The primary aim of this randomized controlled trial was to examine the effect of the non-amphetamine-based stimulant modafinil on CRF among patients undergoing chemotherapy. Previous open label studies reported that modafinil helped alleviate CRF following cancer treatment in 30 brain cancer patients26
and 51 breast cancer patients.17
The findings of the present study confirm these preliminary data and support the use of 200 mg of modafinil as an effective treatment for severe CRF in patients undergoing chemotherapy.
Modafinil is a eugeroic agent that has been associated with minimal toxicities and a low susceptibility for misuse. If tolerable, modafinil could be utilized effectively to alleviate CRF and consequently improve QoL for patients with severe CRF. Modafinil has been shown to significantly reduce excessive daytime sleepiness.19
In the present study, the significant effect found on daytime sleepiness as defined by the Epworth Sleepiness scale (ESS) shows that the fixed 200 mg dose given was biologically active and produced the same significant clinical effects on sleepiness in cancer patients as shown in previous studies of various medical populations.19
Despite increasing knowledge of the negative effect of CRF on psychosocial functioning and treatment outcome for cancer patients, few studies have examined the effectiveness of pharmacologic interventions to control this side effect. The present study addresses this paucity of relevant data. The findings show that modafinil could be a useful agent to control CRF and also characterize the severity level of CRF (i.e., severe CRF) for which modafinil could be most useful. The heterogeneity and size of the present sample indicate the likelihood that these findings will be generalizable for a wide variety of cancer patients undergoing treatment.
Modafinil had an effect on CRF but not on depression. Our previous research showed that paroxetine hydrochloride (Paxil®) alleviated depression but had no significant effect on CRF.27,21
This contrast might indicate that hypotheses of a common underlying pathway for CRF and depression are debatable.14,17
The association between fatigue and depression has always been correlational. Both the previous RCT and the present study are randomized studies where one part of the associated pairing was changed with no effect on the other. While these findings do not suggest a disconnection between CRF and depression, they do, however, bring into question the association between these two symptoms.
Our previous findings are that the more individual questions added to a fatigue measurement scale, the more it correlates with depression.28
This could be suggesting that the consistently high correlations previously reported between fatigue and depression may be measurement artifacts. This study and the previous paroxetine hydrochloride study support this view: fatigue and depression were each effectively treated without affecting the other. When measured properly by a single item scale, fatigue is not clinical depression by another name.
The findings have important clinical implications for cancer-related symptom management. Questions related to the etiology and assessment of CRF in divergent cancer types, stages, and clinical settings remain open, and the mechanism of action of modafinil remains unclear. Nevertheless, modafinil seems a promising agent to diminish CRF for patients with severe baseline CRF. Future studies should focus on describing ways to maximize the benefits of this agent and also evaluate whether and how modafinil could facilitate the effects of behavioral interventions to alleviate CRF.