Drugs for fatigue in MS are just placebo – with side effects

Multiple sclerosis

By Michael Woodhead

24 Nov 2020

Medications commonly prescribed for alleviating fatigue in multiple sclerosis are no better than placebo and may cause side effects, according to a new randomised controlled trial.

Conducted in two MS treatment centres in the US, an RCT involving 141 patients found that drugs such as methylphenidate, modafinil and amantadine had no significant effect on fatigue compared to placebo.

In the study, patients with MS who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 randomised to receive either oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, for up to six weeks.

The trial was designed to allow patients to receive all three study medication and placebo, in turn, with a two week washout periods between medications.

However, data from 136 patients who completed the study showed that although there were some reductions in fatigue, there were no differences between treatment medications and placebo.

From a baseline fatigue (MFIS) scores of 51.3 at baseline the best scores for fatigue achieved with maximum tolerated doses of medication were  41·3 (38·8–43·7) with amantadine, 39·0 (36·6–41·4) with modafinil, and 38·6 (36·2–41·0) with methylphenidate, compared to 40·6 (38·2–43·1) with placebo.

“The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis,” the study authors, led by Dr  Bardia Nourbakhsh, a neurologist at Johns Hopkins University School of Medicine, concludes.

An accompanying commentary notes that about 80% of MS patients have fatigue and it is often their most troublesome problem.

“MS fatigue is complex and difficult to evaluate and treat. Secondary causes of fatigue, such as sleep disturbances, depression, and medication side-effects, warrant consideration and treatment,” it says.

However for primary fatigue, the findings show that drug treatment provides no benefit in a poorly understood condition, and should be used prudently, if at all.

“The results … might surprise some neurologists. We prescribe these drugs for patients with multiple sclerosis who have fatigue and they often report benefit. How can these drugs not be beneficial? The answer lies in the power of the placebo effect,” writes Dr Dennis Bourdette of the Department of Neurology, Oregon Health and Science University.

“We should recognise that other interventions, such as exercise programs, starting a healthy diet, participating in cognitive behavioural counselling, or attending group education programmes about multiple sclerosis, can improve fatigue, perhaps related to placebo effects, but without the side-effects of medications,” he adds.

The findings are published in Lancet Neurology.

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