Fatigue is one of the most common symptoms of MS and can have a major impact on people’s lives. Clinical trials of medications for fatigue have given mixed results. The aim of this study was to compare the effectiveness, safety, and acceptability of amantadine, modafinil and methylphenidate with placebo in people with MS-related fatigue.
Two MS clinics in the United States recruited 141 participants with MS who were affected by fatigue and had low to moderate disability.
Participants were assigned to take the medications (amantadine, modafinil, methylphenidate and placebo) in one of four sequences. They started taking one medicine and took it for six weeks, followed by a two-week washout period and repeated this process for all three medicines and the placebo. Neither participants nor the researchers knew which medication they were currently taking. Fatigue was measured at the beginning of the study and again during week 5 of each treatment period.
Fatigue levels improved with all treatments, including placebo. There was no significant difference between the treatments. However, there was some indication that modafinil and methylphenidate could be beneficial when daytime sleepiness was a significant contributor to fatigue levels. Side effects were more common with the three medications than with placebo.
The researchers concluded that the lack of effect on fatigue levels compared to placebo, and the increased risk of side effects, do not support the routine use of amantadine, modafinil or methylphenidate for treating fatigue in MS.
Fatigue is one of the most common symptoms of MS and can have a major impact on people’s lives. Clinical trials of medications for fatigue have given mixed results. The aim of this study was to compare the effectiveness, safety, and acceptability of amantadine, modafinil and methylphenidate with placebo in people with MS-related fatigue.
How this study was carried out
Two MS clinics in the United States recruited 141 participants with MS who were affected by fatigue and had low to moderate disability.
Participants were assigned to take the medications (amantadine, modafinil, methylphenidate and placebo) in one of four sequences. They started taking one medicine and took it for six weeks, followed by a two-week washout period and repeated this process for all three medicines and the placebo. Neither participants nor the researchers knew which medication they were currently taking.
Methylphenidate, also known as Ritalin, is a central nervous system stimulant used to treat narcolepsy and attention deficit hyperactivity disorder. In the States it is sometimes used to treat MS fatigue, but is rarely used for this purpose in the UK.
Fatigue was measured at the beginning of the study using the Modified Fatigue Impact Scale (MFIS) and again during week 5 of each treatment period. MFIS is a questionnaire which you complete yourself. It assesses the impact of fatigue on different aspects of daily life: physical activity, thinking processes and taking part in social activities. People were included in the study if their MFIS was 33 or greater. You can test yourself using MDCalc's online Modified Fatigue Impact Scale.
Participants also completed the Epworth Sleepiness Scale (ESS) which measures daytime sleepiness and a questionnaire which assessed the impact of fatigue on quality of life.
At the beginning of the study the MFIS score was 51.3 out of a maximum possible score of 84 for the worst fatigue. MFIS scores improved with all treatments, including placebo:
- 51.3 at baseline
- 40.6 with placebo
- 41.3 with amantadine
- 39.0 with modafinil
- 38.6 with methylphenidate
There was no significant difference between any of the treatments.
When the data was analysed more closely, those people who had excessive daytime sleepiness at the start of the study (ESS greater than 10) had improved fatigue levels while taking modafinil and methylphenidate, compared to placebo. In people with no excessive daytime sleepiness, there was no significant difference in fatigue levels between any of the treatments and placebo.
Side effects were more common with the three medications than with placebo, affecting 39% of participants on amantadine and 40% on modafinil and methylphenidate, compared with 31% on placebo.
The design of the study reduced the likelihood that participants could guess which drug they were currently taking; in studies which compare a single fatigue drug with placebo, side effects can allow participants to recognise when they are taking the active treatment, and this can influence the results. The study was carried out at two study centres, with a relatively small group of people, and participants took each treatment for six weeks. Results might differ in other places, with longer-term use of medicines or a larger study.
Overall, the results of this study suggest that none of the medications is more effective than placebo at reducing fatigue levels. However, there was some indication that modafinil and methylphenidate could be beneficial if daytime sleepiness is a significant contributor to fatigue levels.
The researchers concluded that the lack of effect on fatigue levels compared to placebo, and the increased risk of side effects, do not support the routine use of amantadine, modafinil or methylphenidate for treating fatigue in MS.
Nourbakhsh B, Revirajan N, Morris B, et al.
Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial.
Lancet Neurol. 2021 Jan;20(1):38-48.
Find out more about managing fatigue
Fatigue is believed to be the most common symptom in MS and it can often have a major impact on people's lives. The causes of fatigue in MS are not well understood and it is thought to be a combination of factors. It can be caused by the MS itself, through 'short-circuiting' nerves and it can be caused partly by other factors, including heat, inadequate diet, poor fitness and stress. As there are several causes of fatigue, there are also a number of ways that it can be managed and its impact reduced. Most management techniques revolve around ensuring the best levels of energy are available and then using the energy in the most efficient way.
- Sleep. Poor sleep can make fatigue worse. Establishing a bedtime routine, avoiding caffeine and winding down before bedtime can improve sleep quality.
- Heat. Many people find that heat makes their MS worse and can make them feel more fatigued, especially during the summer months. There are several tips for keeping cool on our website, including having regular cold drinks and tepid showers.
- Nutrition. A poor diet and nutrition can make fatigue worse. Sugary snacks might give an initial boost, blood sugar levels quickly drop again leaving energy levels low. A balanced diet can help reduce fatigue and improve energy levels, but preparing food can be tiring work. There are a number of suggestions in Living with fatigue for reducing the impact of fatigue when preparing and eating meals.
- Relaxation techniques. Relaxation can help with fatigue as it promotes good sleep patterns, increases benefit from rest periods during the day and can be used to manage stressful situations.
- Exercise. In the past, people with multiple sclerosis were advised to avoid exertion but now it is known that muscles that are not used regularly become weakened and require more energy to do tasks, making fatigue worse. Exercise can be something energetic or something more leisurely.
How to use energy efficiently
- Planning. This involves taking some time to stop and think about what needs to be done and what can be achieved. Avoid doing too many energy-demanding activities in a short period of time.
- Prioritising and delegating. If energy is limited, this involves working out what are the most important tasks that need to be done and what can wait for another day when energy levels might be higher. Alternatively, the task can be shared or someone else can be asked to help out.
- Organisation. It is helpful to have everything to hand when doing a task, this prevents unnecessary rushing around gathering items.
- Pacing. This involves taking planned breaks or rests within or between activities, doing things more slowly when energy levels are lower, or breaking tasks up into smaller activities.
You can learn more about techniques for managing fatigue in the A-Z of MS or our free Living with fatigue book which you can download or order as a printed version.
