Improved cancer-related fatigue in a randomised clinical trial: methylphenidate no better than placebo

Abstract

IntroductionMethylphenidate is a psychostimulant drug used to treat fatigue in patients with advanced cancer, for which there is no gold standard of treatment.ObjectiveTo explore the efficacy of methylphenidate in the relief of fatigue in patients with advanced cancer.Materials and methodsA randomised double-blind placebo-controlled multicentre clinical trial, stratified according to the intensity of fatigue. The treatment was considered effective if the improvement in mean fatigue intensity between baseline values and day 6 was significantly higher in the methylphenidate group than in the placebo group. The responses were measured using the Edmonton Symptoms Assessment System (ESAS) and the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scales.Results35 patients received placebo and 42 patients received methylphenidate. The populations of both groups were homogeneous. Patients receiving methylphenidate did not exhibit statistically significant improvement of fatigue in comparison to patients receiving placebo (p=0.52). The mean improvement of fatigue (ESAS) on day 6 was −1.9 (±2.5) in the placebo group, and −2.3 (±2.6) in the methylphenidate group (p=0.52). The results obtained with the FACT-F were congruent with those obtained by the ESAS. The responses in patients with severe fatigue were −2.4 (±2.9) in the placebo group and −3.4 (±2.5) in the methylphenidate group; the difference was not statistically significant (p=0.3).ConclusionMethylphenidate was not more efficient than placebo to treat cancer-related fatigue. Fatigue improved significantly after 3 days of treatment and was stabilised on day 6, both with placebo and methylphenidate. The side effects of methylphenidate were mild and infrequent.Trial registration numberEudraCT Registry (2008-002171-27).

Fatigue in Cancer Patients in Palliative Care—A Review on Pharmacological Interventions

“…Nor methylphenidate or nursing telephone intervention showed a statistically significant effect in improved fatigue compared to placebo even if overall symptom burden was decreased [ 38 ]. Additionally, a recent placebo controlled RCT ( n = 100) could not establish evidence for the use of methylphenidate 10 mg/day for 6 days, even if fatigue was significantly improved in both groups [ 33 ].…”

“…Meta-analyses and group comparisons are therefore of little use at present, and instead we suggest that each study should be evaluated individually regarding generalizability of results. Unfortunately, characterization of disease severity in patients included in several studies in this review is scarce, and survival time is only accounted for in two trials [ 14 , 33 ]. Instead, inclusion and exclusion criteria, description of care facilities from which patients were recruited, assessed performance status at baseline and data on dropout rates and reasons for not completing intervention can be used to estimate general disease burden in studied cohorts.…”

“…Psychostimulants was the most commonly studied pharmacological interventions in studies on CRF in palliative care [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. The results in this review revealed a significant effect on the primary outcome only in three trials out of eleven on methylphenidate and modafinil [ 34 , 35 , 39 ].…”

“…Interestingly, several studies showed a significant effect in both treatment arms with similar effects in both placebo and intervention groups indicating an important placebo effect for any pharmacological treatment [ 33 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. Most of the included studies were underpowered resulting in inconclusive data [ 33 , 35 , 37 , 38 , 39 ]. Regarding methylphenidate, earlier studies indicate that they can reverse sedating effects of opioids [ 68 , 69 ] and reduce depressive symptoms [ 70 ], both contributors to fatigue.…”

“…Regarding RCTs on psychostimulants, we assessed that three studies were conducted on patients late in the disease trajectory: Centeno [ 33 ]—patients recruited from palliative care centers with short remaining life expectancy, Pedersen [ 34 ]—palliative inpatients with heavy symptom load and Mitchell [ 36 ]—patients who were not candidates for active oncological treatment recruited from palliative care facilities. Other trials mix palliative and curative patients recruited from oncology clinics [ 35 , 37 ], or include very little information on disease severity of randomized patients, rendering interpretation of results more difficult [ 38 , 39 ].…”