RATIONALE: Despite the high prevalence and medico-social significance of fatigue in post-traumatic brain injury (post-TBI) populations, there are no validated management strategies to control this condition. It is timely to provide clinicians and patients with the best available evidence of the efficacy of current pharmacological and non-pharmacological fatigue management practices.

OBJECTIVES: To assess the effectiveness of pharmacological and non-pharmacological interventions for fatigue in people who have experienced a TBI.

SEARCH METHODS: For this review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO. We also searched relevant conference proceedings, and we searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for ongoing trials. The most recent searches were conducted on 12 February 2025.

ELIGIBILITY CRITERIA: Eligible study designs were randomised controlled trials (RCTs) and randomised cross-over trials (for pharmacological interventions only). Studies with participants of all ages (children and adults) with a TBI (of any severity) were included, where at least 75% of participants had a TBI. Any type of treatment for fatigue was considered. Four categories of interventions were prioritised: pharmacological, cognitive, stimulation/biofeedback, and psychoeducational. These interventions were compared to placebo groups, no treatment, or groups receiving other interventions.

OUTCOMES: The critical outcome was fatigue. Important outcomes include fatigue-related outcomes of psychological functioning (depression and anxiety), cognitive functioning (processing speed), general quality of life, and daytime sleepiness.

RISK OF BIAS: We assessed risk of bias using the original Cochrane risk of bias tool for RCTs (RoB 1).

SYNTHESIS METHODS: We synthesised the results for each outcome by meta-analysis where possible using mean differences (MDs) and standardised mean differences (SMDs) and a fixed-effect model. Where meta-analysis was not possible due to the nature of the data, we narratively reported the results. We used GRADE to assess the certainty of evidence for each outcome. We performed all statistical analyses using RevMan and presented results with 95% confidence intervals (CI).

INCLUDED STUDIES: We included a total of 3518 trial participants (at baseline) across 40 studies, described in 49 publications. The 40 included studies are grouped by type of intervention. There were seven categories of interventions: pharmacological, cognitive, physical activity, stimulation/biofeedback, health visits, psychoeducational, and a final category for trials with multiple interventions (multi-interventions). Four published studies identified in the most recent search are awaiting classification.

SYNTHESIS OF RESULTS: Pharmacological interventions (melatonin; recombinant human growth hormones (rhGH); psychostimulants; atorvastatin; monoaminergic stabiliser (-)-OSU6162) likely reduce fatigue slightly (SMD -0.25, 95% CI -0.44 to -0.06; 8 studies, 395 participants; moderate-certainty evidence). Cognitive interventions (cognitive rehabilitation; technology-enhanced training; functional skills training) may reduce fatigue slightly (MD -0.32, 95% CI -0.59 to -0.06; 6 studies, 222 participants; low-certainty evidence). Stimulation/biofeedback interventions (light therapy; electrical/magnetic stimulation; acupressure) may reduce fatigue slightly, but the evidence is very uncertain (SMD -0.23, 95% CI -0.47 to 0.01; 8 studies, 295 participants; very low-certainty evidence). Psychoeducation interventions (cognitive behavioural therapy; acceptance and commitment therapy; individualised occupational therapy; novel therapies) may reduce fatigue, but the evidence is very uncertain (SMD -0.55, 95% CI -0.74 to -0.35; 8 studies, 474 participants; very low-certainty evidence). There may be little to no difference in psychological functioning (depression), psychological functioning (anxiety), cognitive functioning (processing speed), or daytime sleepiness. However, these results are very uncertain.

AUTHORS' CONCLUSIONS: There is very limited and moderate to very low-certainty evidence from RCTs about treatments to reduce fatigue after TBI. Despite the prevalence of fatigue post-TBI, we lack high-quality studies that evaluate interventions to improve this disabling, but potentially treatable, symptom. There is a need for considerable further work to identify an effective treatment for fatigue in people with TBI.

FUNDING: This Cochrane review had no dedicated funding.

REGISTRATION: Protocol available via DOI: 10.1002/14651858.CD006448.

Physical Medicine and Rehabilitation rater

This high-quality systematic review and meta-analysis using Cochrane methodology concludes that most interventions have too little evidence to draw any conclusions; however, a few have weak evidence of a weak positive effect. There is insufficient evidence to make any treatment even moderately recommended. The depressing facts: 3518 patients; 40 studies (i.e., average of 90 people in each study); 7 categories of intervention (I estimate about 30 different interventions). We need to: a. develop a strong evidence-based rationale for specific treatments; (b) THEN form large collaborative groups to research a single intervention at a time; AND (c) when a treatment is shown to be effective with a reasonable clinically relevant effect OR the trial shows that the chance of a worthwhile benefit is too small to justify further research, we should STOP and move to the next intervention.

Psychiatry rater

A systematic review's value is partially dependent on the number of qualifying studies. While n=40 is impressive, it becomes less so when considering there were at least 14 different interventions. Consequently, there were a very small number of studies for each intervention.