Riluzole Does Not Improve Function After Degenerative Disc Surgery

Caroline Helwick

April 17, 2019

SAN DIEGO — The sodium/glutamate receptor antagonist riluzole, given perioperatively, did not have a significant effect on function in patients undergoing decompression surgery for degenerative cervical myelopathy (DCM), results of the CSM-Protect trial show.

However, secondary findings suggest treatment with riluzole may reduce neck or other pain in these patients.

"While we found that a 6-week perioperative course of riluzole did not have a significant beneficial effect on the primary outcome, change in function at 6 months, we did see interesting effects on three predetermined secondary outcomes," said lead author Michael G. Fehlings, MD, PhD, professor of neurosurgery and Halbert chair in Neural Repair and Regeneration at the University of Toronto, Ontario, Canada.

These improvements were primarily a reduction in neck pain by visual analog scale (VAS), with some improvements also shown for arm/shoulder pain, motor scores on the ASIA scale, and functional domain of the Short-Form Health Survey (SF-36). 

"Patients with DCM are reporting recovery from pain as their top priority. The finding of reduced pain with riluzole is therefore of importance to clinicians and patients," Fehlings said.

He presented the findings here at the American Association of Neurological Surgeons (AANS) 2019 Annual Scientific Meeting.

Potential Benefits of Riluzole

The leading cause of spinal impairment is DCM, also known as cervical spondylotic myelopathy (CSM). Surgical decompression improves function and quality of life, but many patients are left with significant residual disability and some risk for neurological deterioration.

The hypothesis of the CSM-Protect trial was that riluzole, a benzothiazole anticonvulsant, might enhance neurological recovery, attenuate neuropathic pain, and reduce perioperative neurological complications following surgery.

Riluzole inhibits pathologic glutamatergic transmission in the synapses of neurons via sodium channel blockade. It is approved for use in amyotrophic lateral sclerosis (ALS), and in animal models, it has been shown to attenuate oxidative DNA damage in the spinal cord, reduce neurological decline after decompression surgery, protect spinal cord tissue, preserve function, and alleviate neuropathic pain, Fehlings noted.

CSM-Protect trial

CSM-Protect was a multicenter, double-blinded, placebo-controlled randomized trial of adults with moderate-to-severe symptomatic CSM, defined as a modified Japanese Orthopedic Association (mJOA) score of 8-14.

The 290 patients (mean age 58 years) were assigned to surgical decompression plus riluzole (50 mg PO BID for 14 days before surgery and 28 days after surgery) or surgical decompression plus placebo.

The primary outcome was changed in mJOA score from baseline to 6 months postoperatively. Secondary outcomes included change in Nurick grade, change in disability according to the neck disability index (NDI), quality of life as measured by the SF-36 and EuroQol (EQ-5D), neurological function according to ASIA scores, grip strength, and pain on the VAS.

Outcomes were evaluated at enrollment, hospital admission, and 35 days, 6 months, and 1 year after surgery. Ninety percent of patients were followed out to 6 months.

"The randomization was largely successful in terms of controlling for baseline characteristics," he said. "The study maintained strict blinding of subjects, physicians, and data collectors throughout."

Secondary, Not Primary, Outcomes Improved  

"Regardless of the outcome measure, surgery overall had a very dominant and positive effect," Fehling reported. "We saw that following surgery, there was a large change in the mJOA scale, so this randomized trial with prospective data confirms what recent studies have also found.

"There was no additional effect, however, on the primary endpoint with riluzole," he noted.

Mean change in mJOA at 6 months was 2.40 with riluzole and 2.86 with placebo (P = .964), and no differences emerged at 1 year.

On the other hand, the riluzole group experienced significant improvements in pain and several other secondary outcomes.

Changes in Pain With Riluzole vs Placebo

Outcome Change From Baseline, 
(n = 141)
Change From Baseline,
(n = 149)
Difference in Change,
Riluzole vs Placebo
P value
Neck pain at
6 months
–2.23 –1.61 –0.62 .0296
Neck pain at 1 year –2.28 –1.52 –0.76 .0167
Arm/shoulder pain at 6 months –2.12 –1.62 –0.50 .099
Arm/shoulder pain at 1 year –2.10 –1.48 –0.62 0.082

"I wish to caution that any kind of a secondary outcome, even one that is predetermined in a randomized controlled trial, should be considered as exploratory, but I think some of these secondary outcomes may have clinical interest," he commented.

"In particular, for neck pain, and arm and shoulder pain, at 6 months we see interesting effects that suggest riluzole may attenuate both neck and neuropathic pain," he added. "These effects are maintained at a year."  

The ASIA motor score showed a trend for greater improvement with riluzole at 1 year, with mean changes of 3.66 vs 3.17 with placebo. Similarly, mean change in the SF-36 physical component score was greater with riluzole, 6.26 vs 5.22 at 6 months and 6.58 and 6.35, respectively, at 1 year.

"At 1 year, we start teasing out changes in motor scores by the ASIA scale, which likely reflects changes in hand intrinsic function," he commented.

The complication rate was low (5%) and similar between arms. There were no drug-related adverse events, and no patient had to discontinue riluzole.

Fehling and colleagues conclude that perioperative adjuvant treatment with riluzole in the setting of CSM does not enhance functional recovery beyond surgical decompression, "which dominates the clinical picture," however, the effects of riluzole in reducing pain in patients with CSM are of clinical interest and merit further study, perhaps using riluzole for a longer duration.

The findings also have important implications for patients with traumatic spinal cord injury, where neuropathic pain is highly prevalent and which severely impairs quality of life, he added. 

Results Warrant Further Study

The study's invited discussant was Robert F. Heary, MD, professor of neurosurgery and director of the Spine Center of New Jersey, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark. He said the CSM-Protect trial was "well-performed" and he commended the investigators for "their responsible interpretation of the results."

He, too, found the findings promising, with caveats. "Although the study did not show significance with the primary outcome, multiple secondary outcomes did show trends," he said, noting that improvements in neck pain were significantly greater with riluzole, and there was a trend for improvement at 6 months and 1 year in arm and shoulder pain.  

Heary emphasized that pain associated with CSM and spinal cord injury is a very real problem. "Spinal cord injury patients often list their number one problem to be pain, more so than the lack of ability to use their extremities," he noted.

"The experimental data are optimistic for riluzole relative to pain control, and this scenario may warrant further investigation. However, it needs to be noted this was only a secondary goal of the study."

The study was funded by AOSpine. Fehlings has reported no relevant financial relationships.  Heary has reported receiving financial support from DePuy Synthes Spine, Zimmer Biomet Spine, and Thieme Medical Publications.

AANS Annual Meeting. Presented April 15, 2019. Abstract 203.

For more Medscape Neurology news, join us on Facebook and Twitter


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: