Phase II clinical evaluation of Omnitram in neuropathic pain

 描述（由申请人提供）：神经性疼痛是由周围神经损伤引起的，如糖尿病性神经病变。神经性疼痛很难治疗，许多患者的疼痛是现有治疗方法难以治愈的。Omnitram是Syncidol公司开发的一种新型混合机制镇痛药，由O-去甲基曲马多的（-）和（+）对映体组成。（+）-对映异构体是一种有效的μ-阿片受体激动剂，而（-）-对映异构体是一种与（+）-对映异构体协同作用的去甲肾上腺素再摄取抑制剂。Omnitram本质上是一种阿片类药物保留阿片类药物辅助联合治疗，预计滥用可能性较低。O-去甲基曲马多是曲马多的初级代谢产物（M1）。Omnitram提供了与曲马多相同的净药理学，但与曲马多相反，其活性不需要通过细胞色素P450 2D 6（CYP 2D 6）代谢（即，其不依赖代谢）。CYP 2D 6弱代谢者（PM）无法从曲马多中获得疼痛缓解。在接受多种药物治疗的患者中，CYP 2D 6 PM状态的“真实的世界”发生率高达1/3。因此，Omnitram是一个机会，开发一种“改善曲马多”，是有效的所有患者，无论他们的CYP 2D 6代谢状态。Omnitram成功完成了一项1b期随机、双盲、安慰剂对照试验，该试验证明，在健康受试者的实验性疼痛模型中，与安慰剂相比，Omnitram提供了显著的镇痛作用。该快速通道申请旨在通过证明糖尿病神经病变所致神经性疼痛患者的镇痛疗效，进一步推动Omnitram项目的成功。一项科克伦系统评价得出结论，曲马多是一种有效治疗神经性疼痛的药物，疗效与抗抑郁药和抗惊厥药相似。Omnitram提供与曲马多相同的净药理学，因此预测其在治疗神经性疼痛中有效。

 DESCRIPTION (provided by applicant): Neuropathic pain is caused by damage to the peripheral nerves, as occurs in diabetic neuropathy. Neuropathic pain is difficult to treat, and many patients have pain that is refractory to existing treatments. Omnitram is a novel mixed-mechanism analgesic developed by Syntrix that consists of the (-) and (+) enantiomers of O-desmethyltramadol. The (+)-enantiomer is a potent µ-opioid receptor agonist, while the (-)- enantiomer is a norepinephrine reuptake inhibitor that synergizes with the (+)-enantiomer. Omnitram is inherently an opioid-sparing opioid-adjuvant combination therapy that is predicted to have low abuse potential. O-desmethyltramadol is the primary metabolite (M1) of tramadol. Omnitram provides the same net pharmacology as tramadol, but in contrast to tramadol, does not require metabolism by cytochrome P450 2D6 (CYP2D6) for its activity (i.e. it is metabolism-independent). Individuals who are CYP2D6 poor metabolizers (PMs) fail to obtain pain relief from tramadol. The "real world" incidence of CYP2D6 PM status in patients on polypharmacotherapy is as high as 1 in 3. Omnitram is therefore an opportunity to develop an "improved tramadol" that is effective in all patients irrespective of their CYP2D6 metabolic status. Omnitram successfully completed a Phase 1b randomized, double-blind, placebo-controlled trial that demonstrated Omnitram provided significant analgesia compared to placebo in an experimental pain model in healthy subjects. This Fast-Track application aims to further the success of the Omnitram program by demonstrating analgesic efficacy in patients suffering from neuropathic pain due to diabetic neuropathy. A Cochrane systematic review concluded that tramadol is an effective treatment for neuropathic pain with efficacy similar to that reported for antidepressants and anticonvulsants. Omnitram provides the same net pharmacology as tramadol and is therefore predicted to be efficacious in treating neuropathic pain.