N-acetyl Cysteine Safe, But Failed to Lessen MS Fatigue

Treatment with the antioxidant N‐acetyl cysteine is well-tolerated, but failed to outperform a placebo at easing fatigue in people with progressive multiple sclerosis (MS), a small clinical trial found.

More studies now are needed to determine if oxidative stress contributes to fatigue or clinical progression in MS patients, and whether greater and more frequent doses of this treatment could have an effect on patients.

The findings were published in the Annals of Clinical and Translational Neurology, in the study, “A pilot study of oxidative pathways in MS fatigue: randomized trial of N‐acetyl cysteine.”

Oxidative stress is a phenomenon in which molecules called reactive oxygen species build up in cells and tissues, causing damage to a variety of cellular structures. Increased oxidative stress has been implicated in the development and progression of MS, although the relationship between oxidative stress and fatigue, a common symptom of MS, is unclear.

Antioxidants are compounds that can reduce oxidative stress. N-acetyl cysteine, or NAC, is an antioxidant that acts similarly to glutathione, which is a naturally-occurring antioxidant in the brain that is reduced in people with progressive MS and in those with chronic fatigue.

NAC is generally safe for use in people; it is approved for the treatment of acetaminophen-induced hepatotoxicity (a kind of liver damage characterized by increased oxidative stress).

A team led by researchers at the University of California, San Francisco conducted a small, investigator-sponsored clinical trial (NCT02804594) to test NAC as a treatment for fatigue in people with progressive forms of MS.

“We aimed to evaluate associations of oxidative pathways and fatigue in MS through a pilot randomized placebo-controlled trial evaluating an antioxidant, NAC, for patients with progressive MS and fatigue,” the researchers wrote.

The team analyzed data for 15 trial participants: 10 were given NAC (at a dosage of 1,250 mg), and five were given placebo, taken by mouth three times daily (with breakfast, lunch, and dinner) for four weeks.

Among these participants, two-thirds had primary progressive MS, and the rest had secondary progressive MS. Most of the participants were white and female, and all had clinically significant fatigue prior to the trial.

The trial’s main goal was to evaluate treatment safety and tolerability, as determined by the number of recorded adverse events side effects). Rates of adverse events were similar among participants given NAC or placebo. There were no serious adverse events, and most recorded adverse events were not attributable to treatment with NAC.

Two adverse events — an instance of abdominal pain and one of constipation — were deemed related to treatment with NAC. Both events occurred in the same participant. They went away when treatment was interrupted, and did not recur when treatment was resumed six days later. Another participant on NAC experienced a headache.

“NAC was well‐tolerated and appeared safe,” the researchers concluded.

“There were occasional gastrointestinal [digestion-related] side effects and headaches,” which is consistent with the known safety profile of NAC, they added.

The effect of treatment on fatigue was assessed using validated questionnaires, including the Modified Fatigue Impact Scale and Fatigue Severity Scale. In both NAC and placebo groups, the severity of fatigue lessened over the course of the study, but there were no statistically significant differences between the groups for any of the measures.

Levels of glutathione and other biological markers (biomarkers) related to oxidative stress also did not differ significantly between the groups.

“While the hypothesis that NAC was safe and tolerable was met, hypotheses of a beneficial effect of NAC on fatigue or … biomarkers of oxidative stress were not met,” the team wrote.

The researchers noted that this study was limited by its small sample size, and they pointed to a need for further research to determine the best dosage of NAC for use in this type of treatment.

They team said the results also highlight the strong placebo effect that can occur when testing treatments meant to ease fatigue, since clinically significant improvements were seen among participants given both NAC and placebo.

Such an effect may make it difficult to assess an investigational therapy’s efficacy. But, conversely, “strategies to harness the placebo effect for clinical treatment may prove useful if an ethical balance can be achieved,” the researchers wrote.

The team called for more research into whether NAC, or targeting oxidative stress more generally, might be a useful strategy for managing fatigue among people with MS.