Pharmacological Management of Acute Spinal Cord Injury: Overlooked Opportunities to Enhance Long-Term Neurological Function

Background: Complications arising from acute traumatic spinal cord injury are routinely managed by various pharmacological interventions. Despite decades of clinical application, the potential impact on neurological recovery has been largely overlooked. Methods: We first performed an analysis of available clinical trial and observational data to determine what constitutes of acute pharmacological care after spinal cord injury. Then, we conducted an in-depth literature review to evaluate evidence that commonly administered drugs have potential disease-modifying properties in animal models of spinal cord injury. Finally, we searched available databases (e.g., Drug Bank) and literature to determine drugs that have been shown to alter the effectiveness of emerging investigational treatments (e.g., riluzole). Findings: Over 780 unique drugs were administered within the first month after injury. On average, patients received 20 unique drugs (range 1-58) - often in a combinatorial or overlapping fashion (i.e., polypharmacy). Approximately 10% of drugs were administered acutely as prophylaxis (e.g., pain, infections). From our initial review of preclinical literature, 329 studies evaluating 95 unique drugs demonstrate evidence of disease-modifying properties (i.e., beneficial or detrimental) on histological and/or functional outcomes in animal models. A total of 222 commonly administered drugs were found to interact with emerging investigational therapies and alter their efficacy. Interpretation: Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, with potential to both positively and negatively impact neurological recovery. This raises the distinct possibility of drug repositioning, either by broadly introducing or reducing the administration of a drug, in order to enhance neurological outcomes after acute injury. In addition to modifying effects, the potential for interactions between commonly administered drugs and novel therapies warrants caution in emergent clinical trials. Funding Statement: Dr. Jutzeler was supported by a Craig H. Nielsen Foundation, Blusson Integrated Cures Partnership Wings for Life, the Swiss National Science Foundation (Ambizione Grant, PZ00P3_186101). This study was funded in part by the Alfried Krupp Prize for Young University Teachers of the Alfried Krupp von Bohlen und Halbach-Stiftung (Dr. Borgwardt). Dr. Harel was supported by Veterans Affairs Rehabilitation Research and Development Service grant B-0881W. Dr. Ferguson is supported by National Institutes of Health grants R01NS088475, UG3NS106899, and Veterans Affairs RR&D grants 1I01RX002245, I01RX002787. Dr. Kwon is the Canada Research Chair in Spinal Cord Injury and the Dvorak Chair in Spine Trauma. Dr. Bradke is supported by International Foundation for Research in Paraplegia, Wings for Life, Deutsche Forschungsgesellschaft (DFG), ERA-NET AXON REPAIR, and ERA-NET RATER SCI, the excellence cluster ImmunoSensation2, the Special Research Grants 1089 and 1158. Dr. Kramer is supported by a Scholar Award from the Michael Smith Foundation for Health Research and Rick Hansen Institute, as well as the Canadian Institutes of Health Research (ERA-NET RATER SCI), Wings for Life, and the International Foundation for Research in Paraplegia (IRP). Declaration of Interests: Catherine Jutzeler: Nothing to disclose. Bobo Tong: Nothing to disclose. Eric Bailey: Nothing to disclose Noam Y. Harel: Nothing to disclose Fred Geisler: Nothing to disclose Karsten Borgwardt: Reports personal fees from Mentoring and Consulting for Roche Pharmaceutical Research and Early Development (pRED), Basel, outside the submitted work. Adam R. Fergus0n: Nothing to disclose Brian Kwon: Nothing to disclose. Frank Bradke: Nothing to disclose. Jacquelyn J. Cragg: Nothing to disclose Lukas Grassner: Nothing to disclose John L.K. Kramer: Nothing to disclose. Ethics Approval Statement: Approval for this study (secondary analysis) was received by an institutional ethical standards committee on human experimentation at the University of British Columbia.