What is the current evidence to support the use of Riluzole in patients with deficits post spine surgery?

Comment by InpharmD Researcher

Currently, there is a lack of evidence specifically assessing the use of riluzole for the management of neurological deficits post-spine surgery. Available data are primarily derived from spinal cord injury studies that suggest riluzole may offer functional benefits and is generally well tolerated when administered early after injury. However, trials in related conditions, such as degenerative cervical myelopathy, have shown mixed results, with no clear improvement beyond surgical intervention.

Background

A 2025 systematic review scrutinized the efficacy and safety of various pharmacological treatments targeting the acute phase of secondary spinal cord injury (SCI). This review aggregated data from 25 studies encompassing 3017 patients, with an average age of 43.3 years. It aimed to evaluate current management strategies and identify potential therapeutic options to improve outcomes in SCI patients. The findings highlighted that erythropoietin (EPO) was associated with improved motor function and reduced neurological impairment post-SCI, attributed to its antioxidative, anti-apoptotic, and neurogenic properties. Despite its widespread use, methylprednisolone demonstrated uncertain efficacy in enhancing neurological outcomes, aligning with previous evidence suggesting a risk of adverse effects. The review also emphasized the promising potential of monosialotetrahexosylganglioside sodium salt (GM-1) and riluzole, both of which were linked to favorable neurological outcomes. Riluzole has demonstrated neuroprotective effects in preclinical SCI models, including reduced tissue damage and preservation of white matter, motor neurons, and mitochondrial function, findings that suggest potential for improved functional recovery. Clinically, Grossman et al. showed that patients treated within 12 hours of injury had significantly better motor, sensory, and impairment outcomes at 90 days (See Table 3). Additionally, granulocyte colony-stimulating factor (G-CSF) and hepatocyte growth factor (HGF) were noted for providing enhanced motor scores with fewer side effects. However, therapies involving the rho-GTPases inhibitor VX-210 and levetiracetam did not show significant efficacy, underscoring the need for continued research to optimize pharmacological interventions for secondary SCI. [1]

Another 2024 systematic review with meta-analyses evaluated specifically the safety and efficacy of riluzole in the treatment of traumatic SCI. The five included studies varied in design, with four being prospective and randomized, and one being prospective and non-randomized. The participants across these studies encompassed 378 individuals, of whom 187 received riluzole, compared against control groups comprising 191 individuals receiving either placebo or standard care without specific additional interventions. The studies spanned various global locations, including North America, Australia, India, and Iran, and involved administering riluzole in different dosing regimens, most commonly 100 mg PO BID initially, followed by 50 mg BID for a period ranging from 13 days (50 mg BID 8 weeks; 1 study). Regarding acuity of injury, all studies were within the acute period post-SCI. The results indicated a non-significant trend toward improved neurological outcomes in the riluzole group as measured by the American Spinal Injury Association (ASIA) motor scores and ASIA Impairment Scale (AIS) changes at three and six months post-injury. Statistically, riluzole administration resulted in neither a significant reduction in adverse events (AEs) nor mortality when compared to controls. Despite the potential promise suggested by these outcomes, the improvements did not reach statistical significance, highlighting the need for more robust, large-scale randomized trials to establish definitive conclusions about riluzole’s therapeutic role in acute traumatic SCI. The studies also noted the absence of specific AEs directly attributable to riluzole, underscoring its safety profile within the studied parameters. [2]

References:

[1] Migliorini F, Pilone M, Eschweiler J, Katusic D, Memminger MK, Maffulli N. Therapeutic strategies that modulate the acute phase of secondary spinal cord injury scarring and inflammation and improve injury outcomes. Expert Rev Neurother. 2025;25(4):477-490. doi:10.1080/14737175.2025.2470326
[2] Weisbrod LJ, Nilles-Melchert TT, Bergjord JR, Surdell DL. Safety and Efficacy of Riluzole in Traumatic Spinal Cord Injury: A Systematic Review With Meta-Analyses. Neurotrauma Rep. 2024;5(1):117-127. Published 2024 Feb 19. doi:10.1089/neur.2023.0114

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the current evidence to support the use of Riluzole in patients with deficits post spine surgery?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-3 for your response.


 

Safety and efficacy of riluzole in patients undergoing decompressive surgery for degenerative cervical myelopathy (CSM-Protect): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial

Design

Multicenter, double-blind, placebo-controlled, randomized, phase 3 trial

N= 408

Objective

To test the hypothesis that riluzole might enhance neurological recovery and reduce perioperative neurological complications following decompression surgery in patients with degenerative cervical myelopathy

Study Groups

Riluzole (n= 141)

Placebo (n= 149)

Inclusion Criteria

Age 18 to 80 years, modified Japanese Orthopaedic Association (mJOA) score of 8–14

Exclusion Criteria

Undergone previous surgery for degenerative cervical myelopathy, had concomitant symptomatic lumbar spinal stenosis, presented with symptoms resulting from cervical spine trauma (eg, central cord syndrome), had cervical myelopathy secondary to neoplasm or infection, were pregnant or nursing, had hepatic or renal impairment, had a history of substance misuse in the past 3 years, or had systemic infection or active malignancy

Methods

Patients were randomized to receive either oral riluzole 50 mg BID for 14 days before surgery, then 28 days after surgery; or matching placebo. All patients underwent standard surgical decompression of the surgical spine.

Duration

Follow-up: 6 months

Outcome Measures

Primary outcome: Change in functional status at 6 months based on mJOA scale

Secondary outcome: Nurick grade, Neck Disability Index, SF-36 Physical Component Summary

Baseline Characteristics

 

Riluzole (n= 141)

Placebo (n= 149)

   

Age, years

59.2 56.8    

Female

46% 43%    

Race

White

African American

Asian

Other

 

84%

6%

5%

6% 

 

79%

13%

5%

4%

   

Comorbidities

Hypertension

Diabetes

Chronic obstructive pulmonary disease

Anxiety or depression

 

48%

16%

5%

22%

 

42%

8%

4%

19%

   

Clinical presentation

Duration of symptoms, months

Clumsy hands

Impaired gait

Upper limp paraesthesia

Lhermitte's sign

Weakness

mJOA

 

35.6

77%

85%

38%

19%

72%

12.0

 

40.3

82%

85%

42%

14%

72%

11.7

   

Surgical treatment

Operative approach: anterior

Operative approach: posterior

Operative approach: circumferential

Spinal levels

 

43%

55%

2%

4.3

 

48%

49%

3%

4.2

   

Results

Endpoint

Riluzole (n= 141)

Placebo (n= 149)

Mean difference (95% confidence interval [CI])

p-Value

mJOA score

2.45 (2.08 to 2.82)

2.83 (2.47 to 3.19)

-0.38 (-0.90 to 0.13)

0.14

Nurick grade

-1.28 (-1.49 to -1.06)

-1.15 (-1.36 to -0.94)  -0.13 (-0.43 to 0.17) 0.41

Neck Disability Index

-12.46 (-15.10 to -9.82)  -12.02 (-14.74 to -9.29) -0.44 (-4.24 to 3.36) 0.82

SF-36 Physical Component Summary

6.26 (4.53 to 7.99)

5.22 (3.82 to 6.63) 1.04 (-1.19 to 3.27) 0.36

Adverse Events

The adverse events most commonly observed included neck or arm or shoulder pain, arm paraesthesia, dysphagia, and worsening of myelopathy, with serious events occurring in 22% of the riluzole group compared to 19% in the placebo group.

Study Author Conclusions

In this trial, adjuvant treatment for 6 weeks perioperatively with riluzole did not improve functional recovery beyond decompressive surgery in patients with moderate-to-severe degenerative cervical myelopathy. Whether riluzole has other benefits in this patient population merits further study.

InpharmD Researcher Critique

The study was fair in its assessment regarding the lack of benefits observed. However, the results are limited to a certain type of non-traumatic spinal cord injury.



References:

Fehlings MG, Badhiwala JH, Ahn H, et al. Safety and efficacy of riluzole in patients undergoing decompressive surgery for degenerative cervical myelopathy (CSM-Protect): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial. Lancet Neurol. 2021;20(2):98-106. doi:10.1016/S1474-4422(20)30407-5

 

Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial

Design

Multi-center, prospective, randomized, double-blinded, placebo-controlled adaptive Phase III trial

N= 193

Objective

To evaluate the efficacy and safety of riluzole in acute cervical traumatic spinal cord injury (tSCI)

Study Groups

Riluzole (n= 96)

Control (n= 97)

Inclusion Criteria

Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and ​< 12 h from injury

Exclusion Criteria

Injury arising from penetrating mechanism, significant concomitant head injury, pre-existent neurologic or mental disorder, previous history of spinal cord injury, recent history (less than 1 year) of chemical substance dependency or significant psychosocial disturbance 

Methods

Participants were randomized to receive either riluzole at an oral dose of 100 mg BID for the first 24 hours, followed by 50 mg BID for 13 days, or a placebo.

Duration

October 2013; May 2020 (halted by the sponsor); April 2021 (terminated in the face of the COVID-19 pandemic) 

Outcome Measures

Primary: Change in Upper Extremity Motor (UEM) scores at 180 days

Secondary: Neurological Classification of Spinal Cord Injury (ISNCSCI) Total Motor Score, sensory scores 

Baseline Characteristics

 

Riluzole (n= 96)

Control (n= 97)

 

Age, years

96 ± 49.4 47.6 ± 16.0  

Male

79 (82.3%) 79 (81.4%)  

White

69 (71.9%) 71 (73.2%)   

Body mass index (BMI), kg/m2

28.8 ± 6.0 28.4 ± 5.8  

AIS Grade

A

B

C

D

 

49 (51.58%)

19 (20.00%)

26 (27.37%)

0

 

52 (53.61%)

19 (19.59%)

26 (26.80%)

1 (1.05%)

 

Neurological Level of Injury

C3

C4

C5

C6

C7

C8

T2

 

0

47 (48.96%)

29 (30.21%)

13 (13.54%)

5 (5.21%)

0

 

2 (2.06%)

57 (58.76%)

20 (20.62%)

9 (9.28%)

5 (5.15%)

1 (1.03%)

1 (1.03%)

 
Baseline Total Motor Score 18.44 ± 13.39 16.46 ± 12.62  
Baseline Upper Motor Score 14.02 ± 10.46 12.63 ± 10.87  
Baseline Lower Motor Scores 4.38 ± 8.51 3.76 ± 7.42  

Results

Endpoint

Riluzole (n= 96)*

Control (n= 97)

Difference (95% CI); p-Value

Mean change in UEM scores at 180 days

14.65 (n= 66) 16.42 (n= 65) 1.76 (-2.54-6.06); 0.2093

Mean change in Lower Extremity Motor Scores at 180 days

16.10 (n= 68) 17.55 (n= 65) 1.45 (-4.80-7.70); 0.3235

Mean change in Total Motor Scores at 180 days

31.11 (n= 66) 34.00 (n= 65)  2.86 (-6.79-12.52); 0.2792

*193 patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days.

In pre-planned sensitivity analyses, AIS C patients receiving riluzole showed significant improvements in total motor scores (mean difference 8.0; CI 1.5–14.4) and upper extremity motor scores (13.8; CI 3.1–24.5) at 6 months. AIS B patients had greater independence (SCIM score: 45.3 vs. 27.3) and improved mental health (SF-36: 2.01 vs. –11.58; CI 1.2–24.8). AIS A patients on riluzole gained more neurological levels (0.50 vs. 0.12; CI –0.2–0.9) compared to placebo.

Adverse Events

In the riluzole group, 1722 AEs in 96 participants and 110 serious adverse events (SAEs) in 51 participants with 9 deaths

In the placebo group, 1786 AEs in 97 participants and 52 SAEs in 132 participants with 10 deaths

Study Author Conclusions

The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.

InpharmD Researcher Critique

Given the rarity of tSCI and the difficulty of conducting large trials, RISCIS results may inform future guidelines, yet the study’s conclusions are limited by under-enrollment due to premature termination, with only 55% of the planned sample size recruited, and a cohort primarily consisting of severe AIS A and upper cervical injuries, which have limited recovery potential.



References:

Fehlings MG, Moghaddamjou A, Harrop JS, et al. Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial. J Neurotrauma. 2023;40(17-18):1878-1888. doi:10.1089/neu.2023.0163

 

A Prospective, Multicenter, Phase I Matched-Comparison Group Trial of Safety, Pharmacokinetics, and Preliminary Efficacy of Riluzole in Patients with Traumatic Spinal Cord Injury

Design

Prospective, multicenter, open-label, phase I trial

N= 36

Objective

To evaluate the pharmacokinetics and safety of riluzole in patients with acute spinal cord injury (SCI), and to obtain preliminary data on its effects on neurological outcomes

Study Groups

Cervical (n= 28)

Thoracic (n= 8)

Inclusion Criteria

Adults ≥18 and ≤70 years; no other life-threatening injury; nonpenetrating spinal cord injury at a neurologic level from cervical vertebra 4 (C4) to thoracic vertebra 11 (T11); American Spinal Injury Association (ASIA) Impairment Scale grade A, B, or C; no cognitive impairment that would preclude informed consent (including moderate or severe traumatic brain injury); and received the initial dose of riluzole within 12 hours of injury

Exclusion Criteria

Hypersensitivity to riluzole or any of its components; unable to receive riluzole orally or by nasogastric tube; history of liver or kidney disease (e.g., hepatitis A, hepatitis B, hepatitis C, or cirrhosis); a recent history of regular substance abuse (illicit drugs or alcohol); unconscious; penetrating spinal cord injury; pregnancy as established by urine pregnancy test; currently involved in another spinal cord injury research study; has a mental disorder or other illness which, in the view of the site investigator, would preclude accurate medical and neurological evaluation

Methods

Riluzole was administered orally or via nasogastric tube at a dose of 50 mg every 12 hours for a total of 28 doses, starting within 12 hours of injury. Baseline data were collected at enrollment before the first dose, and the first day of riluzole administration was defined as day 1. Data collection included prehospital demographic and clinical history, neurological assessments using the ISNCSCI and AIS on multiple days, Spinal Cord Independence Measure (SCIM) at 90 and 180 days, medical and surgical treatments, laboratory evaluations including liver function tests on specified days, and the monitoring of medical complications and serious adverse events.

Duration

April 12, 2010 to June 20, 2011

Outcome Measures

Pharmacokinetics, safety, and neurological outcome

Baseline Characteristics

  Cervical (n= 28)

Thoracic (n= 8)

Age, years

41.3 ± 17.4 45.4 ± 16.4

Female

4 (14%) 2 (25%)

BMI, kg/m2

26.4 ± 4.1 28.1 ± 4.3

AIS

A

B

C

 

12 (43%)

8 (26%)

8 (26%)

 

7 (88%)

1 (13%)

0 (0%)

Cause

Motor vehicle accident

Fall

Sports

Assualt 

 

13 (46%)

8 (26%)

5 (18%)

2 (7%)

 

7 (88%)

1 (13%)

0 (0%)

0 (0%)

Surgery, yes

25 (89%)

8 (100%)

Corticosteroids, yes

10 (36%) 4 (50%)

Abbreviations: AIS=  American Spinal Injury Association Impairment Scale; BMI= body mass index. 

Registry patients were matched to the riluzole cohort based on injury level and severity; however, the baseline characteristics presented reflect only those individuals who received riluzole.

Mean time to the first dose of riluzole was 8.7 h for the riluzole cohort

Results

Pharmacokinetics of riluzole were assessed in 33 patients on day 3 and 32 patients on day 14, with quantifiable peak and trough plasma samples. Riluzole exposure (Cmax, Cmin, and AUC₀–₁₂) varied widely among patients and changed over time. Mean Cmax, Cmin, and AUC₀–₁₂ were significantly higher on day 3 (129 ng/mL, 46 ng/mL, and 982 ng·h/mL) compared to day 14 (77 ng/mL, 19 ng/mL, and 521 ng·h/mL), corresponding with lower clearance (50 vs. 106 L/h) and smaller volume of distribution (557 vs. 1298 L) early after injury.

Motor outcomes were evaluated in riluzole-treated patients with cervical spinal cord injuries, stratified by admission impairment grade. Grade A patients (n= 10) had a modest motor score gain of 7.2 points by 42 days, while grade B (n= 8) and grade C (n= 7) patients showed greater improvements, gaining 28.1 and 34.1 points, respectively. At 180 days, mean total motor scores were 56.6 for riluzole patients and 52.5 for matched registry controls. The most pronounced improvements were seen in grade B patients, with a 4.13-fold increase from admission to 180 days, particularly in lower extremity motor scores.

At 90 days, riluzole patients as a group had significantly higher gains than registry controls (mean difference 15.5 points; p= 0.021), primarily driven by improvements in grade B patients (difference 27.9 points; p= 0.037). By 180 days, between-group differences narrowed and were no longer statistically significant. Median motor gains also favored the riluzole group at both 90 and 180 days, suggesting more robust functional recovery.

Adverse Events

Common Adverse Events (riluzole vs. registry controls): Infection (26 vs. 22%); pulmonary (23 vs. 27%); hematological (12 vs. 15%); cardiac (7 vs. 13%); neurological/psychiatric (15 vs. 7%); GI/GU (11 vs. 9%); skin (8 vs. 7%)

Serious Adverse Events: None attributable to riluzole.

Percentage that Discontinued due to Adverse Events: One patient was withdrawn after developing elevated liver enzymes; riluzole was stopped as a precaution, and liver function normalized by follow-up.

Study Author Conclusions

Riluzole administered enterally within 12 h of SCI was well tolerated. There were no SAEs attributable to riluzole. Bearing in mind the limitations of the study, the exploratory pilot data suggest that riluzole may have a beneficial effect on motor outcome in cervical SCI that was manifest at 90 days postinjury. Improvement in lower extremity motor score appeared to be the primary effect. Further study of the PK, safety, and effects of riluzole on neurological outcome in acute traumatic SCI will be carried out in a phase II trial.

InpharmD Researcher Critique

The trial was open-label, which may have introduced positive bias, and riluzole-treated patients were compared to a historical rather than a contemporaneous control group. However, both groups received similar standard-of-care, which may have reduced variability in outcome assessments. 



References:

Grossman RG, Fehlings MG, Frankowski RF, et al. A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury. J Neurotrauma. 2014;31(3):239-255. doi:10.1089/neu.2013.2969