García-Hernández Liliana, Déciga-Campos Myrna, Guevara-López Uriah, López-Muñoz Francisco Javier
Departamento de Farmacobiología, Cinvestav-Sede Sur, México D.F., México.
Pharmacol Biochem Behav. 2007 Aug-Sep;87(3):331-40. doi: 10.1016/j.pbb.2007.05.007. Epub 2007 May 21.
Over the decades, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. In order to assess a possible antinociceptive interactions, the antinociceptive effects of rofecoxib p.o., a preferential inhibitor of cyclooxygenase-2, and tramadol-hydrochloride p.o., an atypical opioid analgesic, administered either separately or in combination, were determined using a rat model of arthritic pain. The data were interpreted using the surface of synergistic interaction (SSI) analysis and an isobolographic analysis to establish the nature of the interaction. The SSI was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Female rats received orally rofecoxib alone (1.0, 1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg), tramadol alone (1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg) or 12 different combinations of rofecoxib plus tramadol. Five combinations exhibited various degrees of sub-additive (i.e. less than the sum of the effects produced by the each drug alone) antinociceptive effects (3.2 mg/kg tramadol with 7.8 mg/kg rofecoxib; 5.6 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib; 10.0 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib), whereas the other 7 combinations showed additive antinociceptive effects (i.e. the sum of the effects produced by each agent alone). Three combination of rofecoxib+tramadol (10.0+5.6, 10.0+10.0, and 17.8+5.6 mg/kg respectively) presented high sub-additive interactions (P<0.002: Q=9.5). The combination rofecoxib (17.8 mg/kg)+tramadol (10.0 mg/kg) caused gastric injuries less severe than those observed with indomethacin, but more severe than those obtained with rofecoxib or tramadol in single administration. The antinociceptive interaction of rofecoxib and tramadol suggests that combinations with these drugs may have no clinical utility in pain therapy.
几十年来，非甾体抗炎药（NSAIDs）和阿片类药物是治疗急慢性疼痛最常用的镇痛药。为了评估可能的抗伤害感受相互作用，使用关节炎疼痛大鼠模型，测定了口服环氧化酶-2的选择性抑制剂罗非昔布和非典型阿片类镇痛药盐酸曲马多单独给药或联合给药时的抗伤害感受作用。使用协同相互作用表面（SSI）分析和等效应线图分析来解释数据，以确定相互作用的性质。SSI是通过组合药物产生的总抗伤害感受作用减去每种药物单独产生的抗伤害感受作用来计算的。雌性大鼠口服单独的罗非昔布（1.0、1.8、3.2、5.6、10.0、17.8、31.6和56.2mg/kg）、单独的曲马多（1.8、3.2、5.6、10.0、17.8、31.6和56.2mg/kg）或罗非昔布加曲马多的12种不同组合。五种组合表现出不同程度的次相加（即小于每种药物单独产生的效应之和）抗伤害感受作用（3.2mg/kg曲马多与7.8mg/kg罗非昔布；5.6mg/kg曲马多与10.0或17.8mg/kg罗非昔布；10.0mg/kg曲马多与10.0或17.8mg/kg罗非昔布），而其他7种组合表现出相加抗伤害感受作用（即每种药物单独产生的效应之和）。罗非昔布+曲马多的三种组合（分别为10.0+5.6、10.0+10.0和17.8+5.6mg/kg）呈现出高度次相加相互作用（P<0.002：Q=9.5）。罗非昔布（17.8mg/kg）+曲马多（10.0mg/kg）组合引起的胃损伤比吲哚美辛引起的损伤轻，但比罗非昔布或曲马多单次给药引起的损伤重。罗非昔布和曲马多的抗伤害感受相互作用表明，这些药物的组合在疼痛治疗中可能没有临床应用价值。
