Effectiveness of Non-Pharmacological Interventions for Fatigue in Long COVID: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
TL;DR
Exercise-based rehabilitation currently has the most consistent evidence base among the evaluated modalities, although the difference in effects between intervention modalities was not statistically significant.
Abstract
Background: Persistent fatigue is one of the most common and disabling symptoms of long COVID, yet no pharmacological treatments are currently established. Non-drug strategies are increasingly used, but evidence directly comparing these approaches remains limited. This systematic review and meta-analysis evaluated the effects of non-pharmacological interventions on fatigue in adults with long COVID and explored potential sources of heterogeneity. Materials and Methods: Following PRISMA 2020 and the Cochrane Handbook, we searched four databases from inception to December 2025 for RCTs comparing non-pharmacological interventions with control conditions in adults with WHO-defined long COVID. The primary outcome was pre-specified as fatigue severity; no secondary outcomes were pre-specified. Methodological quality was assessed using the RoB 2 tool. Random-effects models were used to pool SMDs, with exploratory subgroup, sensitivity, and publication bias analyses. Results: Thirteen RCTs (1276 participants) were included. Non-pharmacological interventions significantly reduced fatigue [SMD = −0.43, 95% CI: −0.68 to −0.18, p < 0.001], with substantial heterogeneity (I2 = 72.1%). Subgroup analyses showed that exercise training yielded significant benefit [SMD = −0.64, 95% CI: −1.11 to −0.18, p = 0.006], whereas cognitive behavioural therapy, non-invasive neuromodulation, and nutritional supplementation did not reach statistical significance. Interventions lasting ≥8 weeks were associated with greater improvement (between-subgroup p = 0.027). Sensitivity analyses confirmed robustness, and no publication bias was detected. Conclusions: Non-pharmacological interventions, particularly exercise-based programmes, are associated with reduced fatigue in people with long COVID, with interventions lasting ≥8 weeks showing greater average improvements. Exercise-based rehabilitation currently has the most consistent evidence base among the evaluated modalities, although the difference in effects between intervention modalities was not statistically significant (p = 0.286). Further high-quality trials are required to determine the comparative effectiveness of emerging approaches and to identify optimal treatment strategies.