Methylphenidate

Methylphenidate

PEP Topic 
Fatigue
Description 

Methylphenidate is a type of psychostimulant used to treat attention-deficit hyperactivity disorder and narcolepsy. Methylphenidate is closely related to amphetamine and is a schedule II drug. It is taken by mouth and available by numerous different brand names. It can be habit forming, and individuals can develop tolerance to its effects. Methylphenidate use for patients with cancer has been evaluated in anxiety, depression, fatigue, and cognitive impairment. Methylphenidate has been evaluated alone and as part of multimodal approaches combined with other interventions, such as exercise.

 

Effectiveness Not Established

Research Evidence Summaries

Bruera, E., Driver, L., Barnes, E. A., Willey, J., Shen, L., Palmer, J. L., . . . Escalante C. (2003). Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. Journal of Clinical Oncology, 21, 4439–4443.

doi: 10.1200/JCO.2003.06.156
Print

Intervention Characteristics/Basic Study Process:

The study involved patient-controlled administration of immediate-release methylphenidate 5 to 20 mg per day, taken as often as every two hours based on the hypothesis that treatment with a psychostimulant (methylphenidate) would reduce perceived fatigue.

Sample Characteristics:

  • In total, 30 patients with a median age of 51 years (range 24–79) were included. 
  • Most patients were women. 
  • The sample included a mix of primary cancer diagnoses, including head and neck, gynecologic, and hematologic cancers.
  • All patients had normal thyroid function and a hemoglobin level of 10 mg/dL or greater at study inception.
  • Patients with central nervous system disease, a history of seizures, or significant hepatic, renal, or cardiac dysfunction were excluded.

Setting:

Patients were recruited from a palliative care outpatient clinic or a pain clinic of a large university cancer center.

Phase of Care and Clinical Applications:

Unspecified

Study Design:

The study used a single-center pilot study prospective, open-label design; no comparison group was included.

Measurement Instruments/Methods:

  • Functional Assessment for Chronic Illness Therapy–Fatigue (FACIT-F)
  • Edmonton Symptom Assessment Score (ESAS)
  • Patients rated their drowsiness, ability to sleep at night, pain, depression, and nervousness using a numeric scale from 0 to 10.

Results:

Of the patients, 93% (n = 28) reported improvements in fatigue from baseline to day 7 of study participation (as measured by the fatigue item on the ESAS and FACIT-F). Of the patients, 93% took three or more methylphenidate tablets daily. All patients chose to continue methylphenidate for at least four weeks beyond the initial study period of seven days. The following side effects were reported by two or less participants:  restlessness, dizziness, anorexia, skin rash, and self-limited vertigo and tachycardia.

Limitations:

  • This was an open-label study, with no randomization, control, or comparison group.
  • A small convenience sample was used.
  • No stratification existed for the presence or absence of depression.
  • Safety was not evaluated in patients with central nervous system disease, a history of seizures, or significant hepatic, renal, or cardiac dysfunction.

Nursing Implications:

No special training is required to deliver the intervention; the costs are related to drug acquisition.

Bruera, E., Yennurajalingam, S., Palmer, J.L., Perez-Cruz, P.E., Frisbee-Hume, S., Allo, J.A., . . . Cohen, M.Z. (2013). Methylphenidate and/or a nursing telephone intervention for fatigue in patients with advanced cancer: A randomized, placebo-controlled, phase II trial. Journal of Clinical Oncology, 31(19), 2421–2427. 

doi: 10.1200/JCO.2012.45.3696
Print

Study Purpose:

Compare the effects of methylphenidate (MP) (psychostimulant) with those of a placebo (PL) on cancer-related fatigue. The effect of a combined intervention including MP plus a nursing telephone intervention (NTI) also was assessed.

Intervention Characteristics/Basic Study Process:

Patients with a fatigue score of greater than or equal to 4 out of 10 on the Edmonton Symptom Assessment Scale (ESAS) randomly were assigned to one of the following four groups: MP plus NTI, PL plus NTI, MP plus control telephone intervention (CTI), and PL plus CTI.

Sample Characteristics:

  • N = 141
  • MEDIAN AGE = 58 years
  • MALES: 33%, FEMALES: 67%
  • KEY DISEASE CHARACTERISTICS: Diagnosis of advanced cancer
  • OTHER KEY SAMPLE CHARACTERISTICS: Four or above on the ESAS, normal score on the Mini Mental State Examination (MMSE), no severe comorbid conditions including severe anxiety, major depression, substance abuse, or erythropoietin use

Setting:

  • SITE: Multi-site  
  • SETTING TYPE: Outpatient  
  • LOCATION: Outpatient palliative care and oncology clinics at MD Anderson Cancer Center and at Lyndon B. Johnson General Hospital, both in Houston, TX

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Mutliple phases of care
  • APPLICATIONS: Pediatrics, elder care, palliative care

Study Design:

Randomized, controlled trial; placebo controlled

Measurement Instruments/Methods:

  • Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
  • ESAS
  • MMSE
  • Hospital Anxiety and Depression Scale (HADS)
  • Pittsburgh Sleep Quality Index (PSQI)

Results:

The groups MP alone, NTI alone, or MP plus NTI proved not significantly better than PL for cancer-related fatigue. Anxiety improved with the telephone intervention (p = .01), as did sleep (p < .001).

Conclusions:

MP, used alone or in combination with NTI, was not superior to the control group or the PL for fatigue or depression. NTI was associated with improvement in anxiety and sleep.

Limitations:

  • Risk of bias (no blinding)
  • No statistical control for multiple comparisons, which could lead to a type one error
  • Limited duration of two weeks  
  • Content of CTI not described

Nursing Implications:

Although the use of MP did not prove to be effective for cancer-related fatigue, several cancer-related symptoms significantly were improved with NTI. Further research in this area would be ideal, but NTIs remain potentially effective for patient support and education and can have a positive effect on patient experience.

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
Print

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.

Hardy, J. R., Carmont, S. A., O'Shea, A., Vora, R., Schluter, P., Nikles, C. J., . . . Mitchell, G. K. (2010). Pilot study to determine the optimal dose of methylphenidate for an n-of-1 trial for fatigue in patients with cancer. Journal of Palliative Medicine, 13, 1193–1197.

doi: 10.1089/jpm.2010.0185
Print

Study Purpose:

To identify a dose of methylphenidate to test formally in a subsequent N-of-one trial of fatigue.

Intervention Characteristics/Basic Study Process:

Patients with fatigue 4/10 or more at baseline received titrated doses of methylphenidate beginning at 5 mg/day up to 15 mg twice daily (BID) at three-day intervals.

Sample Characteristics:

  • In total, nine patients (20% male, 80% female) were included.   
  • Age ranged from 56 to 86 years.
  • Patients had breast, ovarian, and other cancers.
  • No demographic information was available.

Setting:

  • Single site  
  • Outpatient  
  • Queensland, Australia

Phase of Care and Clinical Applications:

Patients were undergoing the transition phase on “stable treatment,” not on chemotherapy.

Study Design:

The study was a prospective trial.

Measurement Instruments/Methods:

  • Wu Cancer Fatigue Scale
  • Functional Assessment of Cancer Treatment–Fatigue (FACT-F)
  • Edinburgh Depression Scale
  • Daily toxicity and symptom diaries
  • Karnofsky Performance Status (KPS)
  • Global Impression of Change
     

Results:

  • Nine patients began taking 5 mg of methylphenidate daily; seven patients increased to 5 mg BID; six patients increased to 10 mg BID; five patients received the maximum dose of 15 mg BID, and three patients were unwilling to increase the dose to the maximum because they were satisfied with the response at a lower dose.
  • No statistical information was provided; overall, fatigue and depression improved until day 9 of the study (5 mg BID dose of methylphenidate) after which the rate of improvement was slower.
  • There was little correlation between performance status and maximum tolerated dose.
  • Although toxicity was difficult to measure due to small numbers and side effects at baseline, no patient discontinued due to toxicity.
     

Conclusions:

Methylphenidate 5 mg BID was chosen as the ideal dose to test against placebo.

Limitations:

  • The study had a small sample size, with less than 100 patients.
  • The study lacked a control group.
  • There was significant attrition.
  • There was one treatment site in one country.
  • The study lacked racial/ethnic diversity.
  • The aim of the study was not to determine if methylphenidate was effective in managing fatigue but rather to find an ideal dose to use for a future randomized, controlled trial.

Nursing Implications:

Nurses in research can use a 5-mg BID dose of methylphenidate to test against placebo.

Johnson, R. L., Block, I., Gold, M. A., Markwell, S., & Zupancic, M. (2010). Effect of methylphenidate on fatigue in women with recurrent gynecologic cancer. Psycho-Oncology, 19, 955–958.

doi: 10.1002/pon.1646
Print

Study Purpose:

To evaluate the effect of methylphenidate on fatigue in women with recurrent gynecologic cancer.

Intervention Characteristics/Basic Study Process:

Women with recurrent gynecologic cancer currently receiving chemotherapy and reporting fatigue at baseline were prescribed methylphenidate. The dose started at 5 mg taken at 8 am and noon and was titrated up to 10 mg at two weeks if the patient reported a limited response. Data were obtained at baseline and two, four, and eight weeks.

Sample Characteristics:

  • In total, 13 women were included. 
  • Average age was 59 years (range 23–87).
  • All patients had recurrent gynecologic cancer:  ovary (n = 25), endometrial (n = 1), cervical (n = 1), vaginal (n = 1), sex cord endometrial (n = 1), ovary and endometrial (n = 1), and unknown histology (n = 2).
  • Patients were Caucasian (n = 29), Native American (n = 1), African American  (n = 1), and unknown (n = 1); no other demographic was information available.

Setting:

  • Single site   
  • Outpatient   
  • Comprehensive cancer center in the United States; University of Oklahoma

Phase of Care and Clinical Applications:

Patients were undergoing the active treatment on chemotherapy phase of care.

Study Design:

The study was a prospective trial.

Measurement Instruments/Methods:

  • Fatigue Symptom Inventory (FSI) 
  • Functional Assessment of Cancer Treatment–General (FACT-G)
  • Brief Symptom Inventory (BSI)

Results:

Thirty-two women were initially enrolled; only 13 completed the eight-week follow-up. Scores on the FSI decreased statistically significantly from baseline at all measurement points (week 2, p = 0.0088; week 3, p = 0.0007; week 3, p = 0.0001). BSI scores also decreased, with scores at weeks 4 and 8 significantly lower than baseline (p = 0.015 and 0.0015, respectively). There was an overall change in FACT-G scores over time (p = 0.0351), with significant change in physical well-being (p = 0.0235) and emotional well-being (p = 0.0099). There was no change in family/social and functional well-being.

Conclusions:

Methylphenidate may be beneficial to women with recurrent gynecologic cancer experiencing treatment-related fatigue.

Limitations:

  • The study had a small sample size, with less than 100 patients.
  • The study lacked a control group.
  • There was significant attrition.
  • The group was very select (recurrent gynecologic cancer).
  • There was one treatment site in one country.
  • The study lacked racial/ethnic diversity.

Nursing Implications:

Findings suggest that methylphenidate may be beneficial in this small select type of patients. No adverse drug information was formally collected (the authors reported several patients withdrew from the study due to blurred vision, confusion, and dizziness but did not address whether these might be drug- or disease-related); thus, nurses would need to monitor patients closely who receive these drugs.

Lower, E. E., Fleishman, S., Cooper, A., Zeldis, J., Faleck, H., Yu, Z., & Manning, D. (2009). Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial. Journal of Pain and Symptom Management, 38, 650–662.

doi: 10.1016/j.jpainsymman.2009.03.011
Print

Study Purpose:

To test the hypothesis that d-methylphenidate (d-MPH) would produce a significant reduction in fatigue compared to placebo.

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive the study drug or an identical appearing placebo; packaging and labeling were done by a pharmacist not involved in other aspects of the study. Patients received 5 mg of the drug twice daily by mouth. Measures were performed at baseline and at weeks 1 and 8, which was the end of the double-blind treatment phase. Weekly dose modifications were performed at the investigators' discretion based on the magnitude and duration of response assessed weekly by Clinical Global Improvement–Impression (CGI-I) scores. The maximum allowable total daily dosage was 50 mg/day in two to three doses per day.

Sample Characteristics:

  • In total, 154 patients (94.1% women) with cancer who met the proposed International Classification of Diseases, 10th Revision (ICD-10) criteria for a diagnosis of cancer-related fatigue were included. 
  • Mean age was 52.8 years (standard deviation = 9.3 years) (range 18–70).
  • Patients had multiple types of cancer, excluding primary or metastatic brain tumors. The highest proportion of patients had breast or ovarian cancer.
  • Patients were included if they
    • Were treated with at least four cycles of chemotherapy concluded at least two months prior to study entry
    • Had no concurrent cancer treatment, history of major psychiatric illness, learning or attentional deficitis, or prior treatment with the study drug. 
    • Were nonpregnant and nonlactating women.
  • Additional screening and criteria were established for depression and cognitive function. 

Setting:

  • Multisite
  • Twenty-four academic or community-based cancer treatment centers in the United States

Study Design:

This was a double-blind, randomized, controlled study.

Measurement Instruments/Methods:

  • CGI-I scale
  • Functional Assessment of Chronic Illness Therapy–Fatigue subscale (FACIT-F)
  • Swanson, Nelson, and Pelham Attention Deficit/Hyperactivity Scale (SNAP)
  • High Sensitivity Cognitive Screen (HSCS)
  • Eastern Cooperative Oncology Group (ECOG) performance status
  • Mini-Mental State Exam (MMSE)

Results:

D-MPH–treated patients had lower ECOG performance status scores than placebo-treated patients (p = 0.03), indicating better performance. The mean highest dose achieved in d-MPH–treated patients was 27.7 mg/day (range 10–70). A significantly greater improvement in FACIT scores from baseline was seen in patients who received d-MPH compared to placebo at week 8 (p = 0.02). In the study group, there was a mean 10.5-point score reduction in the d-MPH group. Reduction in fatigue was seen at an average dose of 27.7 mg/day of the study drug. All patients had reduction in CGI scores, indicating decreased severity of symptoms from baseline to week 8. Improvement in these scores was seen in a significantly greater percentage of those given d-MPH (p = 0.02). The most frequent adverse events were headache, nausea, and dry mouth in the treatment group and headache, diarrhea, and insomnia in the placebo group. There was a higher rate of adverse events in the d-MPH group. Eleven percent of the treatment group experienced serious adverse events that led to study discontinuation. Events that led to discontinuation were nausea, vomiting, feeling jittery, and abnormal electrocardiogram.

Conclusions:

D-MPH treatment in an individualized dosing regimen based on therapeutic response and side effects was associated with a significant improvement in fatigue.

Limitations:

  • There was a predominance of breast and ovarian cancers in the sample, suggesting that findings may not be generalizable to broader populations of patients.
  • Baseline performance status was better in the experimental group than in the placebo group. The potential effect of this difference was not analyzed or addressed.
  • The sample did not include patients in active treatment, so the findings are not readily applicable in that situation.
  • The study duration was only eight weeks, so the effect of this intervention over the longer term is not clear from these findings.

Nursing Implications:

Future studies need to be performed that address a broader range of patient types. The effectiveness of d-MPH in combination with other interventions, such as exercise, should be examined.

Mar Fan, H. G., Clemons, M., Xu, W., Chemerynsky, I., Breunis, H., Braganza, S., & Tannock, I. F. (2008). A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Supportive Care in Cancer, 16, 577–583.

doi: 10.1007/s00520-007-0341-9
Print

Study Purpose:

To investigate the effects of d-methylphenidate (d-MPH) on fatigue and cognitive function in women undergoing adjuvant chemotherapy for early breast cancer.

Intervention Characteristics/Basic Study Process:

Patients were given 5 mg of placebo for the first chemotherapy cycle to assess for compliance and were then randomized to either d-MPH 5 mg twice daily (BID) or matched placebo. The dosage increased to 10 mg BID after one week and was taken in the morning and at noon.

Sample Characteristics:

  • The sample was comprised of 57 women with breast cancer.
  • Median age was 50 years. 
  • Of the patients, 29 received d-MPH and 28 received placebo.
  • Patients were eligible for the study if they were receiving four cycles of standard adjuvant chemotherapy.

Setting:

  • Multisite
  • Three hospital outpatient clinics in Toronto, Canada

Study Design:

The study was a randomized, controlled trial with a placebo arm.

Measurement Instruments/Methods:

  • High Sensitivity Cognitive Screen (HSCS)
  • Hopkins Learning Test–Revised (HLT-R)
  • Functional Assessment of Cancer Therapy–General (FACT-G)
  • FACT–Fatigue (FACT-F) 
  • Mini-Mental State Examination (MMSE)

All were measured at baseline, end of chemotherapy, and at six-month follow-up.

Results:

The difference between groups was not significant in cognitive function or fatigue.

Conclusions:

The findings do not support the effectiveness of d-MPH at the doses given here in reducing fatigue during active treatment for breast cancer.

Limitations:

  • The study had a small sample size, with less than 100 patients. 
  • The study was underpowered; no trends suggest that d-MPH taken concurrently with adjuvant chemotherapy improves quality of life or fatigue.

Nursing Implications:

D-MPH cannot be suggested as an intervention to relieve cancer-related fatigue or cognitive functioning.

Moraska, A. R., Sood, A., Dakhil, S. R., Sloan, J. A., Barton, D., Atherton, P. J., . . . Loprinzi, C. L. (2010). Phase III, randomized, double-blind, placebo-controlled study of long-acting methylphenidate for cancer-related fatigue: North Central Cancer Treatment Group NCCTG-N05C7 trial. Journal of Clinical Oncology, 28, 3673–3679.

doi: 10.1200/JCO.2010.28.1444
Print

Study Purpose:

To evaluate the efficacy of long-acting methylphenidate in alleviating cancer-related fatigue (CRF), assess tolerability, and determine the effects on quality of life (QOL) in patients with CRF. Prior studies of methylphenidate have yielded mixed results. The drug used here was a mixture of d and l isomers of methylphenidate.

Intervention Characteristics/Basic Study Process:

Patients were stratified according to disease stage, baseline fatigue scores, and whether they were receiving concomitant cancer treatment. They were then randomized to receive methylphenidate or placebo for four weeks. Patients took one tablet (18 mg of long-acting methylphenidate) on days 1 to 7, two tablets (36 mg) on days 8 to 14, and three tablets (54 mg) on days 15 to 28. Tablets were to be taken in the morning. A standard dose modification procedure was used in case of adverse effects attributed to the study drug.

Sample Characteristics:

  • The final evaluable sample included 125 patients (57%–60% female). 
  • Patients had a history of CRF defined by a score of 4 or more on a 10-point fatigue screening scale.
  • Mean age was 59.2 years (standard deviation [SD] = 11.23 years) in the methylphenidate arm and 60.6 years (SD = 13.82 years) in the placebo arm. 
  • Of the patients, 29% to 38% had breast cancer across the study groups. Other diagnoses included lung, colon, prostate, and mixed cancers.
  • Patients had an Eastern Cooperative Group (ECOG) performance status of 0 to 2. 
  • Patients had a life expectancy of at least six months. 
  • Patients were excluded if they had any other cause of fatigue, brain tumor or metastases, and psychiatric disorders, among other exclusions.

Setting:

  • Multisite
  • Collaborative trial of the North Central Cancer Treatment Group and the Mayo Clinic

Study Design:

The study was a double-blind, randomized, placebo-controlled trial.

Measurement Instruments/Methods:

  • Brief Fatigue Inventory (BFI), completed weekly
  • Short Form 36 Health Survey (SF-36) Vitality subscale
  • Weekly linear analog self-assessment items used in North Central Cancer Treatment Group (NCCTG) clinical trials for QOL measures
  • Pittsburgh Sleep Quality Index (PSQI), completed at study entry and week 4
  • Subject Global Impression of Change (SGIC) was completed at the end of week 4 to measure patients’ perceived improvements in QOL, physical condition, and emotional state.
  • Adverse events and drug toleration were assessed with symptom experience diaries completed at baseline and weekly by patients.
  • Common Terminology Criteria (CTC) v3.0 was used by providers to grade adverse events at baseline and at each weekly evaluation via weekly telephone calls.

Results:

In advanced stage disease (stage III–IV), mean improvement in fatigue was 19.7 with methylphenidate and 2.1 with placebo (p = 0.02) Early stage patients had less improvement with methylphenidate than those receiving placebo. Similar trends were seen in SF-36 measures; however, differences between groups were not statistically significant. Self-reported adverse events showed a significant increase in nervousness (p = 0.003) and appetite loss (p = 0.034) in the methylphenidate arm. Individuals in the placebo arm reported improvements in self-reported adverse effects in nervousness, shakiness, appetite loss, abdominal pain, and sex drive. Both study groups were similar in terms of gender distribution, age, disease stage, and other baseline measures.

Conclusions:

The study demonstrated benefit for d-methylphenidate compared with placebo in alleviating CRF. Methylphenidate appeared to have some benefit in patients with advanced stage of disease.

Limitations:

There appeared to be some benefit of long-acting methylphenidate in patients with more advanced disease; however, these patients also experienced adverse effects. For use in these patients, benefits in terms of fatigue would need to be weighed against the adverse effects for individual patients from the patient's perspective.

Nursing Implications:

The study findings suggest that further research on effectiveness, particularly in patients with more advanced disease, is warranted.

Roth, A. J., Nelson, C., Rosenfeld, B., Scher, H., Slovin, S., Morris, M., . . . Breitbart, W. (2010). Methylphenidate for fatigue in ambulatory men with prostate cancer. Cancer, 116, 5102–5110.

doi: 10.1002/cncr.25424
Print

Study Purpose:

To test the potential benefit of psychostimulants in managing fatigue in men with prostate cancer.

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to receive methylphenidate or placebo for up to six weeks. Methylphenidate was started at 5 mg once daily and titrated upward by 5 mg every two to three days to a maximum of 30 mg/day. The physician or research nurse was in contact with each patient at least twice weekly for dosage and patient safety evaluation. Study data were collected at the time of study entry and at the end of the six-week study period.

Sample Characteristics:

  • The study was comprised of 39 men with advanced prostate cancer receiving either chemotherapy or hormonal therapy.
  • Mean age was 70 years (standard deviation = 9 years). 
  • Of the patients, 90% were Caucasian, 71% were married, and 70% had a college education.
  • Patients were eligible if they rated an average level of fatigue of 4 or greater on a 10-point scale over the past two weeks.
  • Patients were excluded if they had cognitive impairment, major depression, or medical conditions or were taking medications that contraindicated use of a psychostimulant. 

Setting:

  • Single site
  • Outpatient 
  • Memorial Sloan Kettering

Study Design:

This was a randomized, double-blind, placebo-controlled, intervention study.

Measurement Instruments/Methods:

  • Brief Fatigue Inventory (BFI)
  • Fatigue Severity Scale (FSS)
  • Hospital Anxiety and Depression Scale (HADS)
  • Beck Depression Inventory (BDI)
  • Functional Assessment of Cancer Therapy–Prostate (FACT-P)
  • Systematic Assessment for Treatment of Emergent Events (SAFTEE) questionnaire

Results:

Of the eligible patients screened, 54% declined to participate. Of the patients in the methylphenidate group, 31% were discontinued due to increased blood pressure, and another 16% were removed due to tachycardia. The methylphenidate group showed significant reduction in BFI fatigue scores from 5.13 to 2.19 (p = 0.01). The placebo group also showed significant reduction in scores (p = 0.02). There was a difference between groups in the changes in fatigue during the study, with those in the methylphenidate group showing greater reduction in fatigue (p = 0.07; d = .80). There were no significant differences between groups in depression, anxiety, quality of life, or measures of cognitive function. The separation of study drug and placebo effects emerged at weeks 3 and 6.

Conclusions:

The results suggested that methylphenidate was associated with a decline in fatigue; however, it was also associated with substantial cardiovascular side effects in almost half of the patients. A significant placebo effect was also observed.

Limitations:

  • The study had a small sample size, with less than 100 patients. 
  • There was substantial difficulty accruing patients for the study, and the sample was not sufficiently powered.

Nursing Implications:

Psychostimulants may be helpful to some patients in managing fatigue, but their use should be accompanied by close monitoring of potential side effects.

Sarhill, N., Walsh, D., Nelson, K. A., Homsi, J., LeGrand, S., Davis, M. P. (2001). Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study. American Journal of Hospice and Palliative Care, 18, 187–192.

doi: 10.1177/104990910101800310
Print

Intervention Characteristics/Basic Study Process:

Methylphenidate immediate release was administered at 5 mg twice daily and was titrated to effect as much as 20 or 30 mg per day if no response occurred after three and five days, respectively. Doses were given in the morning and at noon to limit insomnia. Treatment was discontinued after one week if no improvement was reported.

Sample Characteristics:

  • In total, 11 patients were included.    
  • Age ranged from 50 to 79 years.
  • Men and women were included.
  • Patients had various advanced malignancies.
  • Ethnicity was not reported.

Setting:

  • Inpatient and outpatient   
  • Large university cancer center

Phase of Care and Clinical Applications:

Patients were undergoing the end of life phase of care.

Study Design:

The study used a prospective, case series, open-label design; no comparison group was used.

Measurement Instruments/Methods:

  • No formal fatigue measures were used.
  • Patients self-reported improvement in fatigue.

Results:

Of the 11 patients, two experienced no improvement in fatigue on methylphenidate and one required 30 mg to sustain improvements in fatigue. Eight patients experienced improvements in their self-reported levels of fatigue after treatment with 10 mg daily in a divided dose.

Limitations:

  • The study was open-label, with no randomization or control or comparison group.
  • The study was a small case series.
  • Six patients experienced a side effect, including insomnia (n = 5), agitation (n = 1), anorexia (n = 1), nausea and vomiting (n = 1), and dry mouth (n = 1).

Nursing Implications:

No special training is required to deliver the intervention. Costs are related to drug acquisition.

Schwartz, A. L., Thompson, J. A., & Masood, N. (2002). Interferon-induced fatigue in patients with melanoma: a pilot study of exercise and methylphenidate. Oncology Nursing Forum, 29, E85–E90.

doi: 10.1188/02.ONF.E85-E90
Print

Intervention Characteristics/Basic Study Process:

Patients took methylphenidate 20 mg sustained release every morning and followed an aerobic exercise program for 15 to 30 minutes four days a week. Aerobic exercise is hypothesized to decrease fatigue by improving physical conditioning and mental concentration.

Sample Characteristics:

  • Eight patients were included (compared with four patients who were unable to tolerate methylphenidate and were receiving exercise alone and 16 historic controls). 
  • Most patients were Caucasian, college educated, worked full-time, and had stage III metastatic melanoma.
  • Gender was not reported.
  • All patients were newly diagnosed and being treated with interferon-alpha.
  • Patients had undergone previous surgery but no other therapies.
  • Only two patients exercised regularly prior to study entry.
  • All patients received interferon-alpha at a dose of 5 million IU/m2.
  • Patients were excluded if they had uncontrolled hypertension; anxiety disorders; active central nervous system metastasis; or a history of glaucoma, motor tics, seizure disorders, or Tourette’s syndrome.

Setting:

  • Outpatient
  • Large university cancer center

Study Design:

This was an open-label pilot study with comparison to historic controls.

Measurement Instruments/Methods:

  • Schwartz Cancer Fatigue Scale (SCFS), completed at monthly intervals
  • Functional status for 12-minute walk time
  • Medical Outcomes Study (MOS) Short Form 36 (SF-36)
  • Trail Making Test (TMT) Parts A and B

Results:

All patients adhered (as determined by patient diaries) to the exercise portion of the intervention over the four months of the study. Four of 12 patients were unable to adhere to methylphenidate:  three refused to continue on methylphenidate beyond the first 48 hours of the study (reasons for discontinuation included indigestion, mild nervousness, and unwillingness to take more pills), and one had methylphenidate discontinued by the investigators due to marked anxiety. Patients receiving exercise and methylphenidate or exercise alone experienced lower fatigue levels compared to historic controls. Patients who exercised and took methylphenidate reported the lowest levels of fatigue. The exercise-only group experienced a greater decline in cognitive function when compared with patients who exercised and took methylphenidate. Patients in the in exercise and methylphenidate group lost 8.1 kg, and those in the exercise-only group lost 8.2 kg.

Limitations:

  • The study used an open-label design.
  • The study lacked randomization.
  • The study had a small sample size.
  • The study failed to include a depression measure.

Nursing Implications:

Special training or consultation may be required to prescribe an exercise program for patients with cancer. Cost is related to drug acquisition.

Sugawara, Y., Akechi, T., Shima, Y., Okuyana, T., Akizuki, N., Nakano, T., . . . Uchitomi, Y. (2002). Efficacy of methylphenidate for fatigue in advanced cancer patients: a preliminary study. Palliative Medicine, 16, 261–263.

doi: 10.1191/0269216302pm547xx
Print

Intervention Characteristics/Basic Study Process:

Immediate-release methylphenidate was given at a dose ranging from 5 to 30 mg per day; 11 of 16 patients were given 10 mg per day. The study was based on the hypothesis that methylphenidate may improve fatigue by counteracting the adverse effects of opiates or relieving depression.

Posttreatment assessment was conducted as soon as two days after the initiation of therapy (median of seven days after initiation of methylphenidate).

Sample Characteristics:

  • In total, 16 patients (6 females, 10 males) were included.
  • Five patients had lung cancer and 11 had a mixed group of solid tumor diagnoses.
  • Half of the sample was experiencing pain, and nine were taking corticosteroids.
  • Four patients had been diagnosed with major depression before the initiation of the study.

Setting:

  • Inpatient and outpatient
  • One of two large comprehensive cancer centers

Phase of Care and Clinical Applications:

Patients were undergoing the end of life phase of care.

Study Design:

This was a prospective, open-label, pilot study.

Measurement Instruments/Methods:

A visual analog scale (VAS) was used to assess fatigue before premethylphenidate and after a median of seven days.

Results:

A statistically significant difference was found between the mean fatigue score before treatment with methylphenidate and the fatigue score after treatment. Following treatment with methylphenidate, patients reported lower fatigue scores, and six patients were classified by the investigators as having responded (defined by the investigators as a 30% improvement in fatigue severity score from pre- to posttreatment) to treatment with methylphenidate. Concomitant depression and the use of opioids did not predict methylphenidate efficacy. Two patients discontinued because of insomnia, and one reported mild palpitations but opted to continue methylphenidate. Adverse reactions reported generally were limited.

Limitations:

  • This was a small, convenience sample, with an open-label design and no comparison group that used only one fatigue measure.
  • Patients received different dosages of methylphenidate.

Guideline/Expert Opinion

National Comprehensive Cancer Network. (2011). NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue. Version 1.2011.

Print

Purpose & Patient Population:

To ensure that all cancer patients with fatigue were identified and treated promptly and effectively.  These guidelines included recommended standards of care for assessment and management of fatigue in children, adolescents, and adults with cancer.

Type of Resource/Evidence-Based Process:

The guidelines were evidence- and consensus-based. The guidelines were multidisciplinary, and all recommendations were category 2A unless otherwise stated.

Results Provided in the Reference:

The guidelines provided several algorithms for assessment and management based on age group, level of self-reported fatigue, and phase of treatment.

Guidelines & Recommendations:

Screening

  • All patients with cancer should be screened for the presence or absence of fatigue at regular intervals as a vital sign.
    • Age older than 12 years:  Screen on a 0-to-10 scale or as none, mild, moderate, or severe.
    • Age 7 to 12 years:   Use 1-to-5 scale (1 = no fatigue and 5 = worst).
    • Age 5 to 6 years:  Screen using “tired” or “not tired.”

Focused Evaluation of Fatigue

  • A focused history and assessment of contributing factors should be performed when screening indicates moderate to severe fatigue.
    • Age older than 12 years:  score of 4 to 10
    • Age 7 to 12 years:  score of 3 to 5
    • Age 5 to 6 years:  “tired”
  • Focused history should
    • Rule out recurrence or progression of cancer
    • Include a review of systems
    • Include an in depth fatigue history, including onset and patterns, associated/alleviating factors, and interference with function.
  • Assessment of treatable contributing factors, such as
    • Other related symptoms
    • Anemia
    • Sleep disturbance
    • Medication and side effects
    • Comorbidities
    • Activity and fitness level.

Management and Interventions

  • Active Treatment
    • Education and counseling regarding known patterns of fatigue and reassurance that treatment-related fatigue is not necessarily indicative of progression of disease.
    • General management strategies to include self-monitoring, energy conservation techniques, and use of distraction
    • Nonpharmacologic interventions to include activity enhancement, physically based therapies (such as massage), psychosocial interventions, nutritional consultation, and cognitive behavioral therapy for sleep
    • Pharmacologic interventions to include consider psychostimulants, treatment of anemia as indicated, and consideration of mediation for sleep
  • Posttreatment
    • Education and counseling about known fatigue patterns and self-monitoring of fatigue levels
    • General management and nonpharmacological and pharmacological interventions as for active treatment above
  • End of Life
    • Education and counseling about known fatigue patterns and as an expected end of life symptom
    • General strategies as per active treatment and post treatment
    • Nonpharmacologic interventions to include activity enhancement, psychosocial interventions, and nutrition consultation
    • Pharmacologic interventions as per active and post treatment

Within activity enhancement information, the guideline cites several synthesized reviews regarding the use of exercise and concludes that

  • Improvement in fatigue was not noted with all diagnoses.
  • It is reasonable to encourage all patients to engage in a moderate level of physical activity during and after cancer treatment.
  • Referral to exercise specialists or physical therapy should be triggered by
    • Patients with comorbid conditions, such as chronic obstructive pulmonary disease or cardiac disease
    • Recent major surgery
    • Specific functional or anatomical deficits
    • Substantial deconditioning.
  • Exercise should be used with caution in patients with
    • Bone metastases
    • Immunosuppression or neutropenia
    • Thrombocytopenia
    • Anemia
    • Fever or active infection
    • Limitations due to other illnesses.

Because fatigue is a subjective experience, it was recommended that assessment should use patient self-reports and other sources of data.

Several barriers were identified related to effective treatment for fatigue.  Due to barriers, it was stated that screening for fatigue needs to be emphasized.  Rescreening was emphasized because fatigue may exist beyond the period of active treatment.

Factors identified as potential causative agents that should be specifically assessed were outlined.  These factors were pain, emotional distress, sleep disturbance, anemia, nutrition, activity level, medication side effects, and other comorbidities.

It was noted that fatigue often occurs as part of a symptom cluster, often with sleep disturbance, emotional distress, or pain, so that assessment of these problems and institution of effective treatment is essential.

The importance of comprehensive assessment, including review of all current medications and noncancer comorbidities, was identified.  For example, it was noted that there can be thyroid dysfunction after radiation therapy for various cancers or use of biological and that hypogonadism can be associated with fatigue.

Limitations:

  • The majority of studies regarding the impact of exercise on fatigue were performed in patients with limited types of cancer, and findings may not be applicable to all types of patients.  In addition, the timing and amount of exercise for various groups are not clear.  There are also few longitudinal studies examining fatigue in long-term disease-free survivors, although fatigue can be a long-term or late effect.
  • Although the guideline was structured according to phase of treatment, recommended interventions did not vary according to phase of treatment.  There were minimal differences in recommended content of education and counseling.
  • There was little evidence regarding effective management of fatigue in end of life care.
  • There was no discussion of prevention related to fatigue.

Systematic Review/Meta-Analysis

Minton, O., Richardson, A., Sharpe, M., Hotopf, M., & Stone, P. (2008). A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue. JNCI: Journal of the National Cancer Institute, 100, 1155–1166.

doi: 10.1093/jnci/djn250
Print

Purpose:

To examine the role of methylphenidate and other drugs in the management of cancer-related fatigue

Search Strategy:

DATABASES: Cochrane Register of Controlled Trials, EMBASE, and hand searching of several journals and reference lists

KEYWORDS: neoplasms or cancer or carcinoma or tumour, bone marrow transplant, neutropenia, radiotherapy, fatigue. Complete listing of search terms is provided.

INCLUSION CRITERIA:

  • Randomized controlled trial
  • Designed to test a drug against placebo or usual care
  • Use of a multi-item measure of fatigue

EXCLUSION CRITERIA:

  • Measure of fatigue with single-item tool or visual analog scale

Literature Evaluated:

TOTAL REFERENCES RETRIEVED: Initial searching provided 5,841 articles and abstracts for screening. One hundred sixteen were reviewed in detail.

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Studies were done from 1992–2007. Data were collected from studies on a standard form by two independent reviewers, and any differences were resolved by consensus.

Sample Characteristics:

FINAL NUMBER STUDIES INCLUDED = 27

SAMPLE RANGE ACROSS STUDIES = 12–939

TOTAL PATIENTS INCLUDED IN REVIEW: 6,568 

KEY SAMPLE CHARACTERISTICS: Samples included a variety of tumor types, a variety of treatments, and patients in active treatment as well as after treatment.

Results:

Erythropoietin

Ten trials were included in meta-analysis.

  • Dosages ranged from 3,000–40,000 units, and frequency varied.
  • After 12 weeks of treatment, there was a significant reduction of fatigue (Z = 8.32, p <.001, SMD = -.038).
  • Most patients were anemic.
  • Half of the studies were open label.

Darbepoetin

Four trials were included in meta-analysis.

  • After 12 weeks of treatment, there was a significant effect compared with placebo (Z = 1.96, p = .05, SMD = -0.13).
  • All patients were anemic.

Paroxetine

Two studies were included.

  • After eight weeks of treatment, there was no fatigue benefit (Z = 1.06, p = -.29, SMD = -0.08).

Progestational Steroids

Four studies were included—three with megestrol acetate and one with medroxyprogesterone acetate.

  • After an average of eight weeks of treatment, no benefit was seen (Z = 1.06, p = .29, SMD = -0.18).
  • There was substantial heterogeneity among trials.
  • There was a consistent negative effect across all trials.

Methylphenidate

Two studies were included.

  • There was no overall benefit (Z = 0.63, p = .53).

Single studies

  • One study on 12 patients reported a significant effect of etanercept, an inhibitor of tumor necrosis factor.
  • One study on 466 women with metastatic breast cancer reported a significant effect of ibandronate compared with placebo.

Conclusions:

Findings suggest that there is no overall, effective pharmacologic management of cancer-related fatigue. Meta-analysis of progestational steroids report an overall negative effect, suggesting that this approach is counterproductive for fatigue management.

Limitations:

  • There is some expected bias in results due to lack of complete study data in some trials.
  • Overall effect sizes reported are small, so, though statistically significant, the actual effectiveness in the patient experience is unclear.

Nursing Implications:

The majority of patients who were treated with hematopoietic growth factors were anemic, pointing to the need to correct anemia, rather than any direct effect on the symptom of fatigue. These results point to the need to clinically evaluate such potential causes of fatigue. Even in these cases, the effect size is relatively small.

Minton, O., Richardson, A., Sharpe, M., Hotopf, M., & Stone, P. (2010). Drug therapy for the management of cancer-related fatigue. Cochrane Database of Systematic Reviews, 7, CD006704.

doi: 10.1002/14651858.CD006704.pub3
Print

Purpose:

To evaluate the effectiveness of pharmacologic interventions used for fatigue in patients with cancer

Search Strategy:

Databases searched were PaPaS, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, Dissertation Abstracts International (DAI), metaRegister of Controlled Trials (mRCT) (January 2007–October 2009). Journals searched were British Journal of Cancer, Journal of Clinical Oncology, Journal of Pain and Symptom Management, and Journal of Palliative Medicine. The reference lists of all articles were checked for additional studies. Conference abstracts also were searched.

Search keywords were neoplasms, bone marrow transplantation, cancer, carcinoma, tumour, adenocarcinoma, leukemia, lymphoma, malignant, radiotherapy, fatigue, tired, weary, weariness, exhausted, lack or loss or lost energy or vigor, apathy or lassitude or lethargy, or feeling drained, sleepy, or sluggish.

Studies were included in the review if they

  • Assessed drug therapy for the management of cancer-related fatigue (CRF) compared to placebo, usual care, or a nonpharmacologic intervention.
  • Were randomized, controlled trials (single-blind and open-label were allowed).
  • Included adult patients with a clinical diagnosis of cancer.

Literature Evaluated:

This review was an update of a previous review. The updated search retrieved 647 additional references. Of those, six additional studies met the inclusion criteria. The final sample of studies included was 31.

Sample Characteristics:

The review included 7,104 participants who received a drug intervention for CRF.

Results:

Psychostimulants

  • Four trials examined methylphenidate, and one used dexamphetamine. These included 426 patients total.
  • Evidence existed of a significant effect on fatigue with methylphenidate over placebo, and evidence supported the use of psychostimulants in the treatment of CRF.
  • The standardized mean difference was positive, with a small effect and narrow confidence interval (CI) (total mean difference = –0.28; 95% CI [-0.48, -0.09]; Z = 2.83; p = 0.005).
  • Fatigue was measured with the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) in all studies.

Erythropoietin and Darbepoetin

  • Eleven studies were combined in total and demonstrated a positive effect. The weighted mean difference of studies using the FACT-F outcome measure in erythropoietin gave a score of 4.33, which was a clinically significant difference. The conclusion was limited to patients with anemia who were undergoing chemotherapy. Greater improvement was more likely in those with lower hemoglobin levels.
  • In placebo-controlled trials of darbepoetin, the mean difference using the FACT-F score was -1.96, which was less than the minimally clinical significant difference.
  • Combined analysis for both agents gave a mean difference score of 3.75, which was clinically significant. 
  • Erythropoietin and darbepoetin cannot be recommended because of adverse events associated with these drugs.

Antidepressants/Paroxetine

  • Two studies using paroxetine and a trial using sertraline were analyzed. Analysis showed no benefit for the treatment of CRF.

Progestational Steroids

  • In studies that could be combined, no evidence existed to support continued use for the treatment of fatigue.
  • The clinical significance of results of ibandronate were unclear.
  • One study of etanercept during chemotherapy had statistically significant results, but the study had a small sample size and poor design. It was suggested that additional trials be conducted.
  • One study of donepezil showed no benefit over placebo.

Conclusions:

Four trials of methylphenidate provided evidence for use that was supportive but associated with a small effect size in a dose of 10–20 mg per day. Serious adverse events were minimal; however, clinicians need to review contraindications before prescribing. Additional large-scale trials were suggested using methylphenidate to further evaluate use in CRF. Erythropoietin and darbepoetin can no longer be recommended for CRF because of increased adverse events associated with these drugs. No current evidence exists to support the use of steroids.

Limitations:

  • Reviewers found major limitations in the reporting of trials and multiple methods of measuring outcomes.
  • Some outcomes in trials were not reported due to extensive missing data.
  • These findings point to the need for improved research reporting to meet Consolidated Standards of Reporting Trials (CONSORT) guidelines and the benefit that could be derived from use of consistent methods of measuring outcomes.

Minton, O., Richardson, A., Sharpe, M., Hotopf, M., & Stone, P. C. (2011). Psychostimulants for the management of cancer-related fatigue: a systematic review and meta-analysis. Journal of Pain and Symptom Management, 41, 761–767.

doi: 10.1016/j.jpainsymman.2010.06.020
Print

Purpose:

To focus on the role of psychostimulants, particularly methylphenidate, in the treatment of cancer-related fatigue (CRF).

Search Strategy:

Databases searched were MEDLINE, EMBASE, CINAHL, and Cochrane Register from inception to 2009.

Search keywords were not stated but appeared to be related to cancer-related fatigue and psychostimulants. According to the authors, “An exhaustive list of search terms was used and a systematic review methodology was applied.”

Studies were included if they were randomized, controlled trials testing a psychostimulant against a placebo or usual care in the treatment of CRF.

No exclusion criteria were stated.
 

Literature Evaluated:

The total number of references retrieved was not stated. One author screened relevant titles and abstracts. The final list of included studies was agreed on by all the authors. Data were “extracted and independently reviewed using predesigned data extraction forms. Data were entered into Cochrane review manager software.” More information on search terms and numbers of articles initially reviewed would have been helpful; it was unclear as to who designed the “predesigned data extraction forms.”

Sample Characteristics:

  • The final number of studies included was five.
  • The sample range across studies was 50 to 152 patients (N = 426 patients).
  • Minimal information was provided.
  • Mean age ranged from 50 to 71 years for the various studies (no range was provided).
  • There appeared to be various tumor types and treatment both current and past.
  • No other demographic data were provided.
     

Phase of Care and Clinical Applications:

  • Patients were undergoing the transitional phase of care after initial treatment.
  • The study has clinical applicability for late effects and survivorship and palliative care.

Results:

Four studies measured CRF with the Functional Assessment of Cancer Therapy–Fatigue (FACT-F), and one used the Brief Fatigue Inventory (BFI). There was a significant effect of psychostimulants over placebo (standardized mean difference = –0.28; 95% confidence interval [CI] [–0.48, –0.09]; p = 0.005). There was no difference in the rate of adverse effects between the drug and the placebo.

According to the authors, “evidence suggests that methylphenidate may be effective in management of CRF”; however, there was no large well-conducted clinical trial, and evidence from smaller trials was somewhat contradictory; thus, the authors stated “this advice must be considered to be tentative and provisional.”

Conclusions:

Generally, this was a weak systematic review because the authors talked about performing an extensive search but provided no details about that search. The meta-analysis was also weak because only one (the largest) of the five studies showed improvement with psychostimulants compared to placebo.

Nursing Implications:

Because there was no evidence about the long-term side effects of the medications, methylphenidate may best be used in patients with advanced disease or short-term use in those on active treatment. However, there was a trend toward benefit in some patients, and it may be worth a trial in selected patients as suggested by the authors.

Payne, C., Wiffen, P. J., & Martin, S. (2012). Interventions for fatigue and weight loss in adults with advanced progressive illness. Cochrane Database of Systematic Reviews, 1, CD008427.

doi: 10.1002/14651858.CD008427.pub2
Print

Purpose:

To determine the efficacy of interventions used in the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness by reviewing the evidence contained within Cochrane reviews. This overview does not attempt to rereview the literature or provide information on outcomes not reported within the included Cochrane reviews.

Search Strategy:

The database searched was Cochrane Database of Systematic Reviews.

No keyword or subject heading was searched because it would be unreliable due to the diverse range of interventions and illnesses under review. The authors hand searched the Cochrane Database of Systematic Reviews by title for all reviews that might assess the effect of an intervention on fatigue and/or unintentional weight loss in adults with advanced progressive illness.

Studies were included if they reported interventions with fatigue and/or unintentional weight loss as the primary treatment intent.

Studies were excluded if the treatment of fatigue and/or unintentional weight loss was not a primary indication for the intervention, they were systematic reviews published outside the Cochrane Library, or if they only included children.
 

Literature Evaluated:

Twenty-seven systematic reviews were retrieved. Assessment of Multiple SysTemAtic Reviews (AMSTAR) was used to assess the methodological quality of each systematic review.

Sample Characteristics:

  • The final number of systematic reviews included was 27.
  • The total sample size included 302 studies with 31,833 participants.
  • Adults 18 years or older with an advanced progressive illness known to have clinically significant fatigue and/or weight loss in the latter stages of illness were included. These conditions included degenerative neurological conditions, such as multiple sclerosis, Parkinson’s disease, dementia, irreversible organ failure, cancer with distant metastasis, and acquired immune deficiency syndrome (AIDS).
  • The pharmacological interventions were eicosapentaenoic acid (EPA) and any drug therapy for the management of cancer-related fatigue. The nonpharmacological interventions were exercise, interventions by breast care nurses, and psychosocial interventions.

Phase of Care and Clinical Applications:

  • Patients were undergoing the end of life phase of care.
  • The study has clinical applicability for palliative care.

Results:

The review looked for the following outcomes:

1. Clinically significant improvements in fatigue and/or unintentional weight loss
2. Improvements in quality of life of people who have fatigue and/or unintentional weight loss
3. Withdrawals due to adverse events.

Results relative to fatigue in patients with cancer included identification of five systematic reviews (116 studies with 17,342 participants). 

Nonpharmacologic Interventions

The evidence provided some insight into interventions that may prove beneficial, such as exercise. However, recommendations could not be made for specific exercise interventions that might best manage fatigue. In a systematic review, Cruickshank et al. (2008) reviewed the effect of breast care management strategies on fatigue in women with breast cancer at any stage of their illness. No included study assessed fatigue as an independent outcome, and no conclusions could be drawn. In 2009, Goedendorp reported that for patients undergoing cancer treatment at any disease stage, there was insufficient evidence that psychosocial interventions were beneficial for fatigue management. 

Pharmacologic Interventions

Sufficient evidence was not provided for the use of EPA over placebo in patients with advanced cancer. A small but significant improvement with fatigue was found with the use of methylphenidate in 51 studies with 10,296 participants. Use of erythropoietin and darbepoetin showed evidence of an effect over standard of care or placebo for the treatment of cancer-related fatigue. However, increased safety concerns mean they are no longer recommended in practice for this use, especially if the person’s hemoglobin concentration is greater than 12 g/dL. No benefits over placebo were seen for fatigue with the use of antidepressant drug paroxetine, nor with progestational steroids.

Conclusions:

There was a lack of robust evidence for interventions for fatigue management in the advanced stage of progressive illness related to cancer.

Limitations:

Extraction of data was limited to Cochrane reviews. Fatigue as an outcome indicator was not always sufficiently reported.

Nursing Implications:

Exercise interventions can lead to an improvement in fatigue in patients with cancer; however, this beneficial effect requires further research for those in the advanced stage.

Peuckmann, V., Elsner, F., Krumm, N., Trottenberg, P., & Radbruch, L. (2010). Pharmacological treatments for fatigue associated with palliative care. Cochrane Database of Systematic Reviews, 11, CD006788.

doi: 10.1002/14651858.CD006788.pub2
Print

Purpose:

To determine the efficacy of pharmacological treatment on nonspecific fatigue in palliative care, including patients with advanced cancer and other chronic conditions associated with fatigue.

Search Strategy:

Databases searched were EMBASE, PsychLit, CENTRAL, and MEDLINE. Reference lists of identified articles were reviewed for inclusion, and textbooks were handsearched. Conference proceedings of the American Society of Clinical Oncology (ASCO) from 2000 to 2008 and the 2005 meeting of the European Cancer Conference were included in the search.

An extensive listing of keywords and specific search methods per database are provided in the article.

Studies were included in the review if

  • They were randomized, controlled trials
  • The primary outcome was fatigue or related terms, such as asthenia
  • Participants were 18 years or older
  • The study included evaluation of the effect of pharmacologic treatment of fatigue with psychostimulants, amantadine, corticosteroids, donazepine, and antidepressants if used for the treatment of fatigue. 

Studies were excluded if they studied megestrol or focused on physiologic deficiencies, such as lack of hemoglobin and use of erythropoietin.

Literature Evaluated:

Initial searching provided 2,000 titles. Of those, 22 met the inclusion criteria. They included data from 11 drugs:  amantadine (6), pemoline (3), methylphenidate (3), dexamphetamine (2), paroxetine (2), acetyl-L-carnitine (2), testosterone (2), fluoxetine (1), donepezil (1), modafinil (1), and acetylsalicylic acid (1). If two or more studies of the same medication could be analyzed in the same subpopulation of patients, meta-analysis was performed. Meta-analysis was performed for amantadine, pemoline, methylphenidate, and modafinil.

Sample Characteristics:

  • The final sample of 22 studies included 1,632 patients.
  • Studies were performed in patients with multiple sclerosis (MS) (10), HIV (4), cancer (6), postpolio (1), and endstage chronic obstructive pulmonary disease (COPD) (1).

Results:

Most studies showed some beneficial effect; however, a substantial similar placebo effect was often observed.

Amantadine

  • Meta-analysis was conducted for three (n = 154) studies comparing amantadine to placebo in patients with MS.
  • Standard mean difference (SMD) favored amantadine (SMD = 1.68; 95% confidence interval [CI] [1.24,1.92]; Z = 12.76; p < 0.00001).
  • No statistically significant heterogeneity existed.
  • Study samples were generally small, and several methodologic weaknesses were seen.

Pemoline

  • Pemoline was used in three studies on MS.
  • Meta-analysis demonstrated no benefit (SMD = –0.11; 95% CI [–0.42, 0.2]; Z = 0.71; p = 0.48).
  • There was significant heterogeneity among the studies.

Methylphenidate

  • Two studies in patients with cancer were included.
  • There was a slightly superior effect compared to placebo (SMD = 0.49; 95% CI [0.15, 0.83]; Z = 2.86; p = 0.004).
  • There was significant heterogeneity.

Dextroamphetamine

  • Two studies compared the drug to placebo in patients with cancer. No significant benefits were seen.

Paroxetine

  • There were no significant effects demonstrated in one study in patients with COPD and one in patients with cancer.

Testosterone

  • No significant effects were demonstrated in studies on HIV.

Acetyl-L-carnitine

  • No significant effects were shown in one study on cancer and one on MS.

Modafinil

  • Meta-analysis in two studies on MS showed no significant effect.

Donepezil

  • One study in 142 patients with cancer showed no benefit compared to placebo.

Other

  • Fluoxetine was inferior to testosterone in one study on HIV.
  • Acetylsalicylic acid was associated with relief of fatigue compared to placebo in one study on MS.

Conclusions:

Methylphenidate and amantadine showed promise for reducing fatigue in patients with advanced disease. Amantadine has not been studied in patients with cancer-related fatigue, but it has been shown to be effective in patients with MS. The meta-analysis included only a few studies and the evidence was weak, pointing to the need for additional research in this area. It is not clear whether amantadine would be useful for patients with cancer, as this has not been studied.

Nursing Implications:

The analysis was performed only in palliative care populations and did not include studies of methylphenidate in patients with cancer during active treatment, which also have shown some efficacy. However, side effects included insomnia, anorexia, behavior change, and vertigo in studies reviewed with methylphenidate. In addition, although statistically significant, effect sizes were small. These findings suggest that use in patients with cancer, who also may experience anorexia and sleep disorders from other causes, has potential benefits that would need to be balanced with potential adverse effects. Carnitine, acetylsalicylic acid, and modafinil have been used in a few studies with positive results. These drugs warrant additional investigation to confirm efficacy in different patient populations with fatigue.


Menu