Study Finds Limited Benefit of Common MS Fatigue Medications
Fatigue is one of the most debilitating symptoms of multiple sclerosis (MS), significantly impacting quality of life. A systematic review and meta-analysis evaluating 4 commonly prescribed medications used to manage MS-related fatigue—amantadine, modafinil, methylphenidate, and 4-aminopyridine—suggests that these drugs offer minimal to no benefit for reducing fatigue severity in people with MS. The study, which synthesized data from 16 randomized controlled trials (RCTs), also found that these treatments are more likely to cause side effects leading to medication discontinuation.
Researchers conducted a systematic search of PubMed and CENTRAL databases to identify RCTs comparing these medications against placebo or other interventions. The primary outcomes were fatigue severity, measured using the Fatigue Severity Scale (FSS) or the Modified Fatigue Impact Scale (MFIS), and the frequency of medication discontinuation due to adverse effects.
A pooled analysis using standardized mean differences (SMD) found a slight reduction in fatigue scores in favor of the medications (-0.26 SMD), translating to a decrease of 0.29 points on the FSS and 3.90 points on the MFIS. However, these changes fell below the minimally important difference (MID) thresholds, meaning they are unlikely to be clinically meaningful. Notably, when only trials comparing the medications to placebo were analyzed, the improvement in MFIS scores reached the MID threshold (-5.85, MID ≥ 4), while the FSS score nearly met the threshold (-0.43, MID ≥ 0.45).
Despite these modest potential benefits, the study found that patients taking the medications were significantly more likely to discontinue treatment due to side effects, with a pooled risk ratio of 2.11 (95% CI, 1.19-3.77), favoring controls. While most included studies showed a low risk of bias, the certainty of evidence was rated as low, making it difficult to draw definitive conclusions about the medications' effectiveness.
Given these results, the researchers emphasize the need for exploring alternative pharmacologic and non-pharmacologic interventions for MS-related fatigue. Future trials should consider personalized treatment approaches and use validated outcome measures such as FSS and MFIS to better assess clinical relevance.
Reference
Toljan K, Aboseif A, Amin M. Efficacy of pharmacologic treatments for fatigue in multiple sclerosis: a systematic review and meta-analysis. Mult Scler Relat Disord. 2025;4:96:106352. doi:10.1016/j.msard.2025.106352
