Norketamine for Treatment of Pain

描述（由申请人提供）：慢性疼痛（癌症和非恶性）仍然是一个重要的医疗问题。其治疗，特别是慢性神经性疼痛，是一项特别具有挑战性的任务。用于治疗慢性神经性疼痛的药物和药物递送系统的开发是一项重要的奋进。一组可能用于神经性疼痛的药物是N-甲基-D天冬氨酸（NMDA）受体拮抗剂。这类药物也被证明可以增强吗啡的镇痛作用，并抑制对这种阿片类药物的耐受性。氯胺酮是一种临床上可用的非选择性NMDA受体拮抗剂，已用于胃肠外疼痛。尽管其镇痛效力，副作用（拟精神病，运动，镇静）限制了其使用。这些效应在胃肠外给药后显著，与血浆峰水平相关。透皮给药是一种最大限度地降低血浆峰浓度的给药方法，预计可提供更好的镇痛副作用。成功的经皮给药系统的理想候选者是具有低清除率的强效药物。氯胺酮的快速清除率使其成为经皮递送的不期望的候选物。然而，氯胺酮代谢为去甲氯胺酮。去甲氯胺酮是一种NMDA受体拮抗剂，具有镇痛活性。其清除率明显低于氯胺酮。因此，它代表了一个更好的候选透皮给药系统。在考虑用于透皮系统之前，需要评估去甲氯胺酮在神经性疼痛的临床前模型中的镇痛特性。还将研究自发活动，以验证镇痛不是由于运动功能或镇静的抑制。本提案的目的是表征去甲氯胺酮的镇痛特性，作为初步可行性研究，为其未来在透皮系统中用作镇痛剂提供依据。还将研究去甲氯胺酮的对映异构体。已经观察到氯胺酮对映体的镇痛效力和副作用差异，并且可能发生在去甲氯胺酮中。具体目标是：1）表征S-、R-和RS-去甲氯胺酮在神经性疼痛的大鼠模型中响应热和机械刺激的镇痛特性，和2）表征S-、R-和RS-去甲氯胺酮对完整大鼠中活性水平的影响。这项I期研究的结果对于开发适用于慢性神经性疼痛管理的临床有用的经皮镇痛药物（去甲氯胺酮对映体）的长期目标（II期研究）非常重要。

DESCRIPTION (provided by applicant): Chronic pain (cancer and nonmalignant) remains a significant medical problem. Its treatment, in particular chronic neuropathic pain, is an especially challenging task. The development of drugs and drug delivery systems for the treatment of chronic neuropathic pain is an important endeavor. One group of drugs with potential use for neuropathic pain is the N-methyi-Daspartate (NMDA) receptor antagonists. Drugs from this class have also been shown to enhance the analgesic effect of morphine and to inhibit development of tolerance to this opioid. Ketamine, a clinically available nonselective NMDA receptor antagonist, has been used parenterally for pain. Despite its analgesic potency, side effects (psychotomimetic, motor, sedation) have limited its use. These effects are prominent following parenteral administration being associated with peak plasma levels. Transdermal application, a delivery approach minimizing peak plasma levels, would be expected to provide a better profile of analgesia to side effects. The ideal candidate for a successful transdermal delivery system is a potent drug with a low clearance rate. The rapid clearance rate of ketamine makes it an undesirable candidate for transdermal delivery. However, ketamine is metabolized to norketamine. Norketamine is an NMDA receptor antagonist and has analgesic activity. Its clearance rate is significantly less than that of ketamine. Therefore, it represents a better candidate for a transdermal delivery system. Prior to consideration for use in a transdermal system the analgesic properties of norketamine in a preclinical model of neuropathic pain needs to be evaluated. Locomotor activity will also be studied to verify that analgesia is not due to depression in motor function or sedation. The purpose of this proposal is to characterize the analgesic properties of norketamine as an initial feasibility study to provide a basis for its future use as an analgesic in a transdermal system. The enantiomers of norketamine will also be studied. Analgesic potency and side effect differences have been seen with the enantiomers of ketamine and are likely to occur with norketamine. The specific aims are to: 1) characterize the analgesic properties of S-, R- and RS- norketamine in response to thermal and mechanical stimuli in a rat model of neuropathic pain and 2) characterize the effect of S-, R- and RS- norketamine on activity level in intact rats. Findings from this Phase I study are important to the long-term goal (Phase II studies) of developing a clinically useful transdermal analgesic drug (norketamine enantiomer) suitable for the management of chronic neuropathic pain.