Filitz Jörg, Ihmsen Harald, Günther Werner, Tröster Andreas, Schwilden Helmut, Schüttler Jürgen, Koppert Wolfgang
Department of Anesthesiology, University Hospital Erlangen, Krankenhausstraße 12, D-91054 Erlangen, Germany.
Pain. 2008 Jun;136(3):262-270. doi: 10.1016/j.pain.2007.06.036. Epub 2007 Aug 20.
The combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non-opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/-4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra-additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics.
联合使用具有不同药理特性的镇痛药可能疗效更好且副作用更少。本研究的目的是在人体实验性疼痛模型中，研究弱阿片类药物曲马多和非阿片类药物对乙酰氨基酚单独及联合使用时的镇痛和抗痛觉过敏特性。经当地伦理委员会批准，17名健康志愿者参与了这项采用交叉设计的双盲、安慰剂对照研究。高电流密度（29.6±16.2 mA）的经皮电刺激诱发了自发性急性疼痛（数字评分法[NRS]=10分中的6分）以及对疼痛性机械刺激（针刺性痛觉过敏）的明显痛觉过敏区域。在静脉输注对乙酰氨基酚（650 mg）、曲马多（75 mg）、两者组合（325 mg对乙酰氨基酚和37.5 mg曲马多）或0.9%生理盐水15分钟期间及之后150分钟内，评估疼痛强度以及痛觉过敏区域的范围，评估在输注前、输注期间及输注后进行。曲马多使疼痛最大程度降低了11.7±4.2%，抗痛觉过敏特性可忽略不计。相比之下，对乙酰氨基酚导致了类似的疼痛降低（9.8±4.4%），但有持续的抗痛觉过敏作用（痛觉过敏区域减少34.5±14.0%）。与单独使用对乙酰氨基酚相比，两种镇痛药半量联合使用导致疼痛超相加性降低15.2±5.7%，并增强了抗痛觉过敏作用（痛觉过敏区域减少41.1±14.3%）。我们的研究首次提供了曲马多和对乙酰氨基酚对人体实验性疼痛和痛觉过敏相互作用的结果。药效学建模结合等效应线图技术显示，对乙酰氨基酚和曲马多联合使用在镇痛和抗痛觉过敏方面均有超相加效应。这些结果可能为联合使用这两种镇痛药提供理论依据。
