The application of corticosteroids to reduce secondary inflammation represents the most extensively tested neuroprotective intervention examined to date for human SCI. Based on animal studies, corticosteroids (i.e. methylprednisolone [MP]) became widely used in humans to improve neurological outcomes after SCI. In the first multicentre double-blind randomized controlled trial (RCT), initiated in 1979, 330 patients with acute SCI were administered low and high doses of MP [4]. The study compared two different dosages with no control group and yielded no beneficial effect on neurological function at 6 or 12 months. Based on new data from animal models, indicating a requirement for even higher dosages to have a beneficial neurological effect, a second larger, prospective, placebo-controlled RCT was initiated. In response to MP administered within 8 h of injury, improved neurological function (i.e. sensory and motor scores according to the ISNCSCI) was observed compared to placebo [5]. The timing and dosages from this study were then adopted as the ‘standard of care’ [9, 42, 54]. The National Acute Spinal Cord Injury Study (NASCIS) III randomized, double-blind, multicentre trial (n = 499) was then performed without placebo in order to refine the ideal duration of treatment [7]. They found that administering MP within 3–8 h after injury and continuing for 48 h improved motor function at 6 weeks and 6 months post-injury, though not at 1 year. The NASCIS studies used motor and sensory index scores as primary endpoints, and NASCIS III also incorporated a functional outcome (i.e. the Functional Independence Measure) [5–7]. These studies spurred other RCTs examining the effects of MP, which produced uncertain or mixed results, in addition to growing criticisms regarding the claims and methodologies (e.g. skewed groups, complex weighting scheme, post hoc analysis) of the original NASCIS studies. Also of major concern were the documented adverse effects of MP treatment, including immunological compromise, sepsis, pneumonia, gastrointestinal and pulmonary complications and myopathy [9, 42, 54]. As a result of these concerns, as well as a growing lack of evidence supporting efficacy, MP use in SCI began to fade [42, 51]. The three NASCIS studies included a total of 1242 participants [5–7]. Interestingly, for a time, MP was widely adopted as a treatment even though it was never approved by a regulatory agency as a treatment for acute SCI.

Monosialotetrahexosylganglioside (GM-1) is a naturally occurring ganglioside found in human cell membranes, believed to have neuroprotective and regenerative properties [27, 54]. A small (n = 37) double-blind pilot RCT, examining the effects of GM-1 on neurological recovery after acute SCI, reported a significant improvement in both the Frankel scale and the American Spinal Injury Association (ASIA) motor score with no associated adverse effects [28]. The safety and early success of this pilot study propelled a much larger phase III multicentre trial (n = 760), which began in 1992, and compared two dosages to a placebo control. A priori, a two-grade improvement from baseline in the Modified Benzel Scale (a scale similar to the AIS grades but with additional grades to more clearly identify improvements within the mildest severity of SCI) was chosen as the primary outcome measure. Six months after SCI was selected as the primary trial endpoint [27]. Despite the encouraging evidence from the pilot study, this larger RCT showed no significant difference between those treated with GM-1 and the placebo control group. Although the results were disappointing, the study introduced many important criteria to improve the rigour of human SCI studies, including a defined a priori endpoint, improved outcome definitions and ongoing assessment for the training and reliability of outcome examinations [42].

The inflammatory and immune response by the damaged CNS includes a prominent mobilization of endogenous microglia and exogenous macrophages to the SCI site, which has been suggested to be a significant source of secondary damage and cell death. However, some experimental studies in animals have shown that autologous activated macrophages promote growth and healing, as opposed to harmful inflammation [42, 54]. Based on preclinical evidence, involving the direct injection of autologous activated macrophages into the spinal cord, a small (n = 8) phase I non-randomized study was initiated in 2000. Marked neurological improvements were reported for the treatment group in terms of AIS grade conversion from A (i.e. sensorimotor complete) to C (i.e. sensory and motor incomplete) [38]. These results stimulated a multicentre phase III RCT 3 years later. Recruiting a total of 43 subjects, autologous activated macrophages failed to show significant improvements in the primary outcome measure (i.e. AIS grade conversion) within the treatment group at 6- and 12-month follow-up [43]. Although disappointing, this study represented a milestone for acute SCI: the first time a cell-based therapy had been administered after SCI [42].

Minocycline is a broad-spectrum antibiotic that has been investigated for its potential to decrease inflammatory reactions following SCI [54, 63]. Although laboratory results have shown conflicting results with regard to its efficacy in animal models, a phase II placebo-controlled clinical trial was recently completed in Canada, administering minocycline within 12 h of injury [10, 54]. This study included 44 individuals with complete and incomplete SCI and confirmed the safety of minocycline use in humans, but did not show any significant neurological improvement compared with the placebo group. Although motor improvement in the treatment arm for incomplete SCI was greater than that of the placebo group, it remains within the range of plausible spontaneous neurological recovery outcomes [40]. The authors suggested that the low numbers in each treatment arm and the heterogeneity of the study groups warranted further research into the efficacy of minocycline after acute SCI [40].

Increased activation of voltage-gated sodium ion channels is thought to play a pivotal role in secondary cell death after SCI through a variety of secondary injury mechanisms (e.g. swelling, acidosis and glutaminergic excitotoxicity) (see chapter 19) [19]. Based on this information, riluzole, a sodium channel blocker, has been proposed as a pharmacological intervention to modulate concentrations of glutamate, thereby protecting the spinal cord from secondary damage [51, 54]. Currently administered for management of amyotrophic lateral sclerosis (ALS), riluzole is in the early stages of clinical trials in SCI [54]. A phase I safety trial administering an initial dose of riluzole (n = 36) within 12 h post-injury reported no increased risk of adverse events. Compared to historical controls, riluzole also had a small beneficial effect on motor outcomes and a tendency for greater AIS grade conversion [31]. A multicentre phase II trial is currently being conducted by the North American Clinical Trials Network (NACTN), as well as a multicentre phase II/III trial known as Riluzole in Spinal Cord Injury Study (RISCIS) [19, 22, 49, 63].