A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease

Background: Fatigue is a commonly encountered symptom of human immunodeficiency virus (HIV) disease, associated with significant psychological and functional morbidity and poor quality of life. Preliminary studies on the treatment of fatigue from the cancer and multiple sclerosis literature suggest that psychostimulants may be effective in reducing fatigue. Objective: To compare the efficacy of 2 psychostimulant medications, methylphenidate hydrochloride (Ritalin) and pemoline (Cylert), with a placebo intervention for the treatment of fatigue in patients with HIV disease. Methods: In this double-blind trial, 144 ambulatory patients with HIV disease and persistent and severe fatigue were randomized to treatment with methylphenidate, pemoline, or placebo. Medications were titrated up to a maximum dose of 60 mg of methlyphenidate hydrochloride, 150 mg of pemoline, or 8 capsules of placebo daily. Fatigue was measured using 2 self-reported rating scales, the Piper Fatigue Scale (PFS) and the Visual Analogue Scale for Fatigue (VAS-F). We also used the timed isometric unilateral straight leg-raising task, a measure of muscular endurance. Quality-of-life and psychological well-being measures included the Beck Depression Inventory, the Brief Symptom Inventory, and the 36-Item Short-Form Medical Outcomes Study Health Status Survey. Side effects were monitored using the Systematic Assessment for Treatment Emergent Events and the Extra-pyramidal Symptom Rating Scale. All measures were rated weekly. Results: One hundred nine subjects completed the 6-week trial; 15 patients (41%) receiving methylphenidate and 12 patients (36%) receiving pemoline demonstrated clinically significant improvement compared with 6 patients (15%) receiving placebo. Patients receiving methylphenidate or pemoline demonstrated significantly more improvement in fatigue on several self-reported rating scales (PFS total score, P = .04; affective subscale, P = .008; sensory subscale, P=.04; and VAS-F energy subscale, P = .02). Analysis of the regression slopes by means of hierarchical linear modeling demonstrated a significantly greater rate of improvement in PFS total scores among patients receiving psychostimulants compared with the placebo group (P = .02). There were no significant differences in the efficacy between methlyphenidate and pemoline on any outcome measure studied. Improvement in fatigue was also significantly correlated with improvement in measures of depression, psychological distress, and overall quality of life. Severe side effects were relatively uncommon among this sample, and only hyperactivity or jitteriness occurred significantly more often among subjects receiving active medication. Conclusions: Many patients with HIV- and acquired immunodeficiency syndrome-unrelated fatigue respond favorably to treatment with methylphenidate or pemoline. Both psychostimulants appear to be equally effective and significantly superior to placebo in decreasing fatigue severity with minimal side effects. Moreover, improvement of fatigue was significantly associated with improved quality of life and decreased levels of depression and psychological distress.