Meert T F, De Kock M
Janssen Research Foundation, Department Neuropsychopharmacology, Beerse, Belgium.
Anesthesiology. 1994 Sep;81(3):677-88. doi: 10.1097/00000542-199409000-00022.
Data on the analgesic properties of alpha 2 agonists and their interactions with opioids are conflicting. Experiments were conducted in rats to evaluate whether various available alpha 2 agonists can potentiate the analgesic properties of opioids and to determine the route of administration needed for optimal interaction.
The tail-withdrawal reaction test was used as an analgesia assay. In separate experiments, the interactions between systemic (subcutaneous, intravenous, and intraperitoneal) and spinally (epidural and intrathecal) administered alpha 2 agonists and opioids were evaluated. The antagonism of medetomidine plus fentanyl with naloxone and/or idazoxan also was studied.
All alpha 2 agonists tested, when injected subcutaneously with fentanyl, potentiated the opioid-induced analgesia. In terms of a reduction of the amount of fentanyl needed to produce a deep surgical analgesia (tail-withdrawal reaction latency > or = 10 s) over more than 2 h, the relative order of potency of the alpha 2 agonists tested was: medetomidine > dexmedetomidine > xylazine > clonidine > detomidine. For some of these alpha 2 agonists there was a biphasic effect: at the larger doses tested, a reduction in the fentanyl potentiation was present. The potentiation of the opioid activity with alpha 2 agonists was also demonstrated in terms of a longer duration of analgesia after combined treatment with fixed doses of opioids. The interaction between the alpha 2 agonists and the opioids remained present when a more profound criterion of analgesia (tail-withdrawal reaction latency > or = 30 s) was used. Furthermore, the interactions between the alpha 2 agonists tested and fentanyl or sufentanil appeared to be independent of the route of administration. Potentiations were observed after simultaneous subcutaneous injections of both groups of compounds, after the combination of intraperitoneal (alpha 2 agonist) plus subcutaneous (opioid), intravenous (alpha 2 agonist) plus epidural (opioid) and simultaneous epidural or intrathecal administrations. With regard to antagonism of the analgesic activity of combined treatment with alpha 2 agonists plus opioids, naloxone provided total antagonism, whereas the alpha 2 antagonist idazoxan overcame only the alpha 2 agonist-induced potentiation of fentanyl.
The tested alpha 2 agonists can potentiate the analgesic properties of opioids, but they have no intrinsic antinociceptive effects on spinal reflexes on their own. The potentiating activities of the alpha 2 agonists could be measured both in terms of a reduction of the amount of opioid needed to reach a particular level of analgesia and in terms of a longer duration of analgesia with a fixed dose of the opioid. The potentiations were observed with various alpha 2 agonists and opioids and appeared independent of the routes of administration.
关于α2激动剂的镇痛特性及其与阿片类药物的相互作用的数据存在冲突。在大鼠中进行了实验，以评估各种可用的α2激动剂是否能增强阿片类药物的镇痛特性，并确定实现最佳相互作用所需的给药途径。
采用甩尾反应试验作为镇痛测定方法。在单独的实验中，评估了全身（皮下、静脉内和腹腔内）和脊髓（硬膜外和鞘内）给予的α2激动剂与阿片类药物之间的相互作用。还研究了美托咪定加芬太尼与纳洛酮和/或咪唑克生的拮抗作用。
所有测试的α2激动剂与芬太尼皮下注射时，均增强了阿片类药物诱导的镇痛作用。就减少产生超过2小时深度手术镇痛（甩尾反应潜伏期≥10秒）所需的芬太尼量而言，所测试的α2激动剂的相对效价顺序为：美托咪定＞右美托咪定＞赛拉嗪＞可乐定＞地托咪定。对于其中一些α2激动剂存在双相效应：在测试的较大剂量下，芬太尼增强作用减弱。与固定剂量阿片类药物联合治疗后，从镇痛持续时间更长方面也证明了α2激动剂对阿片类药物活性的增强作用。当使用更严格的镇痛标准（甩尾反应潜伏期≥30秒）时，α2激动剂与阿片类药物之间的相互作用仍然存在。此外，所测试的α2激动剂与芬太尼或舒芬太尼之间的相互作用似乎与给药途径无关。在两组化合物同时皮下注射后观察到增强作用，腹腔内（α2激动剂）加皮下（阿片类药物）、静脉内（α2激动剂）加硬膜外（阿片类药物）联合以及同时硬膜外或鞘内给药后也观察到增强作用。关于α2激动剂加阿片类药物联合治疗的镇痛活性的拮抗作用，纳洛酮提供了完全拮抗作用，而α2拮抗剂咪唑克生仅克服了α2激动剂诱导的芬太尼增强作用。
所测试的α2激动剂可增强阿片类药物的镇痛特性，但它们自身对脊髓反射没有内在的抗伤害感受作用。α2激动剂的增强活性可以通过减少达到特定镇痛水平所需的阿片类药物量以及固定剂量阿片类药物镇痛持续时间更长来衡量。在各种α2激动剂和阿片类药物中均观察到增强作用，且似乎与给药途径无关。
