Neuropathic Pain in Multiple Sclerosis: The Efficacy of 3 Neuroprotective Drugs

The researchers sought to determine whether the use of fluoxetine, riluzole, and amiloride led to an improvement in neuropathic pain compared with placebo in patients with SPMS in a trial.

Fluoxetine, riluzole, and amiloride did not compare favorably with placebo for improving neuropathic pain symptoms in adults with secondary progressive multiple sclerosis (SPMS), according to a study published in Multiple Sclerosis and Related Disorders.

Pain impacts about 70% of people with SPMS, but there is limited evidence to guide treatment decisions. A recent phase 2b double-blind randomized controlled trial compared fluoxetine, riluzole, and amiloride, which are commonly used and tolerated, with placebo across 445 adults with SPMS, assessing pain and brain volume loss.

Researchers in the current study conducted a pre-specified secondary analysis of neuropathic pain severity from the MS-SMART trial cohort and analyzed whether overall pain severity is associated with brain imaging variables. They hypothesized that at least 1 experimental trial agent would affect neuropathic pain severity because the drugs had indicated they impacted pain pathways.

Adults in the UK (n=445) aged 25 to 65 with SPMS and Expanded Disability Status Score (EDSS) between 4.0 and 6.5 were randomly assigned to fluoxetine 20 mg, riluzole 50 mg, amiloride 5 mg (n=111 each), or placebo tablets (n=112) daily for 4 weeks and then twice daily until trial completion at 96 weeks. Patients with moderate-severe depression were excluded from the study.

Overall past-week pain intensity on a numerical rating scale was 3.07 at baseline (99.3% reporting).

Regression analysis at 96 weeks indicated no statistically significant benefit in neuropathic pain symptoms for the drugs compared with placebo. Overall pain or pain interference did not improve at study complete in any group. There was a weak yet statistically significant positive correlation of depressive and fatigue symptoms and both pain severity and NPS sum score.

The study findings do not support the use of fluoxetine, riluzole or amiloride for the treatment of neuropathic pain related to SPMS, the researchers stated.

Study limitations included generalization to patients with other MS subtypes, such as primary progressive and relapsing remitting MS.

“From a mechanistic perspective, neither modulation of glutamatergic or serotonergic pathways, nor of acid-sensing ion channels, was associated with analgesia in this population. These results add to a limited yet clinically important evidence base concerning treatment of neuropathic pain in pwMS, and in people with secondary progressive MS in particular,” the researchers concluded.


Foley P, Parker RA, De Angelis F, et al. Efficacy of fluoxetine, riluzole and amiloride in treating neuropathic pain associated with secondary progressive multiple sclerosis. Pre-specified analysis of the MS-SMART double-blind randomised placebo-controlled trial. Multiple Sclerosis and Related Disorders. Published online May 28, 2022. doi: 10.1016/j.msard.2022.103925