Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study
Stankoff B, Waubant E, Confavreux C, Edan G, Debouverie M, Rumbach L, et al.;
Commented by , 20 May 2005
Background
Fatigue is one of the most disabling and common symptoms in MS. The efficacy of pharmacological treatment has generally been poor in placebo controlled clinical trials (amantadine and pemoline). Modafinil is a wakefulness-drug introduced for treatment of narcolepsy and pilot trials have shown promising results in MS patients with fatigue (ref. 1; ref. 2). Still, these trails are either single blinded or open labelled and there is an evident need for a randomized, placebo-controlled, double-blind trail evaluating the efficacy of modafinil, which the paper by Stankoff et al provides.
Aim
To evaluate the efficacy and safety of modafinil for treatment of fatigue in MS in a randomized, double-blind, placebo-controlled, parallel group study.
Methods
The authors studied 115 MS patients with relapsing remitting or progressive disease, stable disability and a baseline score of 45 or more on the Modified Fatigue Impact Scale (MFIS). Fifty-six patients were randomized to receive treatment with modafinil, initially 100 mg twice a day increasing by 100 mg every week to 400 mg/day depending on tolerance. Fifty-nine patients received placebo.
The primary outcome variable was change of MSIF at day 35 and statistical evaluation consisted of intention-to-treat (ITT) analysis as well as ANOVA. Furthermore, Fatigue Impact Scale, Epworth Sleepiness scale and Montgomery/Asberg Depression Rating Scale was performed.
Results
The mean MFIS score was 63 ± 9 at baseline in the placebo group and 63 ± 10 in the modafinil group. The MFIS score improved in the treatment period in the placebo group (49 ± 17) as well as in the modafinil group (52 ± 19).
This effect was significant in both groups (p < 0,001) although there was no significant difference between the two groups. Similar results were found using other fatigue rating scales. No patient worsened in EDSS and there was no safety concern.
Dr Blinkenberg's comments
The study showed no improvement of fatigue in MS patients treated with modafinil compared with placebo, which is problematic since the drug is widely used and the cost of treatment is considerable. Still there are some important questions that need to be answered before firm conclusions can be made.
The responsiveness of the MFIS has not been characterized in longitudinal studies and to what extent this self reported questionnaire reflects fatigue rather than e.g. cognitive impairment has not been clarified. Another important issue is the heterogeneity of fatigue as a symptom, covering excessive daytime sleepiness, lack of energy or a more classic wear out phenomenon.
Furthermore there is comorbidity with depressive disorders and sleep disorders as well as medical conditions, which often confound a proper characterization of the symptom. It will probably be beneficial to stratify patients in future studies in order to improve treatment outcome.
In this regard, the authors propose excessive daytime sleepiness as a better indication for using modafinil in MS patients based on a post hoc analysis of the data. It is evident that we need more studies in this important field, a better characterization and stratification of patients, better methodological validation and possibly also better drugs.
References
1. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002; 72; 179-83. (Note: Free full text article)
2. Zifko UA, Rupp M, Schwarz S, Zipko HT, Maida EM. Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol 2002; 249; 983-7.