7 ~ -0.4 cm.s) （P = 0.036，与安慰剂/曲马多组相比）；和不适，-2.0 cm (95% CI, -5.6至-1.2 cm) （P = 0.056）。对于其他措施，帕罗西汀/曲马多联合治疗的镇痛效果仍然存在，中位值如下：压痛耐受阈值为389 kPa (95% CI， 141至715 kPa) （P = 0.278，与安慰剂/曲马多相比）；单次腓肠神经刺激疼痛耐受阈值，12.5 mA (95% CI, 6.2 ~ 28.3 mA) (P = 0.278)；疼痛累积阈值为8.2 mA (95% CI, 4.4 ~ 14.6 mA) （P = 0.179）。帕罗西汀联合安慰剂无镇痛作用。由此得出结论，帕罗西汀剂量为20mg，每日一次，连续3天，可显著抑制曲马多对其活性代谢物M1的代谢，并可减少但不能消除曲马多在人体实验性疼痛模型中的镇痛作用，特别是在阿片类药物敏感试验中。
Objective: Tramadol hydrochloride (INN, tramadol) exerts its antinociceptive action through a monoaminergic effect mediated by the parent compound and an opioid effect mediated mainly by the O-demethylated metabolite (+)-M1. O-demethylation is catalyzed by cytochrome P450 (CYP) 2D6. Paroxetine is a very potent inhibitor of CYP2D6. The objective of this study was to investigate the influence of paroxetine pretreatment on the biotransformation and the hypoalgesic effect of tramadol.Methods. With and without paroxetine pretreatment (20 mg daily for 3 consecutive days), the formation of M1 and the analgesic effect of 150 mg of tramadol were studied in 16 healthy extensive metabolizers of sparteine in a randomized, double-blind, placebo-controlled, 4-way crossover study by use of experimental pain models.Results. With paroxetine pretreatment, the area under the plasma concentration-time curve (AUC) of and (-)-tramadol was increased (37% [P = .001] and 32% [P = .002]. respectively), and the corresponding AUCs of (+)- and (-)-M1 were decreased (67% [P = .0004] and 40% [P = .0008], respectively). (+)-M1 and (-)-M1 could be determined in all subjects throughout the study period regardless of paroxetine pretreatment. The sums of differences between postmedication and premedication values of pain measures differed between the placebo/tramadol and the placebo/placebo combination, with median values as follows: pressure pain tolerance threshold, 390 kPa (95% confidence interval [CI], 211 to 637 kPa) versus -84 kPa (95% CI, - 492 to -32 kPa) (P = .001); single sural nerve stimulation pain tolerance threshold, 25.8 m-A (95% CI, 15.3 to 29.8 mA) versus 9.0 mA (95% CI, 1.5 to 14.8 mA) (P = .005); pain summation threshold, 10.7 mA (95% CI, 5.2 to 17.6 mA) versus 5.0 mA (95% CI, 2.8 to 11.2 mA) (P = .066); cold pressor pain, -4.2 cm.s (95% CI, -6.8 to - 1.9 cm.s) versus -0.4 cm.s (-1.4 to 1.4 cm.s) (P = .002); and discomfort, -4.7 cm (95% CI, -10.6 to -2.8 cm) versus 0.5 cm (-0.1 to 1.4 cm) (P = .002). The sums of differences of the paroxetine/tramadol combination also differed from placebo/tramadol for some of the measures, with median values as follows: cold pressor pain, -2.2 cm.s (95% CI, -3.7 to -0.4 cm.s) (P = .036, compared with placebo/tramadol); and discomfort, -2.0 cm (95% CI, -5.6 to -1.2 cm) (P = .056). For the other measures, the hypoalgesic effect was retained on the paroxetine/tramadol combination, with median values as follows: pressure pain tolerance threshold, 389 kPa (95% CI, 141 to 715 kPa) (P = .278, compared with placebo/tramadol); single sural nerve stimulation pain tolerance threshold, 12.5 mA (95% CI, 6.2 to 28.3 mA) (P = .278); and pain summation threshold, 8.2 mA (95% CI, 4.4 to 14.6 mA) (P = .179). Paroxetine in combination with placebo showed no analgesic effect.Conclusions. It is concluded that paroxetine at a dosage of 20 mg once daily for 3 consecutive days significantly inhibits the metabolism of tramadol to its active metabolite M1 and reduces but does not abolish the hypoalgesic effect of tramadol in human experimental pain models, particularly in opioid-sensitive tests.