The newer so-called wake-promoting agents, modafinil and armodafinil, are just beginning to be studied for CRF. Modafinil is a centrally acting, nonamphetamine, central nervous system stimulant. Armodafinil is the R-enantiomer of modafinil and an alpha-1 adrenoceptor agonist. Modafinil and armodafinil are approved by the FDA for narcolepsy, obstructive sleep apnea, and shift-work disorders. Neither of these agents is approved by the FDA for the treatment of CRF. These agents are also not indicated for use in children and adolescents. The mechanism of action of modafinil and armodafinil is different from that of amphetamines, but the exact mechanisms by which these agents improve wakefulness are not known. On the basis of a couple of promising open-label pilot trials,[11,12] a large randomized controlled trial evaluated modafinil for CRF using 200 mg versus placebo in more than 850 patients receiving chemotherapy. Patients had to have fatigue ratings of at least 2 out of 10 to be eligible for this study. During four cycles of chemotherapy, this study failed to show significant differences between arms. Because armodafinil is newer to the marketplace, research on its possible role in CRF has not yet been published. More research is needed to identify whether modafinil and armodafinil can ameliorate fatigue and which populations of cancer survivors can benefit most from them.
With both methylphenidate and modafinil, there have been exploratory data suggesting that patients with more severe fatigue or more advanced disease may receive more benefit from these drugs.[7,8] A small (n = 13), randomized, placebo-controlled study  using methylphenidate (titrated up to 30 mg/day) as an intervention failed to show statistical difference on the primary outcome measure, the brief fatigue inventory (BFI) total score, or activity interference subscale. However, the methylphenidate group showed significant reductions in the BFI severity subscale scores compared with the placebo group. The mean severity score at baseline was 6.5 for the methylphenidate group and 5.7 for the placebo group, placing these patients in a more severe fatigue category. A secondary analysis of the phase III trial evaluating modafinil versus placebo for CRF also revealed that patients with more severe fatigue may have benefited from modafinil. More research is needed to further evaluate whether psychostimulants are beneficial for patients experiencing more severe CRF.
The side effects most commonly described with psychostimulants include insomnia, euphoria, headache, nausea, anxiety, and mood lability.[5,7,8,13,14] High doses and long-term use may produce anorexia, nightmares, insomnia, euphoria, paranoia, and possible cardiovascular complications. Patients with cancer carry a higher risk of cardiovascular complications, depending on the type of cancer and cancer treatment (e.g., cardiotoxic chemotherapy regimens). Cardiovascular complications with psychostimulants can arise even in patients without any significant risk factors. In the study using methylphenidate as an intervention for the treatment of CRF in patients with prostate cancer, 6 subjects (27%) out of a total of 16 subjects in the methylphenidate group were discontinued because of increased blood pressure and tachycardia. It is important to note that none of these subjects were being treated with known cardiotoxic chemotherapeutic regimens such as anthracyclines. Careful and continuous monitoring of certain cardiovascular parameters (mainly blood pressure and heart rate) is critical when psychostimulants are used to treat CRF. In certain complex cases, consulting with cardiology services may be considered. Cardiovascular issues are thought to be less of a risk with modafinil and armodafinil. It is important to consider risk-benefit ratio and to evaluate patients for response and side effects when these agents are used to treat CRF.