The Use Of Uricosuric Agents in Fibromyalgia
Information For Physicians
by R. Paul St. Amand, MD
is a supplement to our paper for patients with fibromyalgia describing
the disease and our method of treatment. The following is a more technical
paper intended for medical personnel. It includes a theory that might
explain the chemistry of the disease and our therapeutic results. A knowledge
of the entity is presumed.
In Fibromyalgia, malfunction of affected
tissues determines the presenting, chief complaint. Possibilities include
a preponderance of musculoskeletal symptoms; "brain" symptoms
(fatigue, irritability, depression, apathy, nervousness, difficulty with
memory and concentration) or the irritable bowel syndrome (gas, bloating,
cramps, constipation alternating with diarrhea). Initial symptoms of widely
separated cycles are often forgotten by patients who present later in
their illness. We do not find tender "points" but distinct,
swollen lesions in varied distributions. Involved areas are sites of total
or partial tendinous, ligamentous, fascial and muscular swellings or contractions.
We "map" palpable lesions on a preprinted body caricature that
shows the induration, size, shape and location of each (Figure
1). There are usually many more than the accepted "11 out of
18." Lesions may not correspond to sites of patient complaints, but
are objectively felt and recorded for future comparison. These steadily
"working" structures augmented by involvement of multiple organs,
readily induce pain and fatigue.
The symptoms and maps of patients with "chronic
fatigue syndrome," identify them as fibromyalgics. They are most
aware of fatigue and cognitive difficulties, because their pain thresholds
are higher than other fibromyalgia patients. We have not seen the myofascial
pain syndrome or systemic candidiasis as separate entities. Therefore,
we treat patients with these different diagnoses in the same manner.
History of uricosuric use and our current guaifenesin treatment:
Over 36 years ago we found uricosuric medications
helped patients with the ill-defined, multifaceted illness that later
became known as "fibromyalgia." Two gout medications, probenecid
and sulfinpyrazone proved effective. Because we had no other treatment,
these were godsends. We tailored the dosage, raising it progressively
until cyclic reversal of the illness began. In less responsive individuals
titration took considerable time. Some patients were allergic to sulfonamides
(probenecid) and suffered hyperacidity with sulfinpyrazone (Anturane TM).
We had no alternate treatment.
A few years ago we realized the expectorant,
guaifenesin, is weakly uricosuric.[1, p 463] It is not sufficiently potent
to treat gout but has proven invaluable in our hands for fibromyalgia.
Analysis of 264 consecutive patients showed beginning lesion reversal
at varying dosages: 300 mg. bid was sufficient for 20 percent of patients;
at 600 mg. bid, another 50 percent were improving; and at 1800 mg. per
day, another 20 percent showed reduction of palpable lesions. Thus, 90
percent of our patients were shown to have attained a sufficient dosage
at 1800 mg a day or less. Obviously, 10 percent required 2400 mg or more.
Guaifenesin is distinctly more effective than our previous medications
and has no listed side effects. Only rarely has a patient had slight nausea,
hyperacidity or rash. Guaifenesin must be dispensed without other ingredients
that do cause complaints. There is no patent on guaifenesin, and it is
inexpensive. Though serum serotonin levels of patients on guaifenesin
have not been investigated, guaifenesin increases the metabolite of serotonin,
5HIAA (5-hydroxyindoleacetic acid) in urine.
Treatment reproduces symptoms, often markedly,
which signals the onset of disease reversal. This is a crucial time for
patients who can require much encouragement during initial, intense cycling.
We encourage them to record periods of intensification or improvement.
Remapping on subsequent visits reveals at a glance areas of partial or
total clearing to confirm adequacy of dosage. Newly involved areas reverse
sooner than older ones. Regression with guaifenesin occurs at a rate of
about one year for every two months of treatment. The lowest dosage patients
(300 mg. bid) show their responsiveness by greatly accelerating this process.
Improvement is sustained initially for only a few hours, later for days
and eventually, for weeks. Duration of the illness and responsiveness
to medication determine recovery time.
Hypothesis and mechanisms:
We believe fibromyalgia is inherited.
Usually there is a family history of similar symptoms or of osteoarthritis
that also "maps" with the same muscular, tendinous and ligamentous
lesions as in fibromyalgia. It is tempting to conclude from our spectrum
of patients (age at onset ranges from 4 to 74) that fibromyalgia today
is the prelude to osteoarthritis tomorrow. The age spread at onset suggests
multiple gene involvement. The 4:1 ratio of affected women to men dictates
that at least one of these should lie on the X chromosome. Symptoms are
noticeable in adolescence or earlier if both parents are afflicted. a
history of "growing pains" is common. We have treated five 4-year-old
girls. One of these complained of pains at age 2. She frequently awakened
at night and required hot baths and massage.
We feel that fibromyalgia is a retention
disease like most cases of gout but with more varied tissue dispersion.
Though patients respond to uricosuric agents, urates are not involved.
The ubiquitous symptoms and number of organs and systems affected point
to a metabolic misadventure induced by the accumulation of an anion different
from urates. This putative ion wreaks havoc throughout many systems and
yet evokes no inflammatory response. It is obviously perceived as a normal
For several reasons we suspect a partial
role for inorganic phosphate (Pi). This is supported by some observations.
Patients note cyclic chipping or peeling fingernails (calcium phosphate).
Dental calculus (calcium phosphate) often breaks off, and sometimes no
longer forms, during treatment. Calcium added to meals allows lower dosages
of medication, probably because calcium binds to phosphate as calcium
phosphate and increases fecal elimination. Examination of 24-hour urine
samples of patients who had begun guaifenesin show large increases in
the excretion of phosphate and, in lesser amounts, calcium and oxalate.
Though other anions might be involved, the preceding suggest a primary
defect in phosphate (and possibly pyrophosphate) metabolism. If so, the
following formula would account for depressed mitochondrial ATP generation:
Delta G =
ATP (Delta G = energy change)
ADP + Pi (Pi = inorganic phosphate)
Bengtsson and Hendriksson biopsied fibromyalgic,
trapezial lesions and reported roughly a 20-percent decrease in ATP despite
specimen dilution with normal tissue.  They also noted a similar decrease
in phosphocreatine, the high energy reservoir. No such changes were present
in unaffected muscle. A decrease in red blood cell ATP has also been documented.
An energy deficit in affected cells would explain the entire syndrome:
all symptoms and the multiple chemical abnormalities of fibromyalgia.
Of ingested phosphate, 80 percent to 90
percent is absorbed. We depend on proximal renal tubular function for
coordinating the retention or excretion of phosphate according to need.
We postulate an enzyme, receptor or pump defect that leads to systemic
accumulation. Phosphates readily enter cells and maintain equilibrium
with phosphates already in the outer mitochondrial chamber. Excess H+
(phosphoric acid in equilibrium with phosphate) in this organelle would
seriously blunt the ion's egress from the matrix to the outer chamber.
Electron generation and transport for ATP formation depend on reversal
of H+ direction back to the matrix. Even a minor inborn error anywhere
in the chemiosmotic sequence including ATP synthase would increase susceptibility
to blockade. The most plausible theory of fibromyalgia is that of defective
ATP generation from a fully operation citric acid (Krebs') cycle that
produces heat instead of energy.
Others have proposed the name "energy
deprivation syndrome" rather than "fibromyalgia," which
connotes only pain in muscles and fibers. Such a change in terminology
would more accurately describe the metabolic error resulting in symptoms
and findings of this illness. Some findings, such as decreased growth
hormone, IGF-I, serotonin, free ionic Ca2+, free urinary cortisol, certain
amino acids; increased serum prolactin, substance P, and angiotensin converting
enzyme, make it obvious that this is a widespread, fundamental disease.
Other highly phosphorylated systems (ITP3, GTP3, etc.) would share in
this dynamic, shifting chemistry that fails to provide energy for needs
in an every-changing neurohormonal milieu. The cycling fibromyalgic at
times almost meets full energy demands; on occasion barely, or not at
all. Moments of adequate energy availability permit some bursts of effort,
but expenditures from activating any system readily deplete the marginal
energy bank. Thus, an accident, emotional stress, infection, or surgery
may initiate the first attack of fibromyalgia. It is difficult to postulate
a more basic cause of the disease.
Whatever anion is involved, its entry into
any cell requires cation buffering. Sodium would allow water retention
that occurs during attacks. Only free cytosolic Ca2+ can sustain the palpable,
muscular contractions. ATP-controlled pumps are responsible for returning
calcium to the endoplasmic reticulum to clear the sarcoplasm and permit
relaxation. As in muscle, the ion must be cleared from the cytosol to
allow cessation of activities peculiar to any cell. Failure forces an
attempt to continue reactions that lead to eventual cellular "fatigue"
and malfunction. Even small, localized calcium sparks from the endoplasmic
reticulum can trigger equally-selective cellular activities. Small, site-specific
ATP action exists to control or modify the effects of these bursts. Muscular
contractions of rigor mortis are an extreme example of this process as
ATP formation ceases and calcium accumulates freely in the sarcoplasm
of the dying structure.
"Amorphous crystals" seen on urinalysis
may be the concentrated precipitates of our putative abnormality. In concentration,
these can abrade the distal bladder and urethra, causing denuded surfaces
and dysuria. Vaginal and vulval involvement leads to dyspareunia and further
trauma during intercourse in many patients. Frequent bouts of cystitis
(superficial or interstitial), vaginitis, urethritis, and often, candidiasis,
are the sequelae. These occurrences and the frequent symptoms of eye irritation,
scalded or metallic oral sensations, pruritus, various rashes, faulty
hair texture and growth, fingernail defects, all strengthen our belief
in a generalized abnormality affecting not only the brain, musculoskeletal
and intestinal systems, but also the body fluids and the integument.
The multiple, overstimulated areas of fibromyalgia
burn fuel steadily. This results in sugar-craving in a futile attempt
to create energy. Increasing carbohydrate intake yields little, due to
the impediment to ATP formation. Sugars and starches induce repetitive
insulin surges that, in susceptible individuals, initiate the "hypoglycemia"
syndrome. Some 40 percent of fibromyalgic females and 20 percent of males
suffer from this as manifested by frontal headaches, tremulousness, sweats,
heart palpitations or pounding, often with tachycardia and the sudden
feeling of anxiety. Symptoms occur a few hours postprandially and often
nocturnally. Episodes last approximately 20 to 30 minutes. Genter and
Ipp reported the release of counter-regulatory hormones during glucose
tolerance tests on normal individuals.  Blood samples taken every few
minutes showed an epinephrine rise fully 10 minutes before the nadir of
the blood sugar. One-half of these young, healthy subjects became maximally
symptomatic as epinephrine neared its peak, some at perfectly normal glucose
levels. Obviously, each of us has an individual brain set point for glucose.
Below this threshold, glucopenia is signaled; and well-defined, corrective
measures are induced. Epinephrine is the trigger for the preceding symptoms,
which when most intense, are labeled "panic attacks.
We no longer perform glucose tolerance tests
since symptoms suffice for diagnosis. It must be noted, however, that
the central nervous system becomes inured to repetitive hypoglycemic attacks,
and as a result, mounts no neurohormonal, counter-regulatory response.
Epinephrine symptoms cease, "panic attacks" end, but cognitive
disorders continue. This situation can only be surmised by the past
history. Within two weeks of proper carbohydrate restriction, epinephrine
signaling of dietary indiscretion is restored.
The term "hypoglycemia" is too
often inappropriate. It would be better named "carbohydrate intolerance
syndrome" and treated accordingly. This syndrome overlaps strikingly
with fibromyalgia but is distinguishable mainly by the epinephrine symptoms.
Patients with the dual afflictions do not feel better without dietary
control, although examination reveals the anticipated, cyclic resolution
of guaifenesin-treated fibromyalgia. Therefore, despite improved physical
findings documented on mapping, there would be no change in the standard,
patient wellness questionnaire.
Many fibromyalgics gain considerable weight.
Arguably, this is due to diminished activity imposed by the disease. Those
with carbohydrate craving, whether or not fully intolerant, suggest an
added factor. One paper has shown an increase in serum pyruvate, but normal
or low serum lactate in some fibromyalgics. The absence of lactate
accumulation points to intact aerobic metabolism. There is ample pyruvate
for acetyl CoA formation within the mitochondrial matrix. One would expect
normal citrate formation and the full, sequential chemistry of the Krebs'
cycle to continue. When this chemical cascade does not form ATP normally,
energy is dissipated as heat. Increased citrate, a powerful signal of
energy abundance, would strongly stimulate acetyl CoA carboxylase and
therefore malonyl CoA and fatty acid formation. This could be the mechanism
for the hot flushes, sweats and weight gain. Insulin causes increased
reabsorption of phosphates and sodium in the proximal renal tubules --
a known effect of that hormone. Insulin also drives tryptophan into cells,
as it does other amino acids, where they are metabolized. The lowered
serum levels of L-tryptophan diminishes availability for brain uptake
and formation of serotonin. These higher insulin surges probably account
for lowered serum levels of several amino acids as well as serotonin.
Thus, the more patients yield to sugar-craving, the more confusing and
intense is the interplay of hypoglycemia and fibromyalgia.
Though highly theoretical, there are facts
in this paper. Guaifenesin has proven our most effective medication to
date. Any source of salicylate will block guaifenesin's benefit at a renal,
tubular level as it does in gout. All plants make varying amounts of salicylate.
Salicylates are readily absorbed through skin.  Even small
amounts in cosmetics and other topicals will negate or slow the effects
of all agents we have used. We have many maps made during treatment that
illustrate lesions becoming static or worsening in previously improving
patients who, unwittingly, began using such preparations. Once warned,
some patients find that over one-half of their usual skin preparations
could have been deleterious. Susceptibility to blockade seems genetically
determined and highly variable. Some patients are blocked by tiny amounts
of offending agents, yet others improve despite moderate usage. Many patients
are carbohydrate intolerant and must also be treated dietarily. These
statements are factual and must be respected or there will be no improvement.
1. Physicians' Desk Reference, Medical Economics Co., Inc., Montvale,
2. Bengtsson, A. and Henriksson, K. G.: The Muscle in Fibromyalgia: A
Review of Swedish Studies. J. Rheumatol., 16(Suppl. 19): 144-149, 1989.
3. Genter, P. and Ipp, E.: Plasma Glucose Thresholds for Counter regulation
After an Oral Glucose Load. Metabolism, 43(1): 98-103, 1994.
4. Hvidberg, A., Fanelli, C.G., Hershey, T., et al.: Impact of recent
antecedent hypoglycemia on hypoglycemic cognitive dysfunction in nondiabetic
humans. 45(1):1030-1036, 1996.
5. Eisinger, J.; Plantamura, A.; and Ayavou, T.: Glycolysis abnormalities
in fibromyalgia. J.Am. Coll. of Nutri., 13(2)144-148,1994.
6. Delaney, T.P. Uknes, S., Vernooij, B., et al.: A central role of salicylic
acid in plant disease resistance. Science, 266: 1247-1249, 1994.
7. Winter, R.: A Consumer's Dictionary of Cosmetic Ingredients. New York,
Crown Trade Paperbacks, 1994.
8. Taylor J.R., Halprin K.M.: Percutaneous absorption of salicylic acid.
Arch. Dermatol. 111(6):740-743, 1975.
9. Brubacher J.R., Hoffman R.S.: Salicylism from topical salicylates:
review of the literature. J.Toxicol. 34 (4) : 431-436, 1996.
10. Yip A.S., Chow W.H., Tai Y.T., Cheung K.L.: Adverse effect of topical
methylsalicylate ointment on warfarin anticoagulation: an unrecognized
potential hazard. Postgrad Med J. 66 (775): 367-369, 1990.
11. Bennett, R.: Poster presentation of the Oregon guaifenesin study,
Academy of Rheumatology meeting, Orlando, FL, 1996.