Neuropharmacology of Pain in Spinal Cord Injury

描述（由申请人提供）：慢性中枢神经性疼痛综合征在大多数脊髓损伤（SCI）患者中发展。标准的镇痛方法（包括非甾体抗炎药、阿片类药物、三环抗抑郁药、抗惊厥药和抗痉挛药）迄今为止对缓解这种慢性疼痛无效，这种慢性疼痛通常可能很严重。然而，最近兴奋性氨基酸受体拮抗剂的基础和临床研究为新的治疗方法开辟了可能性。镇痛临床试验需要创新，例如：1)使用联合药物研究，针对两种或多种导致疼痛综合征的生物学机制；2)更好地定义临床亚群，以描述脊髓损伤疼痛综合征亚群的生物学机制。我们将把每一项创新都引入到这个临床试点中。

DESCRIPTION (provided by the applicant): Chronic central neuropathic pain syndromes develop in the majority of patients who sustain Spinal Cord Injury (SCI). Standard analgesic practices (including non-steroidal anti-inflammatory drugs, opioids, tricyclic antidepressants, anticonvulsants, and antispasmodics) have thus far been ineffective to relieve this chronic pain, which commonly can be severe. However, recent basic and clinical research with excitatory amino acid receptor antagonists opens the possibility for new treatments. Innovations are needed in analgesic clinical trials, such as: 1) the use of combination drug studies which target two or more biological mechanisms contributing to the pain syndrome; and 2) a better definition of clinical subsets to delineate biological mechanisms for subgroups of SCI pain syndromes. We will introduce each of these innovations in this pilot clinical trial. We and others have shown that NMDA receptor and sodium channel antagonists relieve pain in rats following experimental SCI and in patients with SCI. The overall goal of combining two therapies that target different putative pain mechanisms to, in part, reduce the sensitization of central neurons is to allow for the reduction of the dose of either agent to reach the desired outcome with fewer side effects (thereby widening the therapeutic ratio). We propose to evaluate various doses of the sodium channel antagonist lidocaine, when given in combination with varying doses of the NMDA receptor antagonist dextromethorphan, in patients with spontaneous pain and touch-evoked allodynia following SCI. Our primary aim is to determine the best dose-ratio of the two drugs in order to design efficiently the definitive phase III clinical trial evaluating the combination of these two classes of drugs, compared to placebo and each individual component drug. The overall objectives of this pilot grant are to improve the assessment of combination therapy by successfully incorporating a strategy to pick the best combination of doses of two component drugs and, in the process, collect preliminary data for establishing measures of efficacy and safety among the various dose-combinations.