As studies are performed that establish the efficacy of various drug therapies for fatigue, future trials may opt to eschew a placebo in lieu of a direct comparison between an established therapy and a proposed therapy. This approach may be informative and typically generates fewer ethical concerns than the use of a placebo when clearly effective therapy is available. This is not to say that the use of a placebo in these circumstances is unethical; as long as the patient is fully informed and allowances are made for drop-out, use of a placebo can remain an option.

A study that compares two potentially active therapies, whether pharmacologic or non- pharmacologic, may find no difference between them. The investigator must recognize that this finding of "no difference" has two potential interpretations: 1) the two treatments are therapeutically equivalent, and 2) the study methodology was insufficiently sensitive to identify important differences. Thus, a two-arm comparative trial can result in a meaningless outcome, even if randomization, double-blinding and other controls are in place. The problematic nature of finding "no difference" in comparative studies of potentially active therapies is as much a concern in studies of fatigue as it is in analgesic studies

The possibility of a "no difference" finding is inherent in all intervention trials in which the primary outcome is inherently subjective.