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.

• N = 24  
• MEDIAN AGE = 71 years
• MALES: 54%, FEMALES: 46%
• KEY DISEASE CHARACTERISTICS: Gastrointestinal, prostate, lung, breast, and genitourinary cance
• OTHER KEY SAMPLE CHARACTERISTICS: ​Australia-modified Karnofsky Performance Scale (AKPS) ≥ 40; screening fatigue score ≥ 4/10 (National Comprehensive Cancer Network); stable treatment regimen for at least 48 hours; no plan for treatment likely to influence fatigue; no change in thyroxine, antidepressant therapy, or other drugs with sympathomimetic potential for three weeks prior to recruitment

• SITE: Multi-site  
• SETTING TYPE: Not specified    
• LOCATION: Queensland and New South Wales, Australia

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care

Population was estimated using the aggregated N of one multicycle, double-blinded, controlled, crossover study.

• Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
• Wu Cancer Fatigue Scale (WCFS)
• Edinburgh Depression Scale (EDS)
• AKPS performance scale

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.

• Small sample (< 30)
• Selective outcomes reporting
• Measurement validity/reliability questionable
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: Patients self-reported; N of one design; intention to treat analysis used a combination of weighted group estimates and prior values for missing data; of 43 patients originally recruited, only 55.8% completed three cycles of treatment; the mean population response estimate also included patients who did not complete any study cycle, so it is unclear if results are over or underestimated; study cycle times were short and may not have allowed for full drug effects

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.