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.
Gong, S., Sheng, P., Jin, H., He, H., Qi, E., Chen, W., . . . Hou, L. (2014). Effect of methylphenidate in patients with cancer-related fatigue: A systematic review and meta-analysis. PloS One, 9(1), e84391.
To assess the safety and efficacy of methylphenidate for cancer-related fatigue. Secondary outcomes included depression, cognition, and adverse effects.
TYPE OF STUDY: Meta-analysis and systematic review
DATABASES USED: PubMed. EMBASE, PsycINFO, Cochrane Collaboration
KEYWORDS: Methylphenidate, dimethylphenidate, Ritalin, cancer, fatigue, asthenia, tiredness, and randomized controlled trial
INCLUSION CRITERIA: Randomized controlled trials, adults older than 18 years, the trial examined efficacy of methylphenidate on fatigue, and results were sufficient to calculate effect sizes
EXCLUSION CRITERIA: None specified
TOTAL REFERENCES RETRIEVED: N = 374
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: The Jadad scale was used for quality assessment.
PHASE OF CARE: Multiple phases of care
Meta-analysis was done with studies grouped according to the measure of fatigue that was used. In studies using the FACT-F (three studies), results showed a favorable effect of methylphenidate with a mean difference of -3.13 and a signficant overall effect (p -0.01). In studies using the BFI, results showed a favorable effect with mean difference of -0.69, but the Z test of overall effect was not significant. Methylphenidate had no effect on depression (two studies) or cognitive impairment (two studies). Studies varied widely in terms of the duration of treatment. Treatment for greater than four weeks was superior compared to placebo. However, treatment for less than four weeks did not show a significant effect compared to placebo. Rates of adverse effects between those getting methylphenidate and those getting a placebo were not significantly different. Those receiving methylphenidate had significantly more vertigo, anxiety, and nausea.
Results suggest that treatment with methylphenidate for at least four weeks is effective in reducing cancer-related fatigue and is not associated with a high rate of adverse effects. Treatment with methylphenidate did not improve depression or cognitive impairment. Use of different methods of measurement of fatigue showed different results.
Few studies were included, and some of these had very small sample sizes. Included studies did not provide sufficient information on relevant concomitant conditions of patients, such as sleep disorders and anxiety. Dosages and dosage increase approaches with methylphenidate varied.
Findings suggest that treatment with methylphenidate for at least four weeks can be helpful in managing cancer-related fatigue. However, the most appropriate dosages are not clear. Patients can experience side effects, and if methylphenidate is used, nurses need to monitor patients for side effects. Further large studies are needed to strengthen evidence related to effects and side effects of methylphenidate.
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.
To examine the role of methylphenidate and other drugs in the management of cancer-related fatigue
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:
EXCLUSION CRITERIA:
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.
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.
Erythropoietin
Ten trials were included in meta-analysis.
Darbepoetin
Four trials were included in meta-analysis.
Paroxetine
Two studies were included.
Progestational Steroids
Four studies were included—three with megestrol acetate and one with medroxyprogesterone acetate.
Methylphenidate
Two studies were included.
Single studies
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.
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.
To evaluate the effectiveness of pharmacologic interventions used for fatigue in patients with cancer
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
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.
The review included 7,104 participants who received a drug intervention for CRF.
Psychostimulants
Erythropoietin and Darbepoetin
Antidepressants/Paroxetine
Progestational Steroids
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.
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.
To focus on the role of psychostimulants, particularly methylphenidate, in the treatment of cancer-related fatigue (CRF).
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.
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.”
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.”
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.
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.
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.
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.
Twenty-seven systematic reviews were retrieved. Assessment of Multiple SysTemAtic Reviews (AMSTAR) was used to assess the methodological quality of each systematic review.
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.
There was a lack of robust evidence for interventions for fatigue management in the advanced stage of progressive illness related to cancer.
Extraction of data was limited to Cochrane reviews. Fatigue as an outcome indicator was not always sufficiently reported.
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.
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.
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
Studies were excluded if they studied megestrol or focused on physiologic deficiencies, such as lack of hemoglobin and use of erythropoietin.
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.
Most studies showed some beneficial effect; however, a substantial similar placebo effect was often observed.
Amantadine
Pemoline
Methylphenidate
Dextroamphetamine
Paroxetine
Testosterone
Acetyl-L-carnitine
Modafinil
Donepezil
Other
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.
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.
Qu, D., Zhang, Z., Yu, X., Zhao, J., Qiu, F., & Huang, J. (2016). Psychotropic drugs for the management of cancer-related fatigue: A systematic review and meta-analysis. European Journal of Cancer Care, 25, 970–979.
Four studies examined modafinil, and six evaluated used methylphenidate. The meta-analysis showed that methylphenidate reduced fatigue significantly (SMD = –0.28, p = 0.0005) and had no impact on sleep quality. Modafinil did not demonstrate a significant reduction in fatigue. Adverse effects were reported in 6.5% of patients getting methylphenidate, and no differences in study dropouts related to side effects existed between those on methylphenidate and those receiving placebo. The analysis showed no significant difference in risk of adverse events between those receiving either drug and those on placebo.
The findings showed that methylphenidate was associated with improvement in cancer-related fatigue, with no significantly increased risk of side effects. Modafinil was not associated with any improvement.
The findings suggest that methylphenidate is helpful to reduce cancer-related fatigue, with minimal adverse effects. Modafinil was not shown to be beneficial. Nurses need to be aware of the benefits and potential adverse effects when using psychotropic drugs to combat fatigue in patients with cancer.
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.
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.
Patients were recruited from a palliative care outpatient clinic or a pain clinic of a large university cancer center.
Unspecified
The study used a single-center pilot study prospective, open-label design; no comparison group was included.
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.
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.
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.
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.
Randomized, controlled trial; placebo controlled
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).
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.
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.
Escalante, C.P., Meyers, C., Reuben, J.M., Wang, X., Qiao, W., Manzullo, E., . . . Cleeland, C. (2014). A randomized, double-blind, 2-period, placebo-controlled crossover trial of a sustained-release methylphenidate in the treatment of fatigue in cancer patients. Cancer Journal, 20(1), 8–14.
To assess effectiveness of methylphenidate versus placebo to reduce cancer-related fatigue and to analyze cytokine levels and symptoms of cognitive function
Patients were randomized to receive either methylphenidate 18 mg per day for two weeks followed by placebo for two weeks, or to receive placebo for the first two weeks followed by methylphenidate for three weeks. All completed a battery of tests at baseline and were asked to record fatigue level and interference with activities in a daily diary. Additional fatigue measurement occurred at week 1 and week 3. Bloodwork for cytokine levels was obtained at baseline, crossover, and the end of the study.
PHASE OF CARE: Multiple phases of care
Double-blind, placebo-controlled crossover RCT
There were no significant differences between treatment arms for fatigue by BFI scores or diaries. There was no carryover effect of methylphenidate, so data were pooled for analysis. There were no differences in symptom inventory results. The WAIS-III digit span test demonstrated improved cognitive processing speed in the treatment versus placebo condition (p = .01), and the subscale of confusion on POMS was lower with methylphenidate (p = .05). There was a significant correlation between BFI interference and activity level and the Hopkins Verbal Learning Test showing declining memory with higher levels of fatigue (p < .05). Patients receiving methylphenidate missed fewer hours of work due to health (p = .03). There were no significant differences in or correlations with cytokine levels. There were no serious adverse events with methylphenidate.
This study did not show improvement in fatigue with methylphenidate. Findings suggest that some aspects of cognitive function are related to fatigue level.
Findings do not show that methylphenidate improved fatigue symptoms, but it may have had some effect on missing work and some aspects of cognitive function. Further exploration of associations between fatigue and cognitive impairment associated with chemotherapy is warranted.
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.
To compare the effectiveness of immediate-release and sustained-release methylphenidate versus modafinil in improving cognitive function in patients with primary brain tumors.
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.
Patients were undergoing multiple phases of care.
The study was a randomized, clinical trial.
Objective Cognitive Function Instruments
Subjective Anxiety Instruments
Subjective Depression Instruments
Subjective Fatigue Instruments
Subjective Sleep-Wake Disturbance Instrument
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).
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.
To identify a dose of methylphenidate to test formally in a subsequent N-of-one trial of fatigue.
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.
Patients were undergoing the transition phase on “stable treatment,” not on chemotherapy.
The study was a prospective trial.
Methylphenidate 5 mg BID was chosen as the ideal dose to test against placebo.
Nurses in research can use a 5-mg BID dose of methylphenidate to test against placebo.
Jiang, Z., Butler-Bowen, H., Rodriguez, T., Garcon, M.C., Smith, M.H., Relias, V., & Saif, M.W. (2016). Role of methylphenidate in the treatment of fatigue in advanced pancreatic cancer population. Annals of Gastroenterology, 29, 536–543.
To assess the effects of methylphenidate (MPH) in ameliorating fatigue in patients with advanced pancreatic cancer
Records of patients with stage 4 pancreatic cancer who were experiencing fatigue were retrospectively analyzed. The fatigue level was assessed at each visit prior to chemotherapy, and a trial of MPH was done for at least four weeks. MPH was begun at 5 mg by mouth daily and increased to 10 mg for those who did not benefit from the lower dose.
Retrospective
Most patients continued MPH after four weeks, for up to 24 months. Fatigue improved at least from grade 3 to grade 2, or from grade 2 to grade 1 in 55%; and in 23%, fatigue resolved. Fourteen percent stopped MPH because of lack of benefit, and 13% stopped because of adverse effects. The most common adverse effects were weight loss, nausea, anorexia, and insomnia.
MPH appeared to provide some benefit in reducing fatigue for some patients but had important negative side effects in others.
The findings regarding any potential benefit of psychostimulants, such as MPH, for the management of cancer-related fatigue have been mixed. MPH has also been associated with a number of adverse side effects. Nurses need to be aware of side effects and relevant monitoring if MPH is used.
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.
To evaluate the effect of methylphenidate on fatigue in women with recurrent gynecologic cancer.
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.
Patients were undergoing the active treatment on chemotherapy phase of care.
The study was a prospective trial.
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.
Methylphenidate may be beneficial to women with recurrent gynecologic cancer experiencing treatment-related fatigue.
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.
To test the hypothesis that d-methylphenidate (d-MPH) would produce a significant reduction in fatigue compared to placebo.
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.
This was a double-blind, randomized, controlled study.
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.
D-MPH treatment in an individualized dosing regimen based on therapeutic response and side effects was associated with a significant improvement in fatigue.
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.
To investigate the effects of d-methylphenidate (d-MPH) on fatigue and cognitive function in women undergoing adjuvant chemotherapy for early breast cancer.
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.
The study was a randomized, controlled trial with a placebo arm.
All were measured at baseline, end of chemotherapy, and at six-month follow-up.
The difference between groups was not significant in cognitive function or fatigue.
The findings do not support the effectiveness of d-MPH at the doses given here in reducing fatigue during active treatment for breast cancer.
D-MPH cannot be suggested as an intervention to relieve cancer-related fatigue or cognitive functioning.
Mitchell, G.K., Hardy, J.R., Nikles, C.J., Carmont, S.A., Senior, H.E., Schluter, P.J., . . . Currow, D.C. (2015). The effect of methylphenidate on fatigue in advanced cancer: An aggregated N-of-1 trial. Journal of Pain and Symptom Management, 50, 289–296.
To determine the efficacy of alleviating fatigue using the psychostimulant methylphenidate hydrochloride (MPH) in patients with advanced cancer
MPH 5 mg was taken orally twice daily versus placebo for three cycles of a pair of three-day periods. Patients completed a daily diary of symptom scales and side effects.
Population was estimated using the aggregated N of one multicycle, double-blinded, controlled, crossover study.
Eight patients had individual improvements in fatigue with MPH compared to a placebo on the FACIT-F and WCFS scores, but the mean population estimate showed no important difference. Seven patients showed an improvement in EDS scores, but the mean population estimate showed no important difference. There was no change in AKPS scores. There were six adverse events with three events possibly related to MPH.
Although there may be some individual improvement in fatigue with MPH use, the results of this small sample size were difficult to generalize.
Continued studies on the effects of psychostimulants on cancer-related fatigue are needed. This study adds to the growing body of evidence that methylphenidate is not generally helpful in reducing fatigue. The strength of this study's results are limited by design issues.
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.
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.
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.
The study was a double-blind, randomized, placebo-controlled trial.
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.
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.
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.
The study findings suggest that further research on effectiveness, particularly in patients with more advanced disease, is warranted.
Richard, P.O., Fleshner, N.E., Bhatt, J.R., Hersey, K.M., Chahin, R., & Alibhai, S.M. (2014). A phase II, randomized, double-blind, placebo-controlled trial of methylphenidate for reduction of fatigue in prostate cancer patients receiving LHRH-agonist therapy. BJU International. Advance online publication.
To determine if a 10-week regimen of methylphenidate could alleviate fatigue and improve quality of life in men with prostate cancer being treated with luteinizing hormone-releasing hormone agonists
Subjects were randomized to receive either methylphenidate or a placebo for up to 12 weeks. Methylphenidate was given at a dose of 5 mg daily for two weeks followed by 5 mg twice daily for eight weeks. The dose was tapered back to 5 mg per day for the last two weeks. Patients were contacted by phone at week 2 for reminders to take the medication and to assess drug tolerance. Assessments were done when patients were seen in-clinic at weeks 6, 10, and 12.
Double-blind, placebo-controlled, randomized trial
FACIT scores improved significantly over the course of the study in all patients, but improvement was only statistically significant in the methylphenidate group (p = .008). The between-group difference in improvement was significant (p = .02). BFS scores also showed improvement in the methylphenidate group over time (p = .0006) but differences between study groups were not statistically significant. One patient discontinued the medication due to side effects.
Methylphenidate was shown in this small study to improve fatigue scores.
Methylphenidate may be helpful to some patients in managing fatigue during cancer treatment. Due mostly to sample size limitations, this study does not provide strong evidence for use of methylphenidate in men with prostate cancer.
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.
To test the potential benefit of psychostimulants in managing fatigue in men with prostate cancer.
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.
This was a randomized, double-blind, placebo-controlled, intervention study.
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.
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.
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.
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.
Patients were undergoing the end of life phase of care.
The study used a prospective, case series, open-label design; no comparison group was used.
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.
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.
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.
This was an open-label pilot study with comparison to historic controls.
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.
Special training or consultation may be required to prescribe an exercise program for patients with cancer. Cost is related to drug acquisition.
Siu, S.W.K., Law, M., Liu, R.K.Y., Wong, K.H., Soong, I.S., Kwok, A.O.L., . . . Leung, T.W. (2014). Use of methylphenidate for the management of fatigue in Chinese patients with cancer. American Journal of Hospice & Palliative Medicine, 31, 281–286.
To determine whether methylphenidate is useful for the management of fatigue in Chinese patients with cancer in the palliative care setting
Oral methylphenidate 5 mg daily; reassessed at day 8 and day 29 (if patient was still in study)
Prospective study
For patients < 65 years old, scores were significantly lower at day 8 than at baseline but not at day 29. There were no significant differences at day 29 or in patients > 65 years old. Ten out of 24 patients stopped methylphenidate before day 8, with eight of the withdraws due to side effects of medication.
This study demonstrated no clinically significant effect for methylphenidate on cancer-related fatigue.
Methylphenidate is not recommended for the management of cancer-related fatigue.
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.
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).
Patients were undergoing the end of life phase of care.
This was a prospective, open-label, pilot study.
A visual analog scale (VAS) was used to assess fatigue before premethylphenidate and after a median of seven days.
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.
National Comprehensive Cancer Network. (2011). NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue. Version 1.2011.
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.
The guidelines were evidence- and consensus-based. The guidelines were multidisciplinary, and all recommendations were category 2A unless otherwise stated.
The guidelines provided several algorithms for assessment and management based on age group, level of self-reported fatigue, and phase of treatment.
Screening
Focused Evaluation of Fatigue
Management and Interventions
Within activity enhancement information, the guideline cites several synthesized reviews regarding the use of exercise and concludes that
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.