Research and Development, Orion Corporation Orion Pharma, P.O.Box 425, 20101, Turku, Finland.
Department of Anesthesiology, University of California, 9500 Gilman Drive, San Diego, CA, 92093, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Aug;393(8):1459-1473. doi: 10.1007/s00210-020-01850-0. Epub 2020 Mar 16.
An α-adrenoceptor agonist, clonidine, is extensively used in both anesthesia and intensive care medicine. However, clonidine may produce pronounced hemodynamic side effects such as hypotension and bradycardia which may limit its usefulness in certain conditions. Fadolmidine is a potent α-adrenoceptor agonist with different physicochemical properties than clonidine. Here, the effects of fadolmidine and clonidine on analgesia (an increase in thermal skin twitch response latency), sedation, blood pressure, heart rate, respiratory rate, and body temperature were evaluated either up to 8 h after either intrathecal or epidural bolus injections or during a 24-h continuous intrathecal infusion at equipotent analgesic doses in non-anesthetized Beagle dogs. Fadolmidine and clonidine produced a dose-dependent and equipotent maximal antinociception after intrathecal bolus injection (ED: 67 μg and 78 μg, respectively), but the duration of action of fadolmidine was more long-lasting. During the intrathecal infusion, fadolmidine achieved a good analgesic effect without evoking cardiovascular side effects, e.g., hypotension; these were evident during clonidine infusion. Epidurally, the antinociceptive potency of fadolmidine was weaker (ED: 128 μg) than when intrathecally administered and weaker than that of epidural clonidine (ED: 51 μg). At analgesic doses, fadolmidine injection induced moderate initial hypertension concomitantly with a decrease in heart rate whereas clonidine evoked hypotension and bradycardia. These results suggest that especially when non-opioid long-term pain relief is needed, an intrathecal infusion of fadolmidine can provide long-term antinociception with less of the known use-limiting adverse effects associated with clonidine.
α-肾上腺素受体激动剂可乐定被广泛应用于麻醉和重症监护医学。然而，可乐定可能会产生明显的血流动力学副作用，如低血压和心动过缓，这可能限制了其在某些情况下的应用。法多芬是一种强效的α-肾上腺素受体激动剂，其理化性质与可乐定不同。在这里，我们评估了法多芬和可乐定对镇痛（热皮 twitch 反应潜伏期延长）、镇静、血压、心率、呼吸频率和体温的影响，这些影响是在鞘内或硬膜外推注后长达 8 小时内，或在非麻醉比格犬中以等效镇痛剂量连续鞘内输注 24 小时时评估的。鞘内推注后，法多芬和可乐定产生剂量依赖性和等效的最大抗伤害作用（ED：分别为 67μg 和 78μg），但法多芬的作用持续时间更长。在鞘内输注期间，法多芬在不引起心血管副作用（如低血压）的情况下实现了良好的镇痛效果，而在可乐定输注期间则出现了这些副作用。硬膜外，法多芬的镇痛作用强度较弱（ED：128μg），弱于鞘内给药，也弱于硬膜外可乐定（ED：51μg）。在镇痛剂量下，法多芬注射会引起初始中度高血压，同时伴有心率下降，而可乐定会引起低血压和心动过缓。这些结果表明，特别是当需要非阿片类长期缓解疼痛时，鞘内输注法多芬可以提供长期的镇痛作用，同时减少与可乐定相关的已知限制使用的不良反应。
