Editorial
Pharmacotherapy of Chronic Fatigue Syndrome
Another Gallant Attempt

JAMA. 2004;292:1234-1235.

Stephen E. Straus, MD

AUTHOR INFORMATION:
Corresponding Author: Stephen E. Straus, MD, National Center for
Complementary and Alternative Medicine, National Institutes of Health, 31
Center Dr, Bldg 31, Room 2B11, Bethesda, MD 20892 (strauss@mail.nih.gov).


Editorials represent the opinions of the authors and THE JOURNAL and not
those of the American Medical Association.

National Center for Complementary and Alternative
Medicine, National Institutes of Health, Bethesda, Md.


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 al, 16 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.


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