A Longitudinal Study of the Neurologic Safety of Acute Baclofen Use After Spinal Cord Injury
The objective of our study was to determine whether treatment with baclofen is neurologically safe with respect to exposure during recovery from spinal cord injury. We performed a secondary longitudinal analysis of a cohort of adult patients with traumatic acute spinal cord injury. Cumulative baclofen dose was computed over the first 4 weeks following injury from concomitant medication information from a completed clinical trial. The main outcome measure was neurologic status, which was assessed over 52 weeks with “marked recovery” defined as the conversion to higher sensory and motor function. To complete the drug safety profile, drug toxicity was assessed with assays from standard blood work. Multivariable Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). Of the cohort (n = 651), 18% (n = 115) received baclofen within 4 weeks post injury. Baclofen use was associated with higher rates of marked neurologic recovery, even after adjustment for injury severity (HR = 2.1, 95% CI 1.5–3.0 for high dose vs none). Baclofen exposure was not associated with liver or renal side effects. The use of other medications indicated for spasticity was not associated with neurological outcomes. Overall, this longitudinal analysis provides level 3 evidence on the neurologic safety of baclofen and potential beneficial effects on recovery in the early days after acute traumatic spinal cord injury. The usefulness of concomitant medication files from completed clinical trials is highlighted. We also highlight the importance of incorporating logical patient questions and neurological outcomes into research addressing drug safety.
Keywordsspinal cord injury baclofen anti-spasticity drug safety patient-oriented research
Dr. Cragg is supported by the Society in Science—Branco Weiss Postdoctoral Fellowship and the Michael Smith Foundation for Health Research (MSFHR). Dr. Kramer is supported by a Scholar Award from the MSFHR and Rick Hansen Institute, as well as the Canadian Institutes of Health Research, ERA-NET NEURON, Wings for Life, and the International Foundation for Research in Paraplegia (IRP). Dr. Jutzeler is supported by the IRP and is a Craig H. Nielsen Foundation postdoctoral fellow. Ms. Warner is supported by the University of British Columbia Four Year Fellowship.
Required Author Forms
Disclosure forms provided by the authors are available with the online version of this article.
JJC was responsible for the design and conceptualization of the study, data analyses, and drafting the manuscript. BT was responsible for data cleaning, data analyses, and drafting the manuscript. CRJ, FMW, and NC were responsible for interpretation of data and revising the manuscript for intellectual content. FG was responsible for primary data collection, interpretation of data, and revising the manuscript for intellectual content. JLK was responsible for study concept/design, interpretation of data, and revising the manuscript for intellectual content.
Compliance with Ethical Standards
Approval for this study (secondary analysis) was received by an institutional ethical standards committee on human experimentation at the University of British Columbia.
All authors report no disclosures.
- 1.Tator CH (1995) Update on the Pathophysiology and Pathology of Acute Spinal Cord Injury. Brain Pathol 5:407–413. https://doi.org/10.1111/j.1750-3639.1995.tb00619.x CrossRefPubMedGoogle Scholar
- 9.McDonald JW, Sadowsky CL, Stampas A (2012) The changing field of rehabilitation: Optimizing spontaneous regeneration and functional recovery. Handb Clin Neurol 109:317–336. https://doi.org/10.1016/B978-0-444-52137-8.00020-6 CrossRefPubMedGoogle Scholar
- 11.Dr. Wise Young - Baclofen Question. http://sci.rutgers.edu/forum/showthread.php?133388-Dr-Wise-Young-Baclofen-Question. Accessed 6 Apr 2018
- 12.11. Correlation and regression | The BMJ. https://www.bmj.com/about-bmj/resources-readers/publications/statistics-square-one/11-correlation-and-regression. Accessed 6 Apr 2018
- 18.Fawcett JW, Curt A, Steeves JD, et al (2007) Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 45:190–205. https://doi.org/10.1038/sj.sc.3102007 CrossRefPubMedGoogle Scholar
- 21.Albumin: Reference Range, Interpretation, Collection and Panels. https://emedicine.medscape.com/article/2054430-overview. Accessed 6 Apr 2018
- 22.ALP - blood test. http://arh.adam.com/content.aspx?productId=101&pid=1&gid=003470. Accessed 6 Apr 2018
- 23.Hepatitis C, Liver Enzyme Levels | Hepatitis Central. http://www.hepatitiscentral.com/hcv/labs/liverenzymes/. Accessed 6 Apr 2018
- 24.Hyperphosphatemia (High Phosphate) - Managing Side Effects - Chemocare. http://chemocare.com/chemotherapy/side-effects/hyperphosphatemia-high-phosphate.aspx. Accessed 6 Apr 2018
- 25.Blood urea nitrogen (BUN) test - About - Mayo Clinic. https://www.mayoclinic.org/tests-procedures/blood-urea-nitrogen/about/pac-20384821. Accessed 6 Apr 2018
- 26.Bilirubin blood test Information | Mount Sinai - New York. http://www.mountsinai.org/health-library/tests/bilirubin-blood-test. Accessed 6 Apr 2018
- 27.What Is a Creatinine Blood Test? Symptoms, Low & High Ranges. https://www.medicinenet.com/creatinine_blood_test/article.htm. Accessed 6 Apr 2018
- 35.Costa C, Leone G, Saulle E, et al (2004) Coactivation of GABAA and GABAB Receptor Results in Neuroprotection during In Vitro Ischemia. Stroke 35:596–600. https://doi.org/10.1161/01.STR.0000113691.32026.06 CrossRefPubMedGoogle Scholar
- 36.Chumakov I, Milet A, Cholet N, et al (2014) Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy. Orphanet J Rare Dis 9. https://doi.org/10.1186/s13023-014-0201-x
- 43.Short DJ, El Masry WS, Jones PW (2000) High dose methylprednisolone in the management of acute spinal cord injury - A systematic review from a clinical perspective. Spinal CordGoogle Scholar
- 45.Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. https://www.accessdata.fda.gov/scripts/Cder/ob/index.cfm. Accessed 6 Apr 2018
- 46.Baclofen (Baclofen Tablets): Side Effects, Interactions, Warning, Dosage & Uses. https://www.rxlist.com/baclofen-drug.htm#indications_dosage. Accessed 6 Apr 2018
- 47.Smith C, LaRocca N, Giesser B, Scheinberg L (1991) High-dose oral baclofen: Experience in patients with multiple sclerosis. Neurology 1829–1831Google Scholar
- 48.Holtz KA, Szefer E, Noonan VK, et al (2018) Treatment patterns of in-patient spasticity medication use after traumatic spinal cord injury: a prospective cohort study. Spinal Cord. https://doi.org/10.1038/s41393-018-0165-0