Amantadine, Modafinil, Methylphenidate Not Superior To Placebo For MS Fatigue

Amantadine, modafinil, and methylphenidate are not superior to placebo for improving multiple sclerosis fatigue but the medications do cause more adverse events, a clinical trial found.

The placebo-controlled, four-sequence, four-period, crossover, double-blind trial randomly assigned 141 patients with multiple sclerosis who reported fatigue to one of four intervention groups to receive each of the three drugs and the placebo in a different sequence. Each treatment period lasted up to six weeks, with a 2-week washout period separating treatment periods, and included one of the following: oral amantadine (up to 100 mg twice daily); modafinil (up to 100 mg twice daily); methylphenidate (up to 10 mg twice daily); or placebo.

At baseline, all the participants had a Modified Fatigue Impact Scale (MFIS) score of at least 33 (mean 51.3) out of a maximum possible score of 84 for the worst fatigue. The primary endpoint was MFIS score after five weeks of treatment with the maximum tolerated dose for each medicine.

At five weeks, the mean MFIS score with placebo was 40.6, and the mean MFIS score at the maximum tolerated dose with amantadine was 41.3, with modafinil 39.0, and 38.6 with methylphenidate. These differences were not statistically significant.

"The take-home message from this study is that we still do not have good pharmacological options for treating fatigue in multiple sclerosis," said lead study author Dr. Bardia Nourbakhsh, an assistant professor of neurology at Johns Hopkins University in Baltimore.

"Non-pharmacological options such as exercise and cognitive-behavioral therapy are perhaps better alternatives at this point," Dr. Nourbakhsh said by email.

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Adverse events were more common with each of the medications than placebo, affecting 39% of participants on amantadine and 40% of patients on modafinil and methylphenidate, compared with 31% on placebo.

All three serious adverse events in the study occurred in patients taking medication. On amantadine, there was a report of pulmonary embolism and a report of myocarditis. One person had a multiple sclerosis exacerbation requiring hospitalization while taking modafinil.

One limitation of the study is that it was conducted at two specialty clinics for multiple sclerosis, and the results may not be generalizable to all patients with the condition.

Another limitation is that the brief treatment period used. Results for safety and efficacy might look different with long-term use or at higher doses of the study drugs, the researchers note in The Lancet Neurology.

It's also possible that a larger trial might have allowed researchers to detect small but statistically significant differences in mean MFIS scores after treatment, said Dr. Dennis Bourdette, author of an editorial accompanying the study and a professor emeritus of neurology at Oregon Health & Science University in Portland.

"If these differences held for a much larger sample size, they could have achieved statistical significance," Dr. Bourdette said by email. "However, such small differences in the MFIS scores would not be clinically meaningful."

Clinicians prescribing these medicines for fatigue shouldn't expect them to work for this purpose, Dr. Bourdette said.

"We really do not understand what causes multiple-sclerosis-related fatigue, which makes it difficult to devise a treatment that actually works better than placebo," Dr. Bourdette added.

—Lisa Rapaport

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