Modafinil, methylphenidate, and amantadine were not superior to placebo in improving multiple sclerosis (MS) fatigue and resulted in more frequent adverse events, the TRIUMPHANT-MS trial found.
“Our results support the notion that most of the benefits that have been reported in the clinical use of medications for multiple sclerosis fatigue are attributable to the placebo effect,” reported Bardia Nourbakhsh, MD, of Johns Hopkins University in Baltimore, and coauthors in Lancet Neurology.
“The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis,” they wrote.
The trial enrolled 141 MS patients with Modified Fatigue Impact Scale (MFIS) score of more than 33 at two academic MS centers from October 2017 to February 2019. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were scheduled to receive all four study medications in one of four different sequences with 2-week washout periods between agents.
Mean MFIS score was 51.3 (95% CI 49.0–53.6) at baseline. At the maximal tolerated doses, estimated mean values of MFIS scores were 40.6 (95% CI 38.2–43.1) for placebo, 39.0 (95% CI 36.6–41.4) for modafinil, 38.6 (95% CI 36.2–41.0) for methylphenidate, and 41.3 (95% CI 38.8–43.7) for amantadine (P=0.20 for the overall medication effect).
Adverse events were seen in 31% of MS patients on placebo, 40% of those on modafinil, 40% of those on methylphenidate, and 39% of those on amantadine. Three serious adverse events — pulmonary embolism and myocarditis while taking amantadine, and MS exacerbation requiring hospital admission while taking modafinil — were reported.
“The results of the clinical trial by Nourbakhsh and colleagues might surprise some neurologists,” noted Dennis Bourdette, MD, of the Oregon Health and Science University in Portland, in an accompanying editorial. “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,” he wrote. “Placebos have demonstrable effects on the brain, such as analgesic effects via release of endogenous opioids, stimulation of dopamine release in the basal ganglia in Parkinson’s disease, and improving mood and reaction times when compared with psychostimulants. So it really is not surprising to find that placebo can reduce fatigue in people with multiple sclerosis and that a placebo effect is likely to be the primary reason why patients have a reduction in their fatigue when we prescribe medications.”
Fatigue is common in MS, affecting as many as 80% of patients, and is associated with significant quality-of-life impairment. A 2011 study of modafinil for MS fatigue did not support its use for fatigue and showed contradictory results on cognitive performance measures. A 2018 study of methylphenidate found it was less effective than placebo on fatigue, walking, and balance.
Other agents studied have included vitamin B12 injections, L-carnitine, 4-aminopyridine, and pemoline. Some treatments for MS may positively affect fatigue. Approaches combining pharmacologic approaches with behavioral therapy, group therapy, and exercise also have been studied.
In this trial, Nourbakhsh and colleagues recruited adult MS patients who reported fatigue and had an Expanded Disability Status Scale (EDSS) score of 7.0 or less who had not been treated for fatigue in 2 weeks preceding the trial. Average age was 47 and 77% were female. Relapsing-remitting (75%), secondary progressive (13%), and primary progressive (11%) forms of MS were included.
At the time of screening, 79% of participants were taking a disease-modifying therapy. Mean EDSS was 3.0.
The highest mean tolerated doses of medications in the study were 186.4 mg/day for amantadine, 178.3 mg/day for modafinil, and 17.5 mg/day for methylphenidate.
No significant treatment effect on MFIS physical and cognitive subscales was seen, but in pairwise comparisons, methylphenidate improved the psychosocial MFIS subscale compared with placebo (adjusted mean difference −0.5, 95% CI −0.8 to −0.1).
“The average MFIS total score (on a scale from 0 to 84) improved by approximately 10 points on average from baseline in the placebo group, which is similar to previous trials in multiple sclerosis fatigue,” the researchers noted. “Compared with placebo, the MFIS score improved by 0.7 points less on average with amantadine, whereas it improved slightly more with modafinil (1.6 points) and methylphenidate (2.0 points). These differences were neither statistically nor clinically significant, as a minimum difference of four to eight points has been reported to be clinically meaningful.”
“We should recognize that other interventions, such as exercise programs, starting a healthy diet, participating in cognitive behavioral counseling, or attending group education programs about multiple sclerosis, can improve fatigue, perhaps related to placebo effects, but without the side-effects of medications,” Bourdette said. “Until we have an understanding of the pathophysiology of multiple sclerosis fatigue and medications of proven efficacy, recommending non-medicinal interventions for multiple sclerosis fatigue seems prudent.”
Limitations include a study population that recruited from two specialty clinics, which may affect generalizability. “To be closer to the pragmatic end of the pragmatic-explanatory continuum, we did not assess treatment adherence and simplified the study procedures by minimizing the in-person visits,” the researchers pointed out. “The results of the study could be different if the adherence was monitored, and the outcomes were measured in the clinic.”
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Modafinil, methylphenidate, and amantadine were not superior to placebo in improving multiple sclerosis (MS) fatigue and resulted in more frequent adverse events, the TRIUMPHANT-MS trial found.
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Benefits reported in clinical use of these medications for MS fatigue may attributable to placebo effect, the researchers and the editorialist said.
Paul Smyth, MD, Contributing Writer, BreakingMED™
Funding for this study was from the Patient-Centered Outcomes Research Institute (PCORI).
Nourbakhsh has received funding from the National MS Society, PCORI, and Genentech, and personal fees from Jazz Pharmaceutical.
Bourdette has founder stock in Autobahn Therapeutics, which is developing a drug to promote remyelination in multiple sclerosis and receives fees for consultations for Best Doctors and Magellan Health.
Cat ID: 36
Topic ID: 82,36,36,192,925
