Modafinil is a psychostimulant effective in the treatment of excessive sleepiness associated with narcolepsy and in people with shift-work sleep disorder. It is used to increase wakefulness and capacity for attention, to brighten mood, and to enhance memory. Modafinil comes as a tablet for oral intake and has been evaluated in patients with cancer for fatigue and cognitive impairment.
Armodafinil is a similar drug with a slightly different chemical configuration also used as a wakefulness-promoting agent. Armodafinil reaches peak concentration in the blood later after administration than modafinil. Armodafinil has been studied for its effect on fatigue, anxiety, sleep-wake disturbances, and depression in people with cancer.
Day, J., Zienius, K., Gehring, K., Grosshans, D., Taphoorn, M., Grant, R., . . . Brown, P.D. (2014). Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation. Cochrane Database of Systematic Reviews, 12, CD011335.
PHASE OF CARE: Multiple phases of care
Three cognitive interventions aimed at preventing cognitive decline during radiation therapy were reported. Two were pharmacologic. One tested memantine versus a placebo and found significant improvement in overall cognitive function, and one tested methylphenidate versus a placebo but failed to detect any significant differences between groups. The third study was nonpharmacologic and investigated the use of a rehabilitation program to prevent cognitive decline but did not statistically compare differences between groups. Three cognitive interventions aimed at ameliorating cognitive decline were reported. All three were pharmacologic studies. Two studies compared methylphenidate versus modafinil and one study examined donepezil versus a placebo. Both methylphenidate and modafinil interventions resulted in improved cognitive function. Combination therapy resulted in greater adverse events. Donepezil was found to improve the domain of memory after radiotherapy.
The authors reported that there was evidence for the use of memantine for preventing cognitive decline in patients receiving radiotherapy for brain metastasis. Likewise, there was supporting evidence for the use of donepezil in improving memory after radiotherapy for primary or metastatic brain tumors. There was limited evidence for cognitive behavioral or training interventions in preventing cognitive decline.
Patients who receive cranial radiation therapy for primary brain tumors or metastatic lesions are at risk for declining cognitive function. The use of memantine during radiation therapy may aid in preventing cognitive decline. Those who develop cognitive decline after the completion of radiation therapy, even years afterwards, may benefit from donepezil administration. Additional exploration of interventions that may prevent or ameliorate cognitive decline related to cranial radiation therapy is warranted.
Blackwell, L., Petroni, G., Shu, J., Baum, L., & Farace, E. (2009). A pilot study evaluating the safety and efficacy of modafinil for cancer-related fatigue. Journal of Palliative Medicine, 12, 433–439.
The study's primary aim was to evaluate the safety and efficacy of modafinil in improving cancer-related fatigue. Its secondary aim was to determine the effect of modafinil on depression, quality of life, functional status, and cognitive function.
Participants were given 100 mg of modafinil daily for weeks 1 and 2, and then 200 mg daily for weeks 3 and 4. Participants older than 80 were dose-reduced and received 50 mg of modafinil daily for weeks 1 and 2, then 100 mg daily for weeks 3 and 4. There was no control group.
Testing was completed at baseline, week 2, and at the completion of the trial.
This was a prospective, open-label pilot study.
Fatigue (as measured by the BFI) was improved at week 2 for 46% of participants; at week 4, 75% had a significantly improved score (p = 0.025). Functioning (as measured by the FACT-BR) showed an improvement in all subsets of well-being at weeks 2 and 4 (p < 0.05) except social/family. Depression (as measured by the HADS) declined significantly at weeks 2 and 4 (p < 0.001).
Functional status (as measured by the Barthel Index) did not change, but overall ECOG performance status improved, with 40% of patients improving at least one level. Cognitive function was not significantly changed, although the TMT-B did show a trend of overall improvement.
Modafinil did not significantly improve learning and memory, fine motor ability, verbal fluency, or executive function, but results are limited due to the small sample size.
Boele, F.W., Douw, L., de Groot, M., van Thuijl, H.F., Cleijne, W., Heimans, J.J., . . . Klein, M. (2013). The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: A multicenter randomized controlled trial. Neuro-Oncology, 15, 1420–1428.
To investigate the effects of modafinil on fatigue, depression, cognitive impairment, and health-related quality of life in patients with primary brain tumors
The intervention consisted of subjects receiving modafinil versus a placebo over six weeks. The week 1 dosage was 100 mg twice daily and the weeks 2–6 dosages were 200 mg twice daily. The cross-over occurred after the completion of week 6; thus, subjects who initially received the placebo followed the same dosing schedule over the next six weeks while those who had taken modafinil previously were given a placebo. Neuropsychological assessments and self-report measures were completed at baseline, six weeks, and 12 weeks.
PHASE OF CARE: Multiple phases of care
Randomized, controlled, double-blinded clinical trial using a cross-over design. Measurements were performed at baseline, six weeks, and 12 weeks.
The CIS severity and reduced motivation scores for fatigue were lower after treatment with both modafinil (p = 0.01, p = 0.021) and placebo arms (p < 0.001, p = 0.027), but there was no difference in scores between trial arms. Significant improvements in working memory (p = 0.04, p = 0.043), information-processing (p = 0.036, p = 0.04), and attention (p = 0.015, p = 0.013) were found after treatment with modafinil and the placebo, respectively. There were no differences in scores between trial arms. Health-related quality of life measured by the physical component summary of the SF-36 was significantly improved for both modafinil (p = 0.001) and placebo arms (p = 0.008). There were no differences in depressive symptoms following modafinil or placebo.
The results indicate that there were no significant differences observed in fatigue, cognitive functioning, health-related quality of life, and mood between modafinil and a placebo. These findings may be related to the study design, duration of treatment, low study accrual, subject withdrawals, and lack of longitudinal follow-up.
Findings do not support the use of modafinil to improve fatigue, cognitive functioning, mood, and health-related quality of life in patients with brain tumors.
Kohli, S., Fisher, S.G., Tra, Y., Adams, M.J., Mapstone, M.E., Wesnes, K.A., … Morrow, G.R. (2009). The effect of modafinil on cognitive function in breast cancer survivors. Cancer, 115(12), 2605–2616.
The study's primary aim was to examine the effect of modafinil on persistent fatigue after treatment. Its secondary aim was to examine the effect of modafinil on cognitive function of patients with breast cancer.
In phase 1, participants were given 200 mg of modafinil daily for four weeks. Participants with a positive response in phase 1 were randomized to phase 2. In phase 2, participants continued to receive 200 mg of modafinil orally once per day or a placebo for four weeks. Repeated measures were completed at baseline (week 0), week 4, and week 8. Participants were stratified by treatment type: chemotherapy, radiation, or both chemotherapy and radiation.
The study took place at the University of Rochester Medical Oncology Clinic in New York.
The study was a prospective, open-label clinical trial.
Approximately 70% of the participants in the active treatment group had an improvement in continuity of attention from baseline to after treatment (week 8), compared with 52% in the placebo group; however, this difference was not statistically significant (p = 0.19).
In phase 1, modafinil had a significant effect on speed of memory (p = 0.0073) and quality of episodic memory (p = 0.0001). No significant effect in continuity of attention, quality of working memory, or power of attention was observed during this phase.
In phase 2, those who continued modafinil demonstrated significantly greater improvement in cumulative speed of memory (p = 0.029), quality of episodic memory (p = 0.0151), and continuity of attention (p = 0.0101).
Modafinil significantly improved some cognitive functioning, including speed of memory and episodic memory, but failed to demonstrate improvement in working memory.
Lundorff, L.E., Jonsson, B.H., & Sjøgren, P. (2009). Modafinil for attentional and psychomotor dysfunction in advanced cancer: A double-blind randomised, cross-over trial. Palliative Medicine, 23, 731–738.
The study's primary aim was to assess the effectiveness of single-dose modafinil on cognitive function in patients with advanced cancer treated in palliative care settings. Its secondary aim was to assess the effectiveness of modafinil on other symptoms.
On day 1, patients were randomly assigned to receive either 200 mg of modafinil or an oral placebo. On day 4, each patient group was given the alternative treatment that was not dispensed on day 1.
The study took place in the palliative care department of Herning Hospital in Denmark.
The study was a double-blind, randomized, cross-over, single-dose trial.
Patients on the modafinil treatment group saw statistically significant improvements in psychomotor speed with the dominant hand (as measured by the FTT) and speed of processing (as measured by the TMT-B), as compared with the placebo group (p = 0.006). The modafinil treatment group also showed statistically significant improvements in depression and drowsiness as compared with the placebo group (p = 0.042).
The frequency and intensity of side effects were similar on both treatments, and no statistically significant differences were reported. However, four patients experienced disrupted sleep and vivid dreams after modafinil treatment.
Modafinil improved attention and psychomotor speed and diminished depression and drowsiness.
Page, B.R., Shaw, E.G., Lu, L., Bryant, D., Grisell, D., Lesser, G.J., . . . Shah, S. (2015). Phase II double-blind placebo-controlled randomized study of armodafinil for brain radiation-induced fatigue. Neuro-Oncology, 17, 1393–1401.
Patients were randomized to receive a placebo or 150 mg per day dose of armodafinil. Armodafinil was taken daily during seven weeks of radiation therapy and then an additional four weeks. There were no dose modifications or drug holidays. If patients could not tolerate the study agent, it was discontinued. Fatigue, cognitive function, and quality of life were assessed at baseline, at the end of RT, and four weeks after RT. Toxicities were evaluated weekly.
PHASE OF CARE: Active antitumor treatment
Double blinded, placebo-controlled, randomized, controlled trial (n = 26 [armodafinil], n = 28 [control])
Nine patients dropped out of the study by the end of RT. The most common adverse effects were headache, insomnia, nausea, anxiety, arthralgia, dizziness, dry mouth, sinusitis, and throat and respiratory infections. There were no significant differences in adverse events between the study groups. There were no significant differences between groups in fatigue. In both groups, fatigue increased during treatment and improved following the completion of RT. Neurocognitive measures improved slightly over time in both groups with no significant difference between the groups. Among patients with the most fatigue at baseline, those taking armodafinil showed improvements in fatigue at the end of RT. Armodafinil also did not improve neurocognitive outcomes at the end of RT or at four weeks post RT in the subsets of participants with high or low levels of fatigue at baseline.
Armodafinil was not shown to improve fatigue or cognitive function measures in patients receiving brain irradiation. Armodafinil appeared to show some benefit in improving fatigue among those with high levels of fatigue at baseline.
The findings did not provide overall support for effectiveness of armodafinil to reduce fatigue in this study although patients with the highest level of fatigue at baseline appeared to have some benefit. Additional research is warranted to determine if there is any benefit of psychostimulants for fatigue and cognitive impairment in patients with brain tumors undergoing radiation therapy.
Denlinger, C.S., Ligibel, J.A., Are, M., Baker, K.S., Demark-Wahnefried, W., Friedman, D.L., . . . National Comprehensive Cancer Network. (2014). Survivorship: Cognitive function [v.1.2014]. Journal of the National Comprehensive Cancer Network, 12, 976–986.
A uniform NCCN consensus determined that recommendations were appropriate (NCCN Category of Evidence and Consensus = 2A).
Some interventions that may be useful to improve or maintain cognitive function might not be included in these guidelines because this manuscript did not detail search strategies, inclusions and exclusions, or the number of articles included in the recommendations.
The NCCN cognitive function algorithm aids healthcare professionals considering the assessment and treatment of cancer-related cognitive function. Nonpharmacologic interventions should be recommended to oncology survivors experiencing cognitive issues. Pharmacologic interventions may be considered when medical conditions permit and potential contributing factors are ruled out or managed.