Modafinil

Modafinil

PEP Topic 
Fatigue
Description 

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, brighten mood, and enhance memory. Modafinil comes as a tablet for oral intake and has been evaluated in patients with cancer for fatigue and cognitive impairment.

Effectiveness Not Established

Research Evidence Summaries

Berenson, J.R., Yellin, O., Shamasunder, H.K., Chen, C.S., Charu, V., Woliver, T.B., . . . Vescio, R. (2014). A phase 3 trial of armodafinil for the treatment of cancer-related fatigue for patients with multiple myeloma. Supportive Care in Cancer. Advance online publication. 

doi: 10.1007/s00520-014-2486-7
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Study Purpose:

To study effects of armodafinil on cancer-related fatigue in patients with multiple myeloma

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to study groups in this crossover design study. One group was a treatment-only arm that got armodafinil, and the other was a placebo-first arm that received a placebo followed by armodafinil. Patients received armodafinil 150 mg once daily for 56 days in the treatment-only group. In the other group, patients received a placebo for 28 days and armodafinil on days 29–56. Assessments were done at baseline and at days 15, 28, 43, and 56. Five variations of study assessments were used to address potential memorization effects, and the order in which versions were used was varied.

Sample Characteristics:

N = 50  
 
MEAN AGE = 65 years (range = 43–85 years)
 
MALES: 58%, FEMALES: 42%
 
KEY DISEASE CHARACTERISTICS: All had multiple myeloma
 
OTHER KEY SAMPLE CHARACTERISTICS: All had to satisfy the International Statistical Classification of Diseases and Related Health Problems (ICD10) criteria for fatigue and demonstrate at least moderate fatigue with a Brief Fatigue Inventory (BFI) score < 36 to be eligible

Setting:

  • SITE: Multi-site    
  • SETTING TYPE: Not specified    
  • LOCATION: California

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment

Study Design:

Double-blind, randomized, crossover-controlled trial

Measurement Instruments/Methods:

  • Brief Fatigue Inventory (BFI)
  • Hospital Anxiety and Depression Scale (HADS)
  • Epworth sleepiness scale
  • Trail Making Test (TMT) version B
  • Symbol Digits Modalities Test (SDMT)
  • Digit span test
  • Functional Assessment of Chronic Illness Scale–Fatigue (FACIT-F)
  • Functional Assessment of Cancer Therapy–General (FACIT-G)

Results:

Adverse effects observed during armodafinil treatment were similar between groups. Fatigue as measured by the BFI scale decreased significantly for both groups over time with no difference between groups. Outcomes measured by FACIT scores increased significantly in the placebo-first group by day 28, and FACIT fatigue scores improved significantly in both groups. Anxiety decreased significantly from baseline in both groups. Depression scores only declined significantly in the placebo-first group by day 28. Degree of sleepiness decreased significantly in the placebo group. There were no significant changes in study measures between day 28 and day 56 in which all patients received armodafinil.

Conclusions:

Armodafinil was not shown to significantly improve symptoms of fatigue, anxiety, or depression in patients with multiple myeloma.

Limitations:

  • Small sample (< 100)
  • Other limitations/explanation: 20% drop-out rate prior to day 56; more patients in the treatment-only group dropped out.

Nursing Implications:

Armodafinil, a medication similar to modafinil, was not shown to be effective for the reduction of fatigue, anxiety, or depression.

Blackhall, L., Petroni, G., Shu, J., Baum, L., & Farace, E. (2009). A pilot study evaluating the safety and efficacy of modafinal for cancer-related fatigue. Journal of Palliative Medicine, 12, 433–439.

doi: 10.1089/jpm.2008.0230
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Study Purpose:

The primary aim was to evaluate the safety and efficacy of modafinil in improving cancer-related fatigue (CRF) in patients with cancer.

The secondary aim was to assess the effect of modafinil on depression, quality of life (QOL), functional status, and cognitive function.

Intervention Characteristics/Basic Study Process:

After initial assessment for all outcome measures, patients were treated with self-administered modafinil at an initial dose of 100 mg per day during weeks one to two. During weeks three to four, the dose was increased to 200 mg per day. All study parameters were reassessed at week two and at week four (completion of the trial).

Sample Characteristics:

  • Twenty-seven patients were enrolled, and 19 completed the study.
  • Average age was 60 years.
  • Of the participants, 37% were male and 63% were female.
  • Eastern Cooperative Oncology Group (ECOG) Performance: ECOG 1 was 37%; ECOG 2 was 44%; and ECOG 3 was 19%.

Study Design:

This was an open-label pilot study.

Measurement Instruments/Methods:

  • Primary Aim: Brief Fatigue Inventory (BFI)–Fatigue
  • Secondary Aim
    • Cognitive Measures
      • Hopkins Verbal Learning Test (HVLT)—assessed verbal learning and memory
      • Grooved Pegboard Test—fine motor ability and hand-eye coordination
      • Controlled Oral Word Association Test (COWAT)—verbal fluency
      • Trail Making Test (TMT) Parts A & B—visual attention, motor speed, and cognitive flexibility
    • Other Measures
      • Hospital Anxiety and Depression Scale (HADS)—depression
      • Functional Assessment of Cancer Therapy-Brain (FACT-BR)—QOL
      • Barthel Index—functional status
      • ECOG—performance status
      • National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 2.0––scored severity of detected side effects

Results:

BFI was improved at two weeks for 46% of participants, and at four weeks, 75% had a significantly improved score (p = 0.025). FACT-BR showed an improvement in all subsets of well-being except social/family at two and four weeks (p < 0.05). HADS score declined significantly at two and four weeks (p < 0.001). Cognitive function was not significantly changed, except TMT-B showed a trend for an overall improvement. Functional status (Barthel Index) did not change, but overall performance status (ECOG) improved, with 40% of patients improving at least one level. Most side effects were mild. Side effects seen were dizziness, nausea, diarrhea, and heartburn.

Conclusions:

Modafinil use was associated with improvement in fatigue, depression, and QOL measures and was well tolerated.

Limitations:

  • The study had a small sample size, with an almost 30% drop-out rate.
  • The study was an open-label design pilot study.
  • No control comparison was included.

Gehring, K., Patwardhan, S. Y., Collins, R., Groves, M. D., Etzel, C. J., Meyers, C. A., & Wefel, J. S. (2012). A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor. Journal of Neuro-Oncology, 107, 165–174.

doi: 10.1007/s11060-011-0723-1
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Study Purpose:

To compare the effectiveness of immediate-release and sustained-release methylphenidate versus modafinil in improving cognitive function in patients with primary brain tumors.

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive one of the following three interventions for a total of four weeks:  immediate-release methylphenidate, 10 mg twice daily; sustained-release methylphenidate, 18 mg daily; or modafinil, 200 mg daily. Neurocognitive tests were performed prior to the intervention and were repeated approximately 30 days later, after completion of the intervention.

Sample Characteristics:

  • Twenty-four patients with primary brain tumors were included.
  • Mean age was 44.98 years.
  • The sample was 54% male and 46% female.
  • Most (62.5%) of patients’ tumors were in the left hemisphere.
  • Prior treatment history included radiation therapy (83%) and chemotherapy (87.5%). Of all the participants, 62.5% received chemotherapy during the study.

Setting:

  • Single site
  • Outpatient
  • MD Anderson Cancer Center, Houston, Texas

Phase of Care and Clinical Applications:

Patients were undergoing multiple phases of care.

Study Design:

The study was a randomized, clinical trial.

Measurement Instruments/Methods:

Objective Cognitive Function Instruments

  • Wechsler Adult Intelligence Scale, third edition (WAIS-III) Digit Span and Digit Symbol subtests
  • Trail Making Test (TMT) Parts A and B
  • Hopkins Verbal Learning Test (HVLT) Immediate Recall, Delayed Recall, and Delayed Recognition Trials
  • Multilingual Aphasia Examination Controlled Oral Word Association (MAE COWA) category
  • Lafayette Instrument Grooved Pegboard Test

Subjective Anxiety Instruments

  • State-Trait Anxiety Inventory (STAI) to measure state and trait anxiety  
  • Profile of Mood States (POMS) to measure tension and anxiety

Subjective Depression Instruments

  • Beck Depression Inventory (BDI)
  • Profile of Mood States (POMS) Questionnaire, Depression-Dejection Scale

Subjective Fatigue Instruments

  • Brief Fatigue Inventory (BFI)
  • POMS questionnaire, Fatigue-Inertia Scale

Subjective Sleep-Wake Disturbance Instrument

  • Brief Sleep Disturbance Scale (BSDS)

Results:

  • Over time, no differences were found in cognitive function in regard to attention or motor function.
  • Over time, mixed results were found in regard to the speed of processing:
    • The WAIS-III Digit Symbol subtest showed significant improvement (p = 0.02), but TMT Part A did not.
    • The HVLT Delayed Recognition Trial showed a signficiant decline (p = 0.03) in memory, but the other memory-related trials did not.
  • In regard to the use of either stimulant and executive function over time, the TMT Part B score improved significantly (p = 0.02); however, the MAE COWA score declined significantly (p = 0.02).
  • In regard to differences between the methylphenidate and modafinil treatment groups over time, researchers found the following:
    • A significant difference (p = 0.05) in attention. Attention-related scores of patients taking methylphenidate were stable on the WAIS-III Digit Span subtest; the scores of patients taking modafinil worsened over time.
    • A difference in the speed of processing as measured by TMT Part A. Patients using modafinil improved in comparison to patients taking methylphenidate, whose scores either remained stable or declined slightly (p = 0.05).
  • In regard to subjective measures of other symptoms, researchers noted, with use of either stimulant over time:
    • Significant improvement (p < 0.01) of depression, as measured by the BDI and POMS Depression-Dejection Scale.
    • Significant improvement (p = 0.04) of fatigue, as measured by the BFI.
    • Significant improvement of fatigue (p < 0.01), as measured by the POMS Fatigue-Inertia Scale.
    • Significant improvement (p = 0.03) of anxiety, as measured by the state subtest of the STAI.
  • No differences were found over time in regard to sleep-wake disturbances.
  • No differences were found between treatment groups in subjective symptom measures over time.

Conclusions:

Although this study revealed some improvements in specific cognitive domains over time (e.g., executive function, speed of processing), it is unclear whether these improvements were due to the use of a stimulant; a specific medication (modafinil versus methylphenidate); or other variables, such as practice effects related to the absence of alternative neuropsychological tests. Making definitive interpretations based on this small study is difficult because the findings were confounded by the use of two stimulants (one with two different dosage schedules) and the lack of a control group (patients who were not receiving stimulants).

Limitations:

  • The study had a small sample size, with less than 30 participants.
  • The study had risks of bias due to no control group and no blinding.
  • Participant withdrawals were 10% or greater.
  • The investigators were unable to achieve the sample size recommended by the power analysis due to poor accrual and a high drop-out rate (29%). Treatment groups differed significantly in regard to age (p = 0.02) and gender (p = 0.03). Age and gender influence neuropsychological test results.

Nursing Implications:

No evidence was provided to support the use of stimulants to improve cognitive function. The study supports the conduct of future research of this topic in studies with larger sample sizes and in randomized, clinical trials with a nonintervention arm.

Hovey, E., de Souza, P., Marx, G., Parente, P., Rapke, T., Hill, A., . . . Lloyd, A. (2014). Phase III, randomized, double-blind, placebo-controlled study of modafinil for fatigue in patients treated with docetaxel-based chemotherapy. Supportive Care in Cancer, 22, 1233-1242. 

doi: 10.1007/s00520-013-2076-0
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Study Purpose:

To determine whether modafinil could reduce fatigue related to docetaxel chemotherapy

Intervention Characteristics/Basic Study Process:

Patients with metastatic breast or prostate cancer receiving docetaxel chemotherapy and experiencing significant fatigue were randomized to receive modafinil or placebo for 15 days beginning with their third cycle of treatment and repeated for 2–4 subsequent chemotherapy cycles.

Sample Characteristics:

  • N = 83  
  • MEAN AGE = 66.4 years in the modafinil group and 68 years in the placebo group
  • MALES: 78%, FEMALES: 22%
  • KEY DISEASE CHARACTERISTICS: Primarily Caucasian; metastatic breast/prostate cancer; received at least two cycles of docetaxel; MDASI fatigue score (≥ 4/10); Hgb ≥ 10

Setting:

  • SITE: Multi-site  
  • SETTING TYPE: Not specified  
  • LOCATION: Australia

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active anti-tumor treatment

Study Design:

  • Phase II randomized, double-blind, placebo-controlled.
  • Eligible patients were randomized 2:1 to modafinil or placebo and stratified according to tumor type.

Measurement Instruments/Methods:

  • MD Anderson Symptom Inventory (MDASI)
  • Secondary outcomes measures included depression, sleep disturbance, exercise, cognition, and mood states.

Results:

The goal was a 10% or greater relative difference between the two treatment groups.

Conclusions:

The primary endpoint of reduced fatigue during docetaxel chemotherapy was not statistically different between the two treatment arms.

Limitations:

  • Small sample (< 100)
  • Key sample group differences that could influence results
  • Measurement validity/reliability questionable
  • Questionable protocol fidelity
  • Other limitations/explanation: Study had to be repowered due to limited recruitment. Unclear how secondary measures were evaluated. Use of dexamethasone premedication.

Nursing Implications:

Features a trend in docetaxel-related fatigue. Effectiveness was not established for the broader cancer-related fatigue treatment.

Jean-Pierre, P., Morrow, G. R., Roscoe, J. A., Heckler, C., Mohile, S., Janelsins, M., . . . Hopkins, J. O. (2010). A phase 3 randomized, placebo-controlled, double-blind, clinical trial of the effect of modafinil on cancer-related fatigue among 631 patients receiving chemotherapy: a University of Rochester Cancer Center Community Clinical Oncology Program Research base study. Cancer, 116, 3513–3520.

doi: 10.1002/cncr.25083
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Study Purpose:

To examine the effect of modafinil on patient-reported fatigue in patients with cancer who were undergoing chemotherapy.

Intervention Characteristics/Basic Study Process:

Assessments were conducted at baseline after randomization and shortly after cycle two of therapy. Modafinil or placebo was started at 100 mg on day 10 or day five of study cycle two, then increased to a full dose of 200 mg after three days. This regimen then was continued until day seven of treatment cycle four, at which time all patients discontinued medication.

Sample Characteristics:

  • A total of 877 participants were enrolled, and 631 were analyzed.
  • Mean ages for the study groups were 60 and 61 years (range 18–90), and 66% to 68% were female.
  • The most common sites were gastrointestinal, breast, and lung. The sample also included genitourinary, gynecologic, hematologic, and other cancers.
  • Participants were required to be beginning a cancer treatment course of at least four planned cycles of chemotherapy with at least two weeks apart, with no concurrent radiation or interferon treatment.
  • Patients were excluded if they had taken modafinil or any psychostimulant within the past 30 days.
  • Participants had at least a score of 2 on the Brief Fatigue Inventory (BFI) question 3 (worst level of fatigue).
  • Of the patients, 57% had received prior chemotherapy, and 22% to 24% had received prior radiation therapy.
  • Most (67%–70%) participants were married, and about half had some college education.

Setting:

This multisite study was set in 23 geographical areas across the United States among University of Rochester Cancer Center Community Clinical Oncology Program (URCC CCOP) affiliates.

Study Design:

This was a randomized, placebo-controlled, double-blind trial.

Measurement Instruments/Methods:

  • BFI, question 3
  • Epworth Sleepiness Scale (ESS) to measure excessive daytime sleepiness
  • Profile of Mood States depression subscale (POMS-DD)
  • Missing scores at cycle four were replaced with scores from cycle three for those who completed the study and only had evaluable data through cycle three (n = 58 for modafinil; n = 29 for placebo).

Results:

ANCOVA for BFI fatigue score showed an interaction between treatment effects and baseline BFI score (p = 0.017). A significant difference existed between the study groups for those who had severe fatigue at baseline (BFI of 7 or greater), with average score in the modafinil group. No differences in fatigue were observed between the study groups for those who had mild or moderate baseline fatigue. Daytime sleepiness on ESS showed significant improvement in the modafinil group (p = 0.002). No significant differences existed in depression outcomes between the groups. In the modafinil group, 11% of patients experienced adverse events, and in the placebo group, 9% had adverse events. Only three adverse events were judged to be definitely associated with treatment with modafinil: allergic reaction, dyspnea, and headaches.

Conclusions:

The findings supported the use of 200 mg of modafinil as an effective treatment for severe cancer-related fatigue in patients undergoing chemotherapy. Modfinil was not effective for patients with less severe fatigue.

Limitations:

  • It is not clear what the statistical effect was of the replacement of missing cycle four data with data from cycle three. The authors analyzed multiple data replacements to test this and found no differences. This suggests that the time frames of the study measures were irrelevant.
  • The study demonstrated effectiveness for the short term during active treatment with only chemotherapy; the findings may not be the same for other groups of patients or other time frames of observation.
  • Diversity of the sample in terms of racial and some other demographic findings was limited.
  • Although no significant differences existed between study groups that would have affected the study results, the findings may not be applicable to other patients with different demographic characteristics.

Spathis, A., Dhillan, R., Booden, D., Forbes, K., Vrotsou, K., & Fife, K. (2009). Modafinil for the treatment of fatigue in lung cancer: a pilot study. Palliative Medicine, 23, 325–331.

doi: 10.1177/0269216309102614
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Study Purpose:

To determine the feasibility of conducting a randomized, controlled trial to assess the efficacy and safety of modafinil for the treatment of fatigue in patients with lung cancer.

Intervention Characteristics/Basic Study Process:

Patients with non-small cell lung cancer (NSCLC) took modafinil in a fixed dose-titration schedule (100 mg daily on day 1 and increasing in the second week to 200 mg daily) for 14 days.

Sample Characteristics:

  • Twenty patients (6 females, 14 males) were included.
  • Median age was 74 years. 
  • All patients had NSCLC.

Setting:

  • Multisite
  • Inpatient
  • United Kingdom

Study Design:

This was an intervention feasibility study.

Measurement Instruments/Methods:

  • Chalder Fatigue Questionnaire (CFQ)
  • Epworth Sleepiness Scale (ESS)
  • Hospital Anxiety and Depression Scale (HADS)
  • Functional Assessment of Cancer Therapy-Fatigue (FACT-F)

Results:

  • There was a change in fatigue between days 0 and 14.
  • Mean fatigue decreased from 6.9 to 3.7.
  • There were statistically and clinically significant improvements in fatigue scores from days 0 to 7.
  • There was no statistically significant change from days 7 to 14.

Conclusions:

It is feasible to conduct randomized, controlled trials.

Limitations:

The study had a small sample size, with less than 30 patients.

Nursing Implications:

  • This was an inexpensive pharmacologic intervention for cancer-related fatigue.
  • Randomized, controlled trials are needed to confirm the benefit.
  • The intervention was well tolerated in patients with advanced cancer.
  • Poststudy, 10 patients chose to continue taking modafinil.

Systematic Review/Meta-Analysis

Cooper, M. R., Bird, H. M., & Steinberg, M. (2009). Efficacy and safety of modafinil in the treatment of cancer-related fatigue. Annals of Pharmacotherapy, 43, 721–725.

doi: 10.1345/aph.1L532
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Purpose:

To review the efficacy and safety of modafinil for the treatment of cancer-related fatigue (CRF).

Search Strategy:

Databases searched were MEDLINE, International Pharmaceutical Abstracts, and Google Scholar (1950–November 2008).

Search keywords were modafinil, cancer, and fatigue.

Studies were included in the review if they were written in English.

No exclusion criteria were specified.

Literature Evaluated:

Articles were identified using the keywords, and publications were analyzed for significance. References from the identified articles were also reviewed for pertinence.

Sample Characteristics:

  • Four studies were reviewed in detail, comprising a total of 805 patients.
  • Two studies reported patients with breast cancer, one reported patients with cerebral tumors, and one reported that the diagnoses were unknown.

Results:

  • One open-label trial demonstrated the effectiveness of 200 mg of modafinil daily, given for one month, in reducing fatigue and improving patient-reported global effectiveness.  Fifty-one percent of participants reported improvement in sleep and less daytime drowsiness.
  • One open-label trial in women with breast cancer reported that 90% of participants reported improvement in fatigue with 200 mg of modafinil daily for one month.
  • One randomized, dose-controlled trial was conducted in patients with cerebral tumors who had neurobehavioral dysfunction and/or fatigue posttreatment. Improvements in fatigue scores were seen eight weeks after baseline. Adverse effects included headache, insomnia, dizziness, dry mouth, depressed consciousness, and nausea.  The authors concluded that modafinil was effective in improving fatigue, with a low incidence of adverse reactions.
  • One phase III, randomized, placebo-controlled, double-blind trial was conducted in 642 patients with cancer who reported fatigue while receiving chemotherapy. Those receiving modafinil had a significant decrease in fatigue levels compared with patients receiving placebo.

Conclusions:

This review discussed the strengths and weaknesses of four relevant studies. The authors concluded that the preliminary findings demonstrated the benefits of modafinil use with minimal toxicity and that modafinil can be considered a treatment option for patients with CRF. Additional long-term placebo-controlled trials are needed in this area.

Limitations:

  • Some of the evidence reviewed in this study was taken only from abstracts.
  • The literature evaluated and selected were not clearly outlined.
  •  No inclusion and exclusion criteria were specified other than language.

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