Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers
Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers
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DOI：
10.1093/bja/ael344
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发表时间：
2007-02-01
影响因子：
9.8
通讯作者：
Koppert, W.
中科院分区：
文献类型：
--
作者：
Chizh, B. A.;Goehring, M.;Koppert, W.
背景。中枢致敏是神经性疼痛的重要机制；它的人体模型可能有助于早期检测新疗法的疗效。电痛觉过敏模型通过反复刺激皮肤引起中枢致敏。为了评估其预测价值，我们研究了普瑞巴林（一种标准的神经性疼痛治疗药物）和阿瑞吡坦（一种NK1拮抗剂），作为一类在动物模型中有效但在神经性疼痛患者中无效的药物。此外，我们还探讨了这两种药物与COX-2抑制剂帕瑞昔布（parecoxib）合用是否能提高其疗效。这是一项双盲，两期，安慰剂对照研究，采用不完全块设计。32名健康志愿者在测试前6天接受口服普瑞巴林（滴定至300毫克）或阿瑞吡坦（滴定至320毫克），或匹配安慰剂。在3小时内评估致敏性；在2小时，受试者接受帕瑞昔布（40 mg）或生理盐水静脉注射。与安慰剂相比，普瑞巴林显著减少了点状机械性痛觉过敏和动态触觉异常性痛的面积（P < 0.0001）；与安慰剂相比，阿瑞吡坦没有显著减少痛觉过敏或异常性痛的面积。在普瑞巴林+帕瑞昔布治疗组中，与安慰剂+帕瑞昔布相比，异常性疼痛的面积显著减少（P < 0.0001），痛感过敏的面积不显著减少（P=0.09）；阿瑞吡坦+帕瑞昔昔组疗效无明显改善。该模型可用于预测人类早期发育的镇痛效果，探讨其作用机制。该模型还可用于探索镇痛药物组合的疗效，为患者研究提供依据。
Background. Central sensitization is an important mechanism of neuropathic pain; its human models could be useful for early detection of efficacy of novel treatments. The electrical hyperalgesia model invokes central sensitization by repetitive stimulation of the skin. To assess its predictive value, we have investigated pregabalin, a standard neuropathic pain treatment, and aprepitant, an NK1 antagonist, as an example of a drug class active in animal models but not in neuropathic pain patients. Furthermore, we explored if combinations of either of these drugs with the COX-2 inhibitor parecoxib could improve its efficacy.Methods. This was a double-blind, two-period, placebo-controlled study using incomplete block design. Thirty-two healthy volunteers received either oral pregabalin (titrated to 300 mg) or aprepitant (titrated to 320 mg), or matching placebo over 6 days before testing. Sensitization was assessed over 3 h; at 2 h, subjects received either parecoxib (40 mg) or saline i.v.Results. Pregabalin significantly reduced the areas of punctate mechanical hyperalgesia and dynamic touch allodynia vs placebo (both P < 0.0001); no significant reduction in the area of hyperalgesia or allodynia vs placebo was observed with aprepitant. In the pregabalin+parecoxib treated group, the area of allodynia was significantly reduced (P < 0.0001) and the area of hyperalgesia insignificantly attenuated (P=0.09) vs placebo+parecoxib; no efficacy improvement was observed with aprepitant+parecoxib.Conclusions. The model can serve to predict analgesic efficacy in early human development and investigate the mechanism of action. The model could also be used to explore efficacy of analgesic combinations to provide a rationale for patient studies.