Goodchild Colin S, Kolosov Anton, Tucker Adam P, Cooke Ian
Department of Anaesthesia and Perioperative Medicine, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Pain Med. 2008 Oct;9(7):928-38. doi: 10.1111/j.1526-4637.2008.00514.x.
Flupirtine is an established clinical analgesic for mild to moderate musculoskeletal pain states. It has recently been shown to be a KCNQ2-3 potassium channel opener. These experiments were performed to see if this property could be useful in treating pain states characterized by central sensitization with the drug either given alone or in combination with morphine.
Experiments were performed in rats in an observer-blinded fashion with vehicle controls. Nonsedating doses of flupirtine, morphine, and combinations containing both drugs were defined using the rotarod test and open-field activity monitoring. Dose-response relationships were determined for nonsedating doses of both drugs given alone and together in combination in causing antinociception in two nociception paradigms: carrageenan paw inflammation and streptozotocin-induced diabetic neuropathy.
Flupirtine and morphine, when given alone at the highest nonsedating doses, caused slight to moderate antinociception in both paradigms. Flupirtine also caused significant increases in morphine antinociception in both models. In carrageenan paw inflammation, complete reversal of carrageenan-induced hyperalgesia was caused by 10 mg/kg flupirtine in combination with 0.4 mg/kg morphine. These doses of the two drugs were ineffective when given alone, but the combination caused complete antinociception in this model of inflammatory pain. In the diabetic neuropathy model, morphine 3.2 mg/kg given alone caused no significant antinociception. However, a lower dose of morphine (1.6 mg/kg shown to be ineffective when it was given alone) given in combination with flupirtine 10 mg/kg caused highly significant antinociceptive effects causing complete reversal of hyperalgesia caused by diabetic neuropathy (P < 0.001, one-way analysis of variance). This combination of drugs was not sedating.
Flupirtine increases morphine antinociception without causing an increase in sedation. Flupirtine should be investigated as an adjunct analgesic with opioids for the management of patients with pain states involving central sensitization.
氟吡汀是一种已获认可的用于治疗轻至中度肌肉骨骼疼痛状态的临床镇痛药。最近研究表明它是一种KCNQ2 - 3钾通道开放剂。进行这些实验是为了探究该特性在单独使用或与吗啡联合使用治疗以中枢敏化为特征的疼痛状态时是否有用。
以观察者盲法在大鼠中进行实验，并设置溶剂对照组。使用转棒试验和旷场活动监测来确定氟吡汀、吗啡以及含两种药物的组合的非镇静剂量。在两种伤害感受范式中确定单独使用和联合使用非镇静剂量的两种药物引起抗伤害感受的剂量 - 反应关系：角叉菜胶致爪部炎症和链脲佐菌素诱导的糖尿病性神经病变。
在两种范式中，氟吡汀和吗啡在最高非镇静剂量单独给药时，可引起轻微至中度的抗伤害感受。氟吡汀在两种模型中还显著增强了吗啡的抗伤害感受作用。在角叉菜胶致爪部炎症中，10 mg/kg氟吡汀与0.4 mg/kg吗啡联合使用可完全逆转角叉菜胶诱导的痛觉过敏。这两种药物单独给药时无效，但联合使用在该炎性疼痛模型中可引起完全的抗伤害感受。在糖尿病性神经病变模型中，单独给予3.2 mg/kg吗啡未引起显著的抗伤害感受。然而，较低剂量的吗啡（单独给药时无效的1.6 mg/kg）与10 mg/kg氟吡汀联合使用时产生了高度显著的抗伤害感受作用，并完全逆转了糖尿病性神经病变引起的痛觉过敏（P < 0.001，单因素方差分析）。该药物组合无镇静作用。
氟吡汀可增强吗啡的抗伤害感受作用而不增加镇静作用。对于涉及中枢敏化的疼痛状态患者，应研究氟吡汀作为阿片类药物辅助镇痛药的作用。
