Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN
J Neurol NeuroSurg Psychiatry 2002 Feb;72(2):179-83
Ohio State University, Department of Neurology, 449 Means Hall, 1654 Upham Drive, Columbus, Ohio 43210, USA
To assess the efficacy and safety of Modafinil for the treatment of Fatigue in Multiple Sclerosis (MS).
Patients aged 18-65 years with a diagnosis of MS, a stable disability level < or = 6 on the Kurtzke Extended Disability Status Scale (EDSS).
And a mean score > 4 on the Fatigue Severity Scale (FSS) were eligible for the 9 week, single blind, phase 2, two center study.
Exclusion criteria included a diagnosis of Narcolepsy, Sleep Apnea, or clinically significant major systemic disease and recent use of medications affecting Fatigue.
All patients, who remained blinded for the treatment regimen, received placebo during weeks 1-2, 200 mg/day Modafinil during weeks 3-4, 400 mg/day Modafinil during weeks 5-6, and placebo during weeks 7-9. Safety was evaluated by unblinded investigators.
Efficacy was evaluated by self rating scales, using the FSS, the Modified Fatigue Impact Scale (MFIS), a Visual Analogue Scale for Fatigue (VAS-F), and the Epworth Sleepiness Scale (ESS). Adverse events were recorded.
Seventy two patients (MS type: 74% Relapsing/Remitting; 7% Primary/Progressive; 19% Secondary/Progressive) received treatment.
After treatment with 200 mg/day Modafinil for 2 weeks, a significant improvement in Fatigue versus placebo run in was demonstrated.
Mean scores after treatment with 200 mg/day Modafinil were: FSS, 4.7 versus 5.5 for placebo (p< 0.001); MFIS, 37.7 versus 44.7 (p< 0.001); and VAS-F, 5.4 versus 4.5 (p=0.003).
Fatigue scores for 400 mg/day Modafinil were not significantly improved versus placebo run in.
Mean ESS scores were significantly improved (p< 0.001) with 200 mg/day Modafinil (7.2) and 400 mg/day (7.0) versus the score at baseline (9.5).
Serious adverse events were not found at either dose. The most common adverse events were Headache, Nausea, and Asthenia. Sixty five patients (90%) completed the study.
These data suggest that 200 mg/day Modafinil significantly improves Fatigue and is well tolerated in patients with MS.
- J Neurol NeuroSurg Psychiatry. 2002 Feb;72(2):150
The aim was to measure changes in walking patterns and self rated Fatigue in people with Multiple Sclerosis (MS) compared with age matched control subjects, from the morning to the afternoon within a single day.
Fourteen patients with MS and the same number of matched control subjects performed four 10 m gait trials at their preferred walking speed at 10 00 am and then again at 3 00 pm on the same day.
Gait speed, stride length, cadence, and the percentage of the gait cycle spent in double limb support were measured using a foot switch stride analyzer.
Patients with MS also self rated their Fatigue levels in the morning and afternoon using an 11 point scale.
Compared with control subjects, patients walked very slowly, with reduced stride length and around twice as much variability in gait performance.
Although self rated Fatigue significantly increased from the morning to the afternoon, walking patterns remained consistent in both groups over the course of the day.
These findings imply that mechanisms controlling locomotion are separate from those regulating perceived Fatigue.
Objective measures of performance, rather than self report, should be used to monitor change in patients with Multiple Sclerosis.
Modafinil In The Treatment Of Fatigue In Multiple Sclerosis - Results Of An Open-Label Study
Udo A. Zifko, Monika Rupp, Sigrid Schwarz, Harald T. Zipko, Eva M. Maida
Journal of Neurology Volume 249 Issue 8 (2002) pp 983-987
Rehabilitationsklinik Pirawarth Kurhausstr, 100 2222 Bad Pirawarth, Austria;
Arbeitskreis für klinische Forschung in der Neurorehabilitation Kurhausstr, 100 2222 Bad Pirawarth, Austria; Evangelisches Krankenhaus Hans-Sachs-Gasse, Department of Neurology, 10-12 1180 Vienna, Austria
Modafinil is a unique wake-promoting agent that is chemically distinct from traditional stimulants. Results of a placebo-controlled study showed it to improve Fatigue in Multiple Sclerosis (MS) at a dose of 200 mg daily, but not at a dose of 400 mg daily.
To establish the efficacy, safety and appropriate dose of Modafinil in the treatment of Fatigue and sleepiness in patients with Multiple Sclerosis.
A total of 50 patients diagnosed with MS (mean age 40.4 ± 10.3 years, 30 females/20 males; MS type: 36 Relapsing/Remitting, 1 Primary/Progressive, 13 Secondary/Progressive; mean disability level 3.8 ± 1.5 on the Kurtzke EDSS) and complaining of chronic Fatigue were enrolled in a prospective 3-month, two-center, open-label study.
Efficacy was evaluated with the Fatigue Severity Scale (FSS, score range 0-42), the Epworth Sleepiness Scale (ESS, score range 0-24) and by subjective patient appraisal of change of Fatigue, quality of life and overall satisfaction with treatment.
Adverse effects (AEs) were recorded throughout the study. Treatment was started with a single daily dose of 100 mg in all patients. In non-responders the dose was increased by 100 mg increments up to a maximum daily dose of 400 mg.
Three patients discontinued Modafinil because of AEs (Nervousness, Dizziness). Two patients (4 %) were treated with 50 mg, 25 (50 %) with 100 mg, 21 (42 %) with 200 mg and 2 (4 %) with 300 mg daily. No patient required 400 mg daily.
Mean FSS scores were 30.3 ± 8.5 at baseline and 25.4 ± 3.7 at 3 months (p < 0.0001). Mean ESS scores were 9.7 ± 3.9 at baseline and 4.9 ± 2.9 at 3 months (p < 0.0001).
Self-appraisal of change of Fatigue showed clear improvement in 41 patients (87.2 %), some improvement in 4 (8.5 %) and no change in 2 (4.3 %).
Overall clinical condition was clearly improved in 43 patients (91.5 %), somewhat improved in 1 patient (2.1 %), and unchanged in 3 patients (6.4 %). No patient reported worsening of overall clinical condition.
Treatment with Modafinil significantly improves Fatigue and sleepiness and is well tolerated by patients with MS. Unlike the higher dose regimen required in Narcolepsy, a low-dose regimen of Modafinil is effective in MS.
PhysioPathology And Treatment Of Fatigue In MS
Comi G, Leocani L, Rossi P, Colombo B
J Neurol 2001 Mar;248(3):174-9
University of Milan, Department of NeuroScience, Scientific Institute H. San Raffaele, Via Olgettina 60, 20132 Milan, Italy
Fatigue is a common symptom of patients with Multiple Sclerosis (MS). It is reported by about one-third of patients, and for many Fatigue is the most disabling symptom.
Fatigue may be associated with Motor Disturbances and/or Mood Disorders, which makes it very difficult to determine whether the Fatigue is an aspect of these features or a result per se of the disease.
Although peripheral mechanisms have some role in the pathogenesis of Fatigue, in MS there are clear indications that the more important role is played by "central" abnormalities.
NeuroPhysiological studies have shown that Fatigue does not depend on involvement of the Pyramidal Tracts and implicate impairment of volitional drive of the Descending Motor Pathways as a PhysioPathological mechanism.
Metabolic abnormalities of the Frontal Cortex and Basal Ganglia revealed by Positron-Emission Tomography and correlations between Fatigue and Magnetic Resonance Imaging lesion burden support this hypothesis.
Some recent studies also suggest that ProInflammatory Cytokines contribute to the sense of tiredness.
No specific treatments are available. Management strategies include medications, exercise, and behavioral therapy; in most cases a combined approach is appropriate.