Provigil (Modafinil) for Fatigue in Multiple Sclerosis

Provigil (modafinil) is a medication that increases wakefulness in adults with narcolepsy or sleep apnea. Provigil was developed by Cephalon (now part of Teva Pharmaceuticals) but is now available from many companies as a generic.

Provigil can also be used to treat fatigue caused by multiple sclerosis (MS).

How Provigil works

MS is a disease characterized by the immune system mistakenly attacking the fatty coating that protects nerve fibers from damage and increases the speed of nerve signals along the fibers. Without this protective coating, nerve cells are easily damaged, causing the symptoms of MS.

More than 70 percent of MS patients experience fatigue. Fatigue management plans can be used to improve patients’ quality of life, but medications like Provigil are also often prescribed.

The precise mechanism of action of Provigil is not known. Experiments using cells grown in the laboratory have shown that Provigil binds to the dopamine reuptake pump, a protein involved in clearing dopamine (a neurotransmitter or cell-signaling molecule) after a nerve signal has been sent. It is thought that Provigil may lead to an increase in dopamine by blocking its clearance, making more dopamine available for the transmission of nerve signals.

Provigil in clinical trials

The results of a clinical trial to establish the efficacy, safety, and appropriate dosage of Provigil in the treatment of fatigue in patients with MS were published in the Journal of Neurology.

A total of 50 MS patients were enrolled in the open-label study. Efficacy was evaluated using the fatigue severity scale, the Epworth sleepiness scale, and by a subjective patient appraisal of change in fatigue, quality of life, and overall satisfaction with treatment. Adverse events were recorded throughout the study.

Treatment was started with a single daily dose of 100 mg of Provigil in all patients. In nonresponders, the dose was increased by 100 mg increments up to a maximum daily dose of 400 mg. Three patients discontinued treatment because of adverse events such as dizziness and nervousness. Significant improvements in patients’ fatigue were observed at the end of three months.

Overall, the clinical condition of 91.5 percent of patients was improved with no patients reporting a worsening in their clinical condition.

A Phase 3 clinical trial (NCT03185065) comparing the effects of Provigil, methylphenidate, ADS-5102 (a delayed-release formulation of amantadine), or placebo in treating fatigue in MS patients is currently ongoing. A total of 140 participants are randomly divided into four groups and receive treatment with either medication or a placebo. The trial is active but no longer recruiting participants. It is expected to be completed in December.

A Phase 4 clinical trial (NCT03621761) is currently recruiting 330 MS patients in Michigan and Washington state to compare the effectiveness of three treatments for fatigue in MS: a commonly used behavioral treatment strategy (telephone-based cognitive behavioral therapy), Provigil treatment, and a combination of both. Participants will be randomly assigned to one of the three groups and receive treatment for 12 weeks. The primary outcome measure will be the modified fatigue impact scale (MFIS) score, a questionnaire that evaluates fatigue.


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