Background: Traumatic injury to the spinal cord occurs in 1 in every 100,000 Americans per year (with young men 16 to 25 years old representing the largest group), a number that increases markedly during periods of warfare. Although the life expectancy of these affected individuals has increased remarkably from 3 months after World War II to more than 20 years today, patients with spinal cord injury (SCI) suffer from numerous (neurological, renal, and gastrointestinal) complications, with a majority in a state of chronic (central) pain. Accordingly, many of these patients are on anti-inflammatory, analgesic, and narcotic drugs, each with their own side effects. The use of nonsteroidal anti-inflammatory drugs (NSAIDs), which have potent anti-inflammatory and analgesic activity in patients with SCI has been limited due to the drugs' gastrointestinal (GI) side effects resulting in peptic ulceration, hemorrhage, and anemia, which can be particularly devastating in a debilitated patient.

Objective/Hypothesis: The major objective of this proposal is to investigate the utility of a new class of NSAIDs that are associated with phosphatidylcholine (PC) in the treatment and/or prevention of chronic neuropathic pain associated with SCI. The work will be undertaken by two independent laboratories of The University of Texas System with separate expertise in the fields of chronic pain, and NSAID pathogenesis and action. We have previously reported in rodent model systems that PC-NSAIDs have a lower GI toxicity and more enhanced therapeutic effectiveness than the parent NSAID to inhibit fever, inflammation, and pain. Based on this increased benefit/risk ratio, we propose to investigate the utility of PC-NSAIDs to treat and/or prevent hyperalgesia associated with SCI in rats, which has proven to be an excellent model of Chronic Pain Syndrome encountered clinically.

Specific Aims: (1) Determine if PC-NSAIDs will prevent and/or attenuate the development of Chronic Pain Syndrome and promote the recovery of locomotor function in SCI rats. (2) Compare the GI, hepatic, and renal toxicity of PC-NSAIDs and unmodified NSAIDs. (3) Delineate the molecular mechanism for the increased effectiveness of PC-NSAIDs to treat Chronic Pain Syndrome associated with SCI.

Study Design: In these studies, we propose to administer (either intragastrically or intravenously) saline (controls), NSAID (aspirin or ibuprofen), a cyclooxygenase-2 inhibitor (NS-398), PC-NSAID (PC-aspirin or PC-ibuprofen), or methylprednisolone (as a comparator group because it is currently the drug of choice for the treatment of SCI) with treatment beginning at varying periods of time (0.5 hours, 2 hours, 2 days, 10 days, 30 days, and 60 days) post-SCI. During this time, a number of behavioral analyses will be performed to assess pain sensitivity and/or locomotor and cognitive function. At the end of the treatment period, we will examine the gastrointestinal mucosa, liver, and renal tissue for NSAID-induced pathological changes, and we will collect blood for measurement of hematocrit (indicative of GI bleeding), elevated liver enzymes, creatinine, and blood urea nitrogen (indicative of liver and renal impairment). We also propose to measure a number of histological and biochemical indices from the affected neural tissue to assess the anti-inflammatory activity at the site of injury (or at higher levels of the CNS), including the neutrophil/macrophage infiltration, density of myelinated/unmyelinated fibers, cells undergoing mitoses and apoptosis, concentration of prostaglandin (PGE2, 6-keto PGF1a), myeloperoxidase, cytokines (TNFa, IL-1B, and IL-6), and cyclooxygenase mRNA expression. We further propose to compare the bioavailability of NSAID and PC-NSAID in SCI rats to determine whether PC association has an enhanced effect on absorption, tissue distribution, and specifically accumulation of the drug at sites of inflammation as our preliminary data suggests.

Relevance: These studies will help evaluate in a highly relevant animal model, the ability of PC-NSAIDs to potentially prevent the development of Chronic Pain Syndrome if administered (intravenously) shortly after traumatic injury or to diminish hyperalgesia and related symptoms when administered after the development of tissue inflammation. Positive results in these preclinical studies should, in turn, hasten the development of PC-NSAID formulations for parenteral and enteral use for improved treatment of patients suffering from Chronic Pain Syndrome. This new family of drugs that possess enhanced therapeutic activity and low GI side effects should be particularly valuable to the military both for the treatment of battlefield injury to limit the development of neurological inflammation and to treat the large existing population of patients with SCI that are suffering from chronic pain.