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.

• 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. 

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

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

• 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)

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.

• 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.

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.