A slow-release opioids drug system for postoperative pain relief

硬膜外腔注射阿片类药物缓释剂对术后病人的镇痛效果可达3 ~ 4天，是非常方便和实用的。含有阿片类药物的共聚物糊剂是提供更有效和更方便的术后镇痛手段的可能性之一，为了检查这种可能性以及硬膜外给药的旧阿片类药物羟考酮的安全性，羟考酮是最近在美国使用的口服缓释片剂，我们已经进行了大鼠实验并发现向脑桥网状结构中施用羟考酮不会引起任何镇静和镇痛作用，但它的脊髓给药引起了强烈的镇痛作用。Charbacol，毒蕈碱激动剂，产生镇痛作用时，既进入脑桥和脊髓蛛网膜下腔。由于吗啡影响MAPK激酶的磷酸化，我们使用PC 12细胞系检测了羟考酮的这种作用，发现羟考酮不影响MAPK激酶的活化。然后，我们进行了临床研究，以检查硬膜外羟考酮在60例术后患者的效果后，批准与人类调查委员会。我们发现硬膜外注射羟考酮对术后疼痛同样有效，但副作用如恶心和呕吐较少，虽然我们不能制备可用于硬膜外给药的阿片样物质缓释溶液，但即使将这种阿片样物质缓释溶液单次注射到硬膜外腔中，也可提供3-4天的延长镇痛。由于一家制药公司最近开始生产这种具有缓释特性的可注射阿片类药物，因此研究新的可注射阿片类药物给药系统将是有希望的。

It would be very convenient and practical that a slow release of opioid injected into the epidural space is able to be effective for 3〜4 days in postoperative patients. A copolymer paste containing opioid is such one possibility to provide more effective and convenient mean for postoperative analgesia.To examine such possibility as well as safety of epidural administration of an old opioid, oxycodone which, with oral slow releasing tablet, has recently been used in the US, we have done rats' experiments and found that oxycodone administered into the pontine reticular formation did not cause any sedative and analgesic effect, but its spinal administration caused a potent analgesia. Charbacol, a muscarinic agonist, produced analgesic action when administered both into the pontine and into the spinal subarachnoid space. Since morphine affects phosphorylation of MAPK kinase, we examined such effects of oxycodone using PC12 cell line and found that oxycodone did not affect activation of MAPK kinase. Then we have done clinical studies to examine effect of epidural oxycodone in 60 postoperative patients after approving with the human investigation committee. We found that epidural oxycodone is similarly effective for postoperative pain with less side effects such as nausea and vomiting.Although we could not be able to make a slow releasing solution of opioid which is available for epidural administration, it would provide a prolong analgesia for 3-4 days even with a single injection of such slow release of opioid into the epidural space. Since a drug company has recently started to make such injectable opioid with slow releasing property, research for a new drug-delivery system for injectable opioid would be promising.