Pharmacotherapy of Chronic Fatigue Syndrome: Title and subTitle BreakAnother Gallant Attempt

As the ability to treat the physical manifestations of many illnesses improves, physicians grapple more seriously with their emotional, social, and symptomatic dimensions. For example, palliative care is now a critical healing art, while oncology begins to contend with the long-term sequelae of the curative regimens for which it has labored so long to craft. Today, quality-of-life instruments and symptom rating scales are essential metrics of health status and outcomes.

Among the illness symptoms that are now addressed in the context of clinical practice and research, fatigue seems the most refractory to measurement and management. Although fatigue is a recognized complication of certain conditions and treatments—advanced cancers and multiple sclerosis, and a consequence of radiation and recombinant interferon therapy—the tools and techniques used to assess and ameliorate fatigue and the comprehension of its pathogenesis are decidedly inferior to those for other prevalent symptoms like pain and nausea.

Absent optimal metrics and explanations for fatigue, this symptom also elicits the least attention and sympathy. This reality most affects those for whom no underlying illness or treatment can be identified as the proximate cause of their persisting fatigue. Efforts over the past quarter century have attempted to characterize such patients, leading to a series of working definitions of which the most widely used, however still imperfect, parses cases into those with idiopathic chronic fatigue and those with more global and debilitating features that have been termed chronic fatigue syndrome (CFS).^{1 - 4}

As defined, CFS is largely an acquired sporadic condition that affects, arguably, as many as 420 individuals per 100 000 population—adults more often than children and women more often than men.^{5 - 6} Speculations as to its pathogenesis abound: that it arises from a chronic infection, a brain or mood disorder, a sleep disturbance, an immune dysfunction, an autonomic or neuroendocrine imbalance, etc.^{3 - 4 ,7} The data strongly reject the infectious hypotheses and discern a subtle, but still nebulous, problem in regulation of hypothalamic-pituitary-adrenal and related hormonal axes.^{8 - 9}

With the description of CFS have come countless proposals to treat it with drugs, biological agents, dietary interventions, and behavioral and exercise strategies. The self-help sections of bookstores and numerous Web sites beckon to desperate patients with promises of simple solutions for renewed health and energy. Among the strategies that were studied rigorously, only 2 emerged with some consistency as meaningfully beneficial for many patients: cognitive-behavioral therapy and graded exercise.^{4 ,8 ,10 - 15} These are demanding therapies and not universally embraced because of a misperception that their nature places blame for the fatigue on the patient for failing to manifest sufficiently healthy behaviors and habits. Thus, drugs remain the favored solution, should any prove effective.

Unfortunately, pharmacological approaches have failed to resolve CFS. This is not to say that drugs have no place in the management of the pain, feverishness, and depressive features of CFS, for they are helpful.^{4 ,8 ,14} Rather, no drugs prove to ameliorate the core feature of CFS: physical and mental fatigue so profound and oppressive that the term fatigue seems inadequate at times to describe it. Anecdotal reports and pilot studies have provided tantalizing possibilities, but when examined rigorously through well-blinded and adequately powered trials, no drug has kept its promise. Nonetheless, the few dozen randomized controlled trials of CFS conducted over the past 20 years have taught an important lesson: symptoms of CFS fluctuate over time, are subject to substantial placebo-response rates, and may remit spontaneously.¹⁵ Thus, careful and objective study is the only vehicle for acquiring with clarity and some certainty the answers that CFS patients deserve.

It is in this context that the randomized placebo-controlled trial of galantamine hydrobromide for CFS reported by Blacker et al¹⁶ in this issue of JAMA should be understood. On its face, the study appears to be another in a virtually unbroken series of failed drug trials for CFS. Yet, by many criteria, the study is a resounding success. It pursued encouraging pilot data with a cholinesterase inhibitor approved for the management of Alzheimer disease and its plausible underlying hypothesis that defects in cholinergic pathways could also underlie some CFS symptoms.¹⁷ The present data further clarify, at least by exclusion, the pathogenesis of CFS.

Importantly, this study involved investigators in 37 centers from 5 nations to undertake the largest trial ever of CFS treatment. The researchers used well-standardized measures of fatigue, quality of life, sleep, and depression and were committed to achieve a clinically meaningful primary study end point. The fear in conducting complex studies like this one is that any difference between study groups related to some of the many secondary end points would lead to speculation that a treatment had in fact been effective but the investigators gambled on the wrong primary outcome measure. Fortunately for the science, but not for patients, the results were unequivocal in that galantamine was well tolerated but yielded no meaningful benefits to any subset of patients. Yet the study reaffirmed the importance and feasibility of studying CFS rigorously, even if it remains a poorly understood and controversial illness.