Neuropharmacology of Pain in Spinal Cord Injury

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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.