Modafinil and Traumatic Brain Injury (TBI): Can It Improve Recovery?

Traumatic brain injury (TBI) often leaves lasting effects on a person’s ability to think clearly, stay alert, and recover fully. One of the most debilitating symptoms reported by patients is excessive daytime sleepiness (EDS) and persistent fatigue. These can dramatically reduce quality of life and interfere with participation in rehabilitation.

Modafinil, a central nervous system stimulant originally developed for narcolepsy, has drawn attention for its potential to help TBI patients reclaim wakefulness and restore cognitive stamina. But does the science support its use?

Understanding Traumatic Brain Injury and Its Cognitive Effects

Traumatic brain injury is defined as a disruption in normal brain function caused by a blow, jolt, or penetrating injury to the head. The most common causes include falls, motor vehicle collisions, and sports-related impacts (Capizzi et al., 2020).

Following TBI, fatigue and EDS are among the most reported and persistent symptoms, with prevalence ranging from 21% to 70% (Borghol et al., 2018). These symptoms are not just inconvenient—they actively hinder recovery, delaying physical and occupational therapy outcomes and reducing motivation to engage in treatment.

Moreover, fatigue after TBI has been linked to disrupted sleep cycles, reduced hypothalamic orexin levels, and possibly impaired dopamine signaling (Ng & Lee, 2019).

What Is Modafinil?

Modafinil is a wakefulness-promoting agent approved by the FDA for treating narcolepsy, obstructive sleep apnea, and shift-work sleep disorder (U.S. Food and Drug Administration, 2007). It works by modulating dopamine transporters, thereby increasing extracellular dopamine, especially in brain areas related to alertness (Kumar, 2008).

Unlike traditional stimulants such as amphetamines, modafinil is considered to have a lower abuse potential and a more targeted effect on wakefulness without inducing euphoria or hyperactivity.

Modafinil in TBI: What Does the Research Say?

Clinical Evidence: A Mixed Picture

Several studies have evaluated modafinil and its R-enantiomer, armodafinil, for managing fatigue and EDS in TBI populations—with mixed results.

• Borghol et al. (2018) reviewed 23 articles and noted that while some randomized controlled trials showed benefit, others did not find statistically significant improvements in wakefulness. The most common finding was a reduction in EDS but no meaningful impact on fatigue levels.
• In a double-blind trial, Menn et al. (2014) found that 250 mg of armodafinil significantly improved sleep latency compared to placebo in patients with mild to moderate TBI. However, measures of subjective fatigue (Epworth Sleepiness Scale) were not significantly different between groups.
• According to Kumar (2008), modafinil’s mechanism involves dopaminergic and noradrenergic modulation, which supports alertness but may not fully address the multifactorial causes of post-TBI fatigue.

Mechanistic Rationale

Modafinil is believed to:

• Stimulate wakefulness via dopamine transporter inhibition
• Improve attention and executive function, areas often impaired post-TBI
• Avoid the overstimulation associated with other CNS stimulants (Kumar, 2008)

These effects align with pathophysiological insights into secondary TBI injuries, where dopamine deficits and inflammation exacerbate cognitive and emotional impairments (Ng & Lee, 2019).

Considerations for Use in TBI Recovery

Benefits

• Potential to reduce EDS, especially when other treatments are ineffective
• May improve participation in rehabilitation due to better daytime alertness

Limitations

• Inconsistent effects on fatigue across studies
• Some patients report side effects such as headaches and anxiety (Menn et al., 2014)
• Long-term safety data in TBI patients is limited

Clinical Judgment Required

Not all patients are good candidates for modafinil. It may be inappropriate for individuals with:

• A history of stimulant abuse
• Cardiovascular instability
• Uncontrolled anxiety or mood disorders

Clinicians should closely monitor patients and consider modafinil as part of a broader rehabilitation plan, not a stand-alone solution.

Conclusion: Is Modafinil a Viable Option?

Modafinil offers promise—particularly in addressing excessive daytime sleepiness in TBI patients. However, its effect on overall fatigue and long-term cognitive recovery is less conclusive.

Clinicians and researchers agree that more large-scale studies are needed, especially with diverse patient populations and longer treatment timelines. For now, modafinil may serve as a supportive tool, helping patients stay engaged in rehabilitation and daily function when used appropriately.

References

• Borghol, A., Aucoin, M., Onor, I., Jamero, D., & Hawawini, F. (2018). Modafinil for the improvement of patient outcomes following traumatic brain injury. Innovations in Clinical Neuroscience, 15(3–4), 17–23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906085/
• Capizzi, A., Woo, J., & Verduzco-Gutierrez, M. (2020). Traumatic brain injury: An overview of epidemiology, pathophysiology, and medical management. Medical Clinics of North America, 104(2), 213–238. https://doi.org/10.1016/j.mcna.2019.11.001
• Kumar, R. (2008). Approved and investigational uses of modafinil: An evidence-based review. Drugs, 68(13), 1803–1839. https://doi.org/10.2165/00003495-200868130-00003
• Menn, S. J., Yang, R., & Lankford, A. (2014). Armodafinil for the treatment of excessive sleepiness associated with mild or moderate closed traumatic brain injury: A 12-week, randomized, double-blind study followed by a 12-month open-label extension. Journal of Clinical Sleep Medicine, 10(11), 1181–1191. https://doi.org/10.5664/jcsm.4196
• Ng, S. Y., & Lee, A. Y. W. (2019). Traumatic brain injuries: Pathophysiology and potential therapeutic targets. Frontiers in Cellular Neuroscience, 13, 528. https://doi.org/10.3389/fncel.2019.00528
• U.S. Food and Drug Administration. (2007). PROVIGIL® (modafinil) tablets [Prescribing information]. U.S. Department of Health and Human Services. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020717s020s013s018lbl.pdf