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In the early 1990s, I belonged to the first
fibromyalgia discussion group on the internet, the FIBROM-L mailing list.
We were probably the first people on the internet to hear about the guaifenesin
treatment. Dr. St. Amand claimed that the drug guaifenesin could treat
fibromyalgia symptoms by removing excess phosphate from the body, which he
believes to be the cause of fibromyalgia. The removal of the phosphate would
supposedly lead to a reversal of all fibromyalgia symptoms, which would
essentially be as close to a cure as possible. Dr. St. Amand claims that
he has successfully reversed all fibromyalgia symptoms in 90% of his
patients. Additionally, Dr. St. Amand himself claims to have had
fibromyalgia, but that he has been pain free for decades. Given these
claims, many people on the mailing list decided to try it. While some
people experienced positive effects from it, others, including myself, experienced
no effects from it, no matter how carefully the treatment plan was followed,
which involves taking guaifenesin, and also avoiding products that contain
salicylates. In order to try and understand why some people find benefit
from the treatment, and not for others, I decided to research guaifenesin,
salicylates, and related topics. The following web page documents what I
have found so far, and hopefully will be of some help to anyone who has an in
interest in the treatment.
During the 1990s, Dr. Robert Bennett, a
recognized expert in the fibromyalgia field, decided to do a study on
guaifenesin, and Dr. St. Amand was the technical advisor to the study.
The results of this long term study showed that guaifenesin had no effect on fibromyalgia.
However, the debate did not end. Dr. St. Amand claimed that the patients
in the study must have unknowingly been exposed to products that contained
salicylates, which he believes can block the effects of guaifenesin. Dr.
Robert Bennett countered, saying that if there were sufficient quantities of
low levels of salicylates to block guaifenesin, then this should have caused a
decrease in urinary uric acid. Low levels of
salicylates are known to have this effect. But the lab tests from the study
did not show that this occurred. Thus, Dr. Bennett concluded that there
was no such exposure to salicylates.
Dr. Bennett went on to say that much of Dr.
St. Amand's success with guaifenesin, could be
attributed to the placebo effect. The placebo effect
could be very strong in relation to guaifenesin, since guaifenesin has
been advertised as being able to treat the source cause of fibromyalgia, and
that it can reverse all the symptoms. This would make people especially
hopeful that the treatment would work. Any beneficial effect that one
might see from guaifenesin, would create a high amount of optimism, since it
would mean the drug is working, and that you are on your way to a
recovery. Additionally, any worsening of fibromyalgia symptoms during the
treatment, is also a good sign, since these symptoms
are attributed to guaifenesin's reversal process, that rids the body of
"metabolic debris". Thus, even feeling worse, could make a
person feel more optimistic. Plus, many patients
are "mapped", i.e. their bodies are examined for lumps, and if the
lumps decrease in size, this is also supposedly a sign that the guaifenesin is
working by removing the phosphate deposits from the body. Not to mention,
that guaifenesin often causes a change of smell or color in the urine.
Many people attribute these changes to toxins being released from the body,
when in all likelihood, this is simply due to the fact
that the guaifenesin is metabolized by the liver, resulting in a form of lactic
acid, that is then excreted in the urine. Thus, there are many possibly
ways for a patient to get feedback, that would make them believe that the
treatment is working, which would thus strengthen any placebo effect. So
it's understandable why some doctors attribute guaifenesin's benefits to the
placebo effect.
However, in my own opinion, it's unlikely
that the placebo effect could explain all of the people who have stated that
they have benefited from guaifenesin. And if anyone had bothered to do a
simple search of guaifenesin in the medical literature, they would have found
reasons why guaifenesin can have beneficial effects.
In 1996, before the study was published, I
went to a library, and quickly discovered that guaifenesin has a skeletal
muscle relaxant property, a fact that people in the fibromyalgia community were
not aware of. Surprisingly, anyone could have easily discovered this fact
if they looked up guaifenesin in the Merck Index, a drug handbook, which lists
guaifenesin as having this effect. Guaifenesin has known neurological
effects, but most doctors are unaware of this, because it is no longer used in
humans for this effect. However, it is used for this effect in veterinary
medicine. And a slightly different form of guaifenesin, guaifenesin
carbamate, is used in humans as a muscle relaxant, and is sold under the name
Robaxin.
At the time that I discovered this
information, I believed that this was the reason why it helped some people, so
I lost interest in researching it any further. However, in the summer of
2000, I became reinvolved in discussing fibromyalgia via the internet, and
found that people were still discussing guaifenesin. Not only that, but
many web pages that were devoted to guaifenesin, contained false or unproven
medical statements, that were being presented as fact. This prompted me
to do a more thorough investigation of guaifenesin and related substances in
the medical literature, and I found evidence that it's
neurological effect is much more complicated than a simple muscle relaxant
effect. It likely also has an analgesic, or pain relieving
capability. Additionally, guaifenesin may also have the ability to
inhibit platelet aggregation, and therefore act as an anticoagulant. This
may also be significant, as all of the uricosuric drugs that Dr. St. Amand has
used for fibromyalgia, also have this ability.
However, Dr. St. Amand has never considered
any other reason for the effects he has seen from guaifenesin. He
believes that the effect of guaifenesin on fibromyalgia, is related to it's uricosuric ability.
Guaifenesin was selected for treating fibromyalgia by Dr. St. Amand
because it has a uricosuric effect. Uricosuric means that the drug has
the ability to increase uric acid excretion in urine. He had previously
believed that other uricosuric drugs, such as probenecid, had helped
fibromyalgia. But these other drugs often required high doses to be
useful, often leading to side effects. So he experimented with
guaifenesin, and found it to work better than the previous drugs. Dr. St.
Amand believes that it not the excretion of uric acid that helps fibromyalgia,
but that it's due to the excretion of another substance. He hypothesizes
it to be phosphate.
But no medical evidence has been presented
by anyone, that shows that excess phosphate is the
cause of fibromyalgia. Additionally, uricosuric drugs are not known to
increase phosphate excretion, except in very rare circumstances. If Dr.
St. Amand truly believes that phosphate excretion occurs, why has he not
presented evidence of this, not just to the fibromyalgia community, but to the
rest of the medical community also? Very
few drugs are available that mainly increase phosphate excretion, without
causing many side effects. The medical community would welcome a new
option, so why has this never been done? And if he has done this, why has
it been ignored? And why has he never properly researched the effects of
guaifenesin? For example, he makes mention of the fact that guaifenesin
increases urinary excretion of 5HIAA, a serotonin metabolite. While
indeed guaifenesin does affect 5HIAA urine tests, it doesn't really increase
5HIAA. Instead, one of guaifenesin's own metabolites interferes with the
test, creating a false positive. A more precise lab test, which is not usually done, is able to
distinguish between the two different metabolites.
Dr. St. Amand also appears to downplay any
possible side effects from guaifenesin. From his web page, he says
"Guaifenesin is distinctly more effective than our previous medications
and has no listed side effects." Unfortunately, this is not true
either, as many web pages list side effects, including headaches
and dizziness. Coincidentally, headaches and dizziness are symptoms
that some people on guaifenesin initially do experience, yet such symptoms are
often ascribed to the cycling process of reversing fibromyalgia. That is
to say, that Dr. St. Amand believes that guaifenesin is reversing fibromyalgia
by removing phosphate deposits, and this causes cycles in which fibromyalgia
symptoms intensify. However, these symptoms could simply be side effects
from guaifenesin. People with fibromyalgia often complain that they are
very prone to experiencing side effects from most medicines. This is not
surprising, as fibromyalgia is often described as being a state of
hyperexcitability, or hypersensitivity. Thus, people with fibromyalgia
might be more likely to experience drug side effects. Some of the people who try guaifenesin, do so because of their inability
to tolerate the side effects of other drugs. And, as will be shown later,
guaifenesin is a drug that has many possible properties. So one could
easily postulate that people with fibromyalgia, would feel side effects from
guaifenesin, that the average person would either not notice, or would
attribute to the condition for which they were taking guaifenesin (i.e. a
cold).
And, of course, these cycling symptoms could
simply be due to fibromyalgia symptoms that would have occurred anyway,
regardless of taking guaifenesin, People with fibromyalgia often have
flare ups of their symptoms, sometimes due to extraneous factors, but other
times seemingly out of nowhere. Interestingly, people with fibromyalgia who have higher pain
levels, were shown to have less frequent flares than those with lower pain
levels.
Thus, if guaifenesin does have a pain relieving capability, as I
theorize, then the lowering of pain levels may indeed be the cause of why
people on guaifenesin might see more “cycling” or flares. “Cycling” on the guaifenesin
protocol, may simply be due to a lowering of pain levels, and not due to a theoretical
reversal process. And if instead they don’t get any better at all,
but actually get worse, they may avoid seeking out other treatments, and suffer
needlessly, due to the belief that these symptoms represent a good thing.
Not to mention the fact that any phosphate deposits would simply contain
phosphorus and calcium, two of the most abundant and necessary minerals in the
body. So one might wonder why the release of these minerals would cause
any negative symptoms anyway.
Also in doubt, is Dr. St. Amand's claim that
hidden salicylates caused the study on guaifenesin to be flawed.
His claim is based on the belief that salicylates are present in significant
amounts in certain products, especially herbal ones. To quote Dr. St. Amand's web page: "Natural salicylates
are present in barks, but barks also contain glycosides which are converted by
the liver and intestinal tract to other more potent and long-lasting salicylates."
This statement implies that salicylates abound in all trees, but that's not
true. The only glycoside that converts to salicylic acid is
salicin. And the only trees that contain salicin are willows and
poplars. And even then, there are some willow species that contain very
little salicin. Besides these trees, there are only a few other very
specific herbs that contain significant amount of salicylates. So herbs
are unlikely to be a major source of hidden salicyates.
The other supposed major source of salicylates, is from topically applied
products, which Dr. St. Amand believes is more potent than those ingested,
because they "deliver salicylates directly into the blood
stream." However, there is no proof that salicylates can penetrate
through the skin, into the bloodstream, any more efficiently than if the
salicylates were ingested. In fact, as I will reference later, studies
have shown very poor absorption of salicylates from topical products, even
analgesic topicals that contain salicylates specifically to be absorbed to
relieve pain. This makes sense, considering that the skin is meant to
protect the body, while the intestines are meant to absorb substances.
I will attempt to show, based on all
available studies on guaifenesin, that it has several known effects which may
be responsible for claims that it benefits people with fibromyalgia. I
will also attempt to show that there is no proof that either phosphate
retention could be the cause of fibromyalgia, or that uricosuric drugs can directly
cause phosphate excretion.
Guaifenesin has a property
which is not well known by many people (including doctors), but is well
documented in the medical literature. It is capable of acting as a
skeletal muscle relaxant. It does this by depressing transmission of
nerve impulses in the central nervous system. The reason that this
information is not well known, is because guaifenesin
was a grandfathered drug, so it was never subjected to thorough testing, as
later drugs had to be. And it is not used for this property, by
traditional doctors, because other drugs with similar properties,
were found to be more effective.
Guaifenesin's neurological properties first
became known in the late 1940s. During that period, researchers studied
the effects of mephenesin, a drug which is a very close chemical relative of
guaifenesin. Given intravenously to animals, mephenesin was found to have
a ability to induce skeletal muscle paralysis.
Researchers continued to study mephenesin, but they also created and tested
other chemically related compounds, and discovered that mephenesin belongs to a
class of chemicals known as propanediol derivatives, all of which exhibited the
same muscle relaxant effect, to one degree or another. Mephenesin is 1,2-Propanediol, 3-(2-methylphenoxy)-. One of other
compounds created was 1,2-Propanediol,
3-(2-methoxyphenoxy)-, which is commonly known today as guaifenesin. At
the time, it was known as guaiacol glyceryl ether. Unfortunately, the muscle
relaxant effect of propanediols only lasts a short time, due to the drugs being
rapidly metabolized. That is to say, they are converted into other
chemicals, and then these resulting "metabolites" are excreted in the
urine. Thus, because of their short effective duration, the first
propanediol drugs that were created had limited use for humans (the timed
release version of guaifenesin was not created until decades later).
However, they could be used in veterinary medicine, in intravenous anesthetic
preparations for surgery. But another problem was that all of these drugs
have a also hemolytic side effect, i.e. causing
cellular destruction of red blood cells. Guaifenesin, however, has less
hemolytic activity, and it also has greater water solubility, so it became the
preferred drug to use.
Researchers continued to study these drugs
to find a longer lasting form. In the 1950s, such a form was created,
known as a carbamate. The following paper documents a study comparing the
effects of mephenesin, guaifenesin, mephenesin carbamate, and guaifenesin
carbamate:
Journal of Pharm. Expt.
Ther. 1958, 122;239
(Truitt and Little)
This study shows that all these drugs
exhibit a comparable muscle relaxant activity at similar doses. However,
guaifenesin carbamate was effective over a much longer time, so it could be used effectively in humans as a muscle
relaxant. It is now known as methocarbamol or Robaxin, the latter being the
brand name. For the National Library of Medicine entries on these drugs,
see:
http://www.nlm.nih.gov/cgi/mesh/2K/MB_cgi?term=Guaiacol+glyceryl+ether
It has been found that all of these propanediol
derivatives act as central-acting skeletal muscle relaxants by selectively
depressing transmission of nerve impulses at the internuncial neurons of the
spinal cord, brainstem, and subcortical regions of the brain. At low
doses they act to relax hypertonic muscles and to lower response to sensory
stimuli, i.e. pain. Thus, they might be very useful for people with
fibromyalgia. At high enough of a dose, they can cause temporary muscle
paralysis. This is all explained on the following web page:
http://www.vedco.com/products/productpages/FMPro_229.htm
To achieve muscle paralysis, the recommended
dose for large animals is 50mg per pound. Assuming a similar dose rate
for humans, for a person weighing 100 pounds, the recommended dose would be
5000mg. Of course, this amount is meant for extreme relaxation to allow
for surgery. A muscle relaxant effect would still be seen at much lower
doses. Patients on guaifenesin for fibromyalgia take
anywhere from 600 to 3600mg per day. Dr. St. Amand's own wife
takes as much as 4800mg per day. So this effect would likely be
significant in these people.
Additionally, in the previously mentioned
study that compared Robaxin and guaifenesin, it was found that the two drugs
had comparable muscle relaxant effects at similar dose levels. Since the
maintenance dose for Robaxin is 1500mg, we can infer that the same level dose
of guaifenesin would also have significant relaxant effects. And in fact,
many people with who take guaifenesin, take a dose
that is close to that amount.
However, while these drugs were mainly used
as muscle relaxants, they were soon discovered to have more effects than
that. Studies on mephenesin showed that
it could reduce anxiety as well. In one
such study, mephenesin
was found to produce “a relaxation of tense muscles, leading to a feeling
of reduced muscle and psychic tension, often with a sense of well-being.” However, mephenesin required many doses
during the day to achieve these effects, because of it’s
quick metabolization. Thus, other
propanediol derivate drugs were created, in order to find a longer lasting one,
with greater anti-anxiety effects. This
led to the creation of the first “tranquilizer”, Meprobamate,
2-Methyl-2-propyl-1,3-propanediol dicarbamate,
commonly known as Equanil or Miltown. It is no longer used, because the
nervous system effect was not specific to anxiety, plus it was also very
addictive. However, several other propanediols are still in use.
Carisoprodol, or soma, is N-isopropyl-2-methyl-3-propyl-1,3-propanediol
dicarbamate. It is a commonly prescribed muscle relaxant, and is
sometimes prescribed for fibromyalgia. Another propanediol is Felbatol
(felbamate), 2-phenyl-1,3-propanediol dicarbamate, an
anticonvulsant. It should also be noted that some people have been found
to experience allergic symptoms from propanediols, and the medical literature warns
people not to use any propanediol drug if they have experienced side effects
from any one of them. This might explain why some people experience
immediate side effects from using guaifenesin.
It is worth noting that guaifenesin's
relaxant effect on the nervous system might be the reason for its expectorant
property. Guaifenesin was being used as an expectorant,
well before propanediols were discovered, as it can be derived from the bark of
the guaiac tree. However, as shall be shown later, guaifenesin doesn't
appear to have a direct effect on mucus. Instead, it's possible that its
expectorant ability is actually due to its muscle relaxant effect. Some
types of expectorants are known to act via a relaxant effect, as the effect
helps to soothe spasms and allow mucus to flow easier. Two common herbal
remedies that are known to act both as relaxants and expectorants are kava kava
and peppermint oil. Some relaxants, like pepperment oil, are also useful
for digestion problems such as Irritable Bowel Syndrome, so it's not surprising
that some people have reported guaifenesin to be useful for IBS (although IBS
is a multifaceted problem, so relaxants don't work for everyone.) In any
event, this shows how a single property can have widespread and diverse effects
on the body.
But guaifenesin's effect on
the nervous system is not simply limited to acting as a muscle relaxant.
In the 1970s, mephenesin was found to increase levels of the amino acid
glycine. A later study in the 1992, showed evidence that mephenesin
may be an antagonist of excitatory amino acids. This could be
releavant to fibromyalgia, since studies have shown that levels of excitatory amino acids are raised in fibromyalgia,
and may be involved in the pain process of fibromyalgia. And it's also
been found that some people with fibromyalgia find relief of symptoms by avoiding dietary excitotoxins such as MSG and aspartame,
both of which contain excitatory amino acids. Another study in 1994 on mephenesin went on to hypothesize that
this effect on amino acids may be the reason for mepehensin's ability to act as
a muscle relaxant: "Mephenesin acts mainly by inhibitting the polysynaptic
reflexes in the spinal cord, and these reflexes are
mediated by the intersegmental network using EAAs as
neurotransmitters." And a study on other EAA antagnoists have shown them to
have muscle relaxant effects. Interestingly, felbamate, another drug in
the propanediol family, has also been found to a be a broad spectrum antagonist of excitatory amino acids.
Both studies on mephenesin and felbamate indicate that they inhibit NMDA neuron
receptor activity. In fact, it appears that many propanediol drugs, or for that matter most -diol
chemicals, inhibit NMDA receptors. This is important, because drugs that act as NMDA inhibitors may be helping in treating
fibromyalgia pain.
Thus, mephenesin, and therefore guaifenesin,
may indeed have the ability to lower fibromyalgia pain levels. While
there are few studies regarding this effect, one study has shown that mephenesin does have an analgesic
effect. Another study on guaifenesin also shows that it has an analgesic effect.
The related drug carisoprodol (soma) also
appears to have an analgesic effect which is separate from its muscle
relaxant effect: “Pain was induced by a high-frequency electronic
stimulator applied to normal intact teeth. By this method carisoprodol taken
orally was about 5 times as potent as acetylsalicylic acid in raising tooth
pain threshold. Since the pain threshold endpoint did not require activation of
skeletal muscle, carisoprodol must have induced analgesia independently of its
known muscle relaxant action.”
However, even at low doses, at which
guaifenesin doesn't exhibit any of its own analgesic or muscle relaxing effect, it still may have neurological properties that could
be useful for fibromyalgia. One study has shown that guaifenesin at such subeffective doses, is able to increase the
analgesic effect of paracetamol (Tylenol). This might explain why
some people immediately see effects from even the lowest dose of guaifenesin,
as it might be increasing the effectiveness of analgesic medicine that patients
are already taking. And this effect appears not to be specific to any
single analgesic. Veterinary web pages claim that guaifenesin potentiates
the effect of other anesthesia medicines. Plus, guaifenesin is believed to have an additive effect on narcotics.
And finally, guaifenesin is being used transdermally, in combination with
other pain killers, to relieve localized pain: "Guaifenesin
appears to provide benefit as an adjunctive treatment, of painful spasticity.
For the patient population described herein, amitriptyline appeared to offer
limited pain relief when administered transdermally. It appears that combining
gabapentin with doxepin may offer some additional benefit. The addition of
guaifenesin to doxepin may be of particular value when painful spasticity is
present." Doxepin is a tricyclic antidepressant.
As an aside, neurontin at low doses is able to potentiate the anaglesic
property of opioids such as morphine. This potentiating property is
likely due to an antagonistic effect on excitatory amino acids. Increased
levels of EAAs are known to cause tolerance and the loss of antinociceptive response to morphine, and
neurontin has been shown to reduce morphine tolerance. While guaifenesin has not
been tested for a potentiating effect on morphine, Robaxin (guaifenesin
carbamate (methocarbamabol) is known to potentiate morphine. Thus,
perhaps guaifenesin's ability to potentiate the effect of pain killers, is also
due to an EAA antagonistic effect
Given the possibly unique mode of action of
guaifenesin, i.e. an anti-excitatory amino acid effect, it might explain why
some people with fibromyalgia have noticed an effect from it, while others have
not. Many drugs used for fibromyalgia have varying success between
patients. For example, different people
respond to different pain killers, showing that not all people with
fibromyalgia are experiencing the same pain problems. Some people respond to morphine, while others
do not. Other studies have shown
neurochemical differences in the spinal fluid of fibromyalgia patients. Pain in people with primary fibromyalgia coorelates with different
excitatory amino acids, than those with secondary fibromyalgia.
The neurological effects of guaifenesin
might also explain why the original study on guaifenesin didn't show any
results. The patients in the study might have already been taking
analgesics at doses high enough that they wouldn't see any additional effect by
taking guaifenesin. Many people who take
guaifenesin, often do so because they either haven't found any meds that have
worked for them, or they can't tolerate the side effects from such
medicines. In other words, the guaifenesin study might have not
accurately reflected the population who have found the
most benefit from taking guaifenesin.
As an aside, probenecid, the drug previously
used by Dr. St. Amand, may also indirectly antagonize the effects of excitatory
amino acids. Probenecid is an "anion transport inhibitor",
meaning it can affect the transport of certain acids. Probenecid has been
studied with regard to kynurenic acid, a naturally occurring EAA
antagonist. In studies, it's been found that probenecid can affect kynurenic
acid, and in one study on rats, it was found to increase the level of kynurenic in the brain by
a factor of 2.5. And in other studies, kynurenic acid has been found to have analgesic effects.
Unfortunately, propanediol drugs often have
hemolytic side effects, which is why they are not being used to treat
pain. For example, the propanediol drug felbamate,
was definitely found to be able to reduce neuropathic pain.
But research on it was discontinued, when significant hemolytic side
effects were discovered. Guaifenesin has much lower hemolytic side
effects. However it is metabolized quickly from the body, so it was not
considered to be useful. However, most of the research on guaifenesin was
done well before a timed release version of guaifenesin was created, which
would significantly prolong the levels of guaifenesin in the body.
Additionally, the rate of metabolism of guaifenesin appears to have a wide
range of variance between people. A study in MEDLINE shows that the
half-life of guaifenesin in healthy subjects varied from 1.36 to 5.25
hours. This quoted maximum is much much higher than the average half-life
which is usually reported for guaifenesin in the literature. It could be
that some people have a slower metabolic rate, and that this could account for
why some people with fibromyalgia find it useful, while others do not, and why
the effective dose varies widely between people.
By the way, guaifenesin is a centuries old
remedy, as Dr. St. Amand himself notes. He points out that extracts of
the guaiac tree, have a long history of being used for rheumatism. I
assume that he mentions this, as a possible proof that it can treat
fibromyalgia. However the specific history, is
that in the 1500s, explorers to the new world of
As an aside, if one believes that
salicylates can block the effects of guaifenesin, one wonders how guaifenesin
was useful at all in the past as a herbal remedy. Because in those days,
extracts of the guaiac tree were created from the bark of the tree. And
the bark of the tree surely should contain salicylates, according to Dr. St.
Amand's theory that salicylates are abundant in trees and herbs. And even
if salicylates aren't present in the guaiac bark, then they very likely are
present in other herbal remedies, that patients in those days would have been
taking for their pain condition. Surely some of those impure herbal
remedies, would have also contained salicylates. In fact, herbal web
pages specifically mention that it's ok to combine guaiac extracts with other
herbs that contain salicylates:
http://www.nevdgp.org.au/info/ArthritisF/management/herbal.htm
http://www.holistic-online.com/Herbal-Med/_Herbs/h244.htm
Additionally, no herbal web page makes any
mention that guaiac extracts make a person feel worse before they get better.
Uricosuric Drugs and Phosphate Excretion
Dr. St. Amand believes that the increased
phosphate excretion is the reason for guaifenesin's benefit, and that by
reducing excess phosphate in the body one can totally reverse
fibromyalgia. While I believe guaifenesin to have some benefit, there is
no evidence that it can reverse fibromyalgia, nor is there any evidence that
phosphate is the cause of fibromyalgia. In addition, there is no evidence
that uricosuric drugs can increase urinary phosphate excretion.
Previous to using guaifenesin for
fibromyalgia, Dr. St. Amand used other uricosuric drugs, such as anturane
and probenecid. Both are used for gout, due to their ability to increase
urinary uric acid. However, neither is known to be able to enhance
phosphate excretion. The medical literature appears to have no references
to any studies which tests anturane for this ability. However, there are
several studies which have tested for this effect in probenecid.
Probenecid is believed to increase urinary
uric acid by reducing the amount that is reabsorbed via the kidneys back into
the serum. The section of the kidneys where this occurs is known as the
proximal tubule. Probenecid is secreted into the proximal tubule via a
process known as renal tubular secretion, which only occurs for certain weak
acids. One of those acids includes salicylates. Since this process
has a limited capacity, acids compete with each other for secretion. If
salicylate levels are too high, they block probenecid from being secreted.
Once in the proximal tubule fluid,
probenecid is believed to act as an anion transport inhibitor, which is to say
it prevents the kidneys from reabsorbing negatively charged substances,
including such acids as uric acid. The following study extensively tested
the effects of probenecid on urinary electrolytes, and did not find any
increased excretion of urinary phosphate.
Additionally, other studies have confirmed
that probenecid does not increase urinary phosphate excretion, such as the
following:
In that study, the action of probenecid was
monitored in connection with Didronel, a drug used for osteoporosis.
Didronel has a known side effect of increasing serum phosphate levels, an
effect which lasts from 2-4 weeks after discontinuing the drug. Probenecid was
tested to see if it would cause any increase in phosphate excretion, which it
did not. Interestingly, Dr. St. Amand actually recommends Didronel for
osteoporosis for his patients, and it does not appear to cause any worsening of
fibromyalgia symptoms, even in people who exhibit a rise in phosphate levels.
This casts doubt on the phosphate theory, since a rise in serum phosphate
levels should offset the effect of guaifenesin, but it does not.
It's not surprising that uricosuric agents
cannot affect phosphate excretion. The process in the proximal tubule of
the kidneys, where most of the phosphate reabsorption occurs, is highly
controlled and specific to phosphate. In that area of the kidneys, there
exist "type II sodium-phosphate cotransporters", which control
phosphate reabsorption, and they are very specific for phosphate. They
are controlled by several mediators of phosphate homeostasis (eg, parathyroid
hormone [PTH], dopamine, dietary phosphate). If a drug could simply
affect phosphate excretion, and not other minerals, then that would be of
remarkable help for many hyperphosphate disorders. Right now, the way to
treat such disorders, is via a low phosphate diet, combined with using phosphate
binders that block the absorption of dietary phosphate. In severe case,
diuretics are also used. However, these methods are not always very
successful, or can create side effects. A drug that could remove only
phosphate, without affecting other minerals, and without the need to change
one's diet, would be a great discovery.
As for Dr. St. Amand's urine tests on his
patients, which he claims show increased phosphate excretion, it should be
noted that many drugs initially cause side effects that gradually
disappear. Thus, long terminal studies are the only reliable tests.
This is especially true of phosphate excretion which is very much dependent on
hormonal levels. If a drug has the ability to disrupt mineral excretion,
it can take many days and sometimes weeks, before the body is able to
compensate for the disruption, and bring mineral excretion back to
normal. For example, prednisone initially causes increased phosphate
excretion, but the effect disappears after long term use.
The reason for any possible initial increase
in mineral excretion, that is seen from guaifenesin, might be due to the fact
that guafenesin is metabolized by the liver into an acid, which is then
excreted into the urine. In theory, this could increase urinary acidity,
and increased urinary acidity has been associated with increased calcium
excretion. This might explain why Dr. Bennett's study showed a small but
significant increase in urinary calcium. However, when initially starting
guaifenesin, there might be large increases in mineral excretion, until the
body adapts to the changes. For example, high protein diets that increase
urinary acidity, can initially increase mineral excretion, especially calcium
However, a recent long term study on such a diet, has shown that such
effects disappear after several weeks. Thus, only long term studies
show the true effects.
No Evidence that Excess Phosphate Can Cause Fibromyalgia
Symptoms
Phosphorus, commonly referred to as
phosphate, is one of the most common and most necessary minerals in the
body. Phosphate is used everywhere, from the building of bones, to
balancing the body's PH, and most important, for providing energy to run the
body, via the formation of ATP. However, since phosphate is so common in
the foods we eat, a phosphate deficiency is rare. And so is an excess of
phosphate.
This is because the kidneys are the main
factor in regulating proper phosphate levels in the body. And the kidneys
are well able to excrete very large amounts of excess phosphate, up to several
times the amount normally found in one's diet. Kidney
functioning must fail by at least 50%, before they lose their ability to
excrete the amount of excess phosphate that is ingested.
There are several factors that influence the
rate of phosphate excretion by the kidneys. The main influence is the
parathyroid glands, as they controls excretion rates via the production of
parathyroid hormones, or PTH. Thus, phosphate problems mainly occur due
to either kidney or parathyroid problems.
If phosphate excretion is too low, phosphate
serum levels rise, resulting in the condition known as hyperphosphatemia
This is normally due to either kidney failure, parathyroid deficiency
(hypoparathyroidism), or due to the body not reacting properly to parathyroid
hormone. The Merck Manual pages that relate to this condition are found here:
http://www.merck.com/pubs/mmanual/section2/chapter12/12e.htm
http://www.merck.com/pubs/mmanual/section2/chapter12/12d.htm
Such a condition is easily detected via a
blood test. Initially, this condition is symptomless. The main
symptoms occur due to the excess phosphate combining with calcium. This causes
a calcium deficiency, which is the main source of symptoms in hyperphosphatemia.
However, if phosphate levels are high enough, metastatic calcification
occurs. This causes calcium phosphate to accumulate in soft tissues,
resulting in deposits in the heart, lungs, blood vessels, kidneys, brain, eyes,
peri-articular tissues, and skin. But no such condition has been found in
fibromyalgia, so there is no direct proof that excess phosphate is present in
fibromyalgia. And even if it did exist, the effects of excess phosphate would
be first seen in tissues other than the muscles, as studies show that muscle cells appear to be somewhat protected
from serum phosphate levels changes. This is one of the possible
reasons why hyperphosphatemia first causes deposits to initially occur in
soft tissues, but not in muscles.
If excess phosphate really was the cause of
fibromyalgia, then everyone with hyperphosphatemia should develop
fibromyalgia. In fact, since all children, adolescents, and
postmenopausal women have elevated serum phosphate levels, then all of them
should also develop fibromyalgia. But this is not the case.
Nevertheless, Dr. St. Amand believes that uricosuric drugs help fibromyalgia, because
of their supposed effect on phosphate excretion. Dr. St. Amand conducted
a few urinary tests on some of his patients, and found that both urinary
calcium and phosphate levels were raised. Since phosphate levels were
raised the most, Dr. St. Amand believes it is this effect that helps to treat
fibromyalgia. The following quote is taken from his web page: http://www.fibromyalgiatreatment.com
"My theory, simplistically stated, is
that minimal phosphate retention year after year is leading to gradual
excesses. An elevated phosphate in the blood is not tolerated since it would
depress calcium levels. The parathyroid glands will not allow this and
phosphate must be spread evenly not only in body fluids but also within
cells."
If this statement is true, then either serum
calcium levels should be depressed in people with fibromyalgia, or parathyroid
levels should elevated. However, neither condition has been noted in
fibromyalgia. Additionally, an increase of PTH not only increases serum
calcium levels, but also decreases phosphate levels, by increasing urinary
phosphate excretion.
But the body has yet another method for
reducing elevated serum phosphate. It does this by decreasing levels of vitamin D.
Vitamin D regulates the amount of phosphate absorption in the intestines.
The decreased levels of vitamin D results in less phosphate being absorbed, and
thus lowers the serum phosphate.
Thus, there are several ways for the body to
reduce serum phosphate levels, in order to avoid phosphate from being deposited
in cells. Only in cases where phosphate serum levels are very significantly
elevated, would PTH not be able to compensate. If that was so, the
condition would again be easily noted via symptoms and lab tests.
Dr. St. Amand has stated that "Phosphates
readily enter cells". It is true that most phosphate is
contained in the cells. Intracellular phosphate levels are much higher
than extracellular levels. However, because of this concentration
difference, phosphate cannot easily enter cells on its own. An active
process is necessary to push the phosphate into cells. One of the major
ways in which this is accomplished, is via a mechanism known as
sodium-phosphate cotransporters, which are present in all cells. On the
other hand, phosphate can readily exit cells via a passive process. This
is because there is much less phosphate outside of the cells, and thus
phosphate can ready exit cells without much resistance. This process is believed to be dependent on the amount of
phosphate in the cells.
Thus, there are several methods available to cells, that can be used to control
their intracellular levels of phosphate. And in fact, these processes are
constantly at work, exchanging inorganic phosphate between the intracellular
and extracellular space. In muscles, which have high energy needs, and
which therefore contain large amounts of phosphate, the intracellular inorganic phosphate is totally removed and
replaced within a couple of hours, even when the muscles are at rest.
And because phosphate is so necessary for proper muscle functioning, the level
of intracellular phosphate is especially well controlled in muscles. For
example, studies have shown that when intracellular phosphate levels increase in muscles, due to
physical activity, phosphate is released at a greater rate, and its uptake into
cells is reduced. Thus, these two processes can used by cells to
avoid excessively high levels of phosphate. Additionally, the
concentration and electrical difference between the intracellular and
extracellular space is especially high in muscles, making it particularly hard
for phosphate to enter muscle cells on their own. Thus, these factors
help to explain why muscles don't appear to be significantly affected by
elevated serum phosphate levels, even at levels seen in hyperphosphatemia.
Dr. St. Amand also believes that the excess
phosphate combines with calcium in cells to form calcium phosphate deposits in
cells. However, one study has shown that intracellular
calcium levels in fibromyalgia is actually decreased.
Dr. St. Amand believes that the calcium phosphate deposits in cells is the
cause of lower levels of ATP, which is found in fibromyalgia. ATP is a
key chemical that the body creates for storing energy. However, studies
have shown no
relationship to the level of ATP and actual fibromyalgia symptoms.
And there have been no published studies which have found that excess phosphate
is associated with ATP depletion, or for that matter, any fibromyalgia
symptoms. But there are studies which show that ATP deficiencies are
found in people with phosphate deficiencies, which is not surprising, since ATP
requires phosphate. In fact, one study has found that some people with chronic fatigue
syndrome have phosphate diabetes, a condition caused by kidneys excreting
too much phosphate.
If deposits in cells is the cause of
fibromyalgia, then fibromyalgia should develop slowly, as the deposits slowly
grow. And the disease should be progressive, i.e. the deposits would
continue to keep growing, as in conditions such as hyperphosphatemia.
This would then cause symptoms to constantly get worse. However,
fibromyalgia is not believed to be a progessive disease, and many people with
fibromyalgia develop it in a very short period. And if fibromyalgia was a
truly a disease caused by ATP depletion from these deposits, then fibromyalgia
symptoms and other ATP depletion symptoms, should overlap. For example,
ATP depletion can cause muscle problems such as rhabdomyolysis. However,
no such conditions are observed in fibromyalgia.
Some people have pointed to studies which
show that fibromyalgic muscles contain low levels of ATP and high levels of
inorganic phosphate as being proof of the phosphate theory. However,
these same abnormalities have been known for a while, and are quite common in
other conditions. For example, studies have shown that similar muscle
conditions occur due to hormonal disorders, such as a hypothyroidism. Insulin resistance, another
condition commonly found in conjunction with fibromyalgia, is also known to decrease ATP levels in muscles.
In fact, reduced levels of ATP in muscles, can occur in the average person, due to experiencing exercise that causes muscle fatigue.
Basically, what happens is that ATP utilization exceeds the oxidative capacity
of the muscles, leading to a build up of inorganic phosphate. Inorganic
phosphate is formed due to the usage of ATP, and is then reused to synthesize
new ATP. But when the oxidative capacity is exceeded, ATP synthesis can't
match usage, and inorganic phosphate levels rise. Studies have shown that
people with fibromyalgia have lower than normal oxidative
capacity in muscles. But studies also show that untrained muscles have lowered oxidative capacity, and higher
levels of inorganic phosphate, when compared to trained muscles.
Thus, considering that many people with fibromyalgia have reduced physical
activity, due to the pain, it's very likely that untrained muscles is a major
reason why lowered oxidative capacity exists. Numerous studies by Finnish researchers,
have shown that strength excercising by fibromyalgia patients, results in
similar levels of increased muscle strength, when compared to normal people.
This should not be the case, if fibromyalgia muscles contained significant cell
abnormalities. It's because of this and other findings, that many people
have thus come to the conclusion that fibromyalgia studies on muscles do not show any conditions
which are the primary cause of fibromyalgia, and that fibromyalgia is not related to any muscle disorder.
So there presently is no proof to support
the phosphate theory, nor is there any proof that ATP depletion could cause all
the immune, hormonal, and brain disfunctions which have been found in
fibromyalgia, or for that matter chronic fatigue syndrome, which Dr. St. Amand believes
is the same disease as fibromyalgia. This is the reason why, that
although ATP levels were found to be abnormal as far back as the early 1990s,
present day research is not focused on that as being the primary cause of
fibromyalgia or chronic fatigue syndrome symptoms.
But even if we accept this theory, we must
also believe that guaifenesin can lower the serum phosphate level to the point
where it would cause phosphate to be released by the cells into the serum and
be excreted. Such an effect would have to be quite significant, in order
to create a large enough gradient between the blood and the cells to make the
phosphate want to move into the blood. And it has to be large enough to
allow the released phosphate to be excreted, rather than simply being
reabsorbed by other cells. Such a significant effect would be easily
noticed in lab tests. And in fact, such a test should probably be used as
a parameter for how much guaifenesin is needed, in order to make sure that
phosphate isn't being lowered too much. Phosphate blood and urine levels
are usually extremely constant, and assuming one is taking a timed release
version of guaifenesin to achieve a steady decrease of phosphate, a blood test
should be quite reliable. However, such tests have not been published,
nor are they being used for verifying the dose of the drug. Increasing
excretion of minerals can theoretically lead to many health problems.
Yet, Dr. St. Amand only uses symptoms as his guide for doses. In fact,
his treatment protocol expects that you will initially feel worse when taking
guaifenesin, which makes one wonder how one is supposed to know if one is
feeling bad or good effects, without a proper lab test.
Dr. St. Amand himself has said his theory is
purely theoretical, and that perhaps guaifenesin is changing the excretion
level of some other anion. His main reason for originally believing in
the phosphate theory was due to what he had observed in his patients, such
things as weaknesses in teeth and nails, which he believed was due to calcium
deposits resulting from the high level of phosphate. However, weak and
abnormal bone formations can be due to a phosphate diabetes, which we have
previously described. And it can also be due to a much more common
problem, which is a magnesium deficiency. Bones are not only formed from
calcium and phosphate, but also from magnesium. Without magnesium, the
resulting formations will be soft. Teeth will have soft enamel, nails
will be brittle, symptoms which match Dr. St. Amand's observations.
Magnesium is extremely necessary for proper
ATP synthesis, because ATP is stored in the body as a combination of magnesium
and ATP, which is known as MgATP. ATP requires magnesium in order to be
stable. Without magnesium, ATP would easily break down into other
components, ADP and inorganic phosphate.
Magnesium deficiency is very common in the
general
Magnesium is known to regulate or inhibit
many nerve receptors, such as NMDA or 5-HT3, which have been considered as
sources of certain types of fibromyalgia pain. Neurontin, for example, is
used because of its ability to regulate NMDA. Since magnesium also blocks
NMDA receptors, studies have used intravenous magnesium therapy to try and
treat similar types of neuropathic pain:
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10687324&dopt=Abstract
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9785788&dopt=Abstract
And it's because of magnesium's ability to
regulate nerve functions that other fibromyalgia symptoms occur. Migraine
headaches, mitral valve prolapse, and Raynaud's phenomenon, all problems
commonly found in people with fibromyalgia, are also problems that have been
associated with a magnesium deficiency. Without enough magnesium, nerves
fire too easily from even minor stimuli. Noises will sound excessively
loud, lights will seem too bright, emotional reactions will be exaggerated, and
the brain will be too stimulated to sleep, all symptoms commonly found in
fibromyalgia. And if the oversensitivity to light and noise reminds you
of someone suffering from a hangover, they are one and the same problem, as
alcohol is known for decreasing magnesium levels, and magnesium supplementation
has been found to relieve hangover symptoms.
A magnesium deficiency also increases levels
of substance P, a chemical which has been implicated as being responsible for
increased pain levels in FMS. Several studies, such as the following,
show this:
Unfortunately, magnesium deficiency is not
easily detected, as serum levels do not reflect the levels of magnesium in
tissues. This is the reason why it is so overlooked and ignored, both by
doctors and by studies. And unfortunately, oral magnesium supplementation
can be difficult because of absorption problems. Digestion and diet play
a key role in absorption. People with fibromyalgia often have conditions
like Irritable Bowel System, gluten intolerance, or other problems that might
limit absorption. Phosphate can bind to magnesium in the gut, creating
magnesium phosphate, an insoluble salt that can't be utilized. Many forms
of oral magnesium supplements are hard to assimilate. The most common,
magnesium oxide and citrate, happen to be the worst to assimilate, which is why
both have a strong laxative effect. If you suffer from that effect when
you take magnesium, it is often not because you are taking too much, but
because you are not assimilating it well. And it may take long term use
of supplements before magnesium levels are raised in all the tissues, and for
damaged cell functions to be restored.
Therefore, the symptoms which Dr. St. Amand
has attributed to an excess of phosphate, would more likely be due to a
magnesium deficiency.
Dr. St. Amand, and many
patients on guaifenesin, believe that salicylates block guaifenesin's
effects. The theory is that the effects of uricosuric drugs are blocked
by salicylates, due to their interaction in the kidneys. Dr. St. Amand
believes that the reason that Dr. Bennett's study did not show any effects from
guaifenesin, was that the patients were exposed to hidden sources or
salicylates that they weren't aware of, such as those that might be contained
in cosmetics and lotions. Dr. St. Amand believes that sunscreen lotions
can be a significant source of salicylates, yet a lab test has shown that less than 1% of the salicylates over a 48 hour period are
absorbed from these lotions. The form of salicylate in sunscreens is
usually octyl salicylate, because it is water resistant, and thus is not very
easily absorbed compared to other forms of salicylates.
But even in cases of analgesic topicals, where the salicylates aren't hidden
ingredients, and where the salicylates are meant to be absorbed by the skin,
most of is still not absorbed in the blood stream. In a study on an topical analgesic
containing methyl salicylate, one of the more active forms of salicylates, only
22% of the salicylates were recovered in the urine.
But even if hidden sources of salicylates do introduce low levels of
salicylates, there is no process in the kidneys that would allow a very small
amount of salicylates to block a very large amount of guaifenesin. To
give you an idea of how small we're talking about, Dr. St. Amand has stated
that he's had patients who have had their guaifenesin blocked by "Listerine twenty seconds in the mouth once a day".
Listerine contains approximately 0.060% methyl
salicylate. In comparison, Listerine contains over 22% ethanol, which is
more likely to a source of side effects, since ethanol is toxic if swallowed.
The fact is, that on every web page that describes the guaifenesin treatment,
no one accurately describes the kidney functions that relate to salicylates,
uric acid, and uricosuric agents. This process is important to
understand, because one of Dr. Bennett's main arguments against significant
amounts of salicylates being present in the study, is based on this process,
and what would occur if such salicylates were present.
In the kidneys, there is a section called
the proximal tubule. The fluid in the kidneys pass through there, and
this is where much of the useful components of the fluid is reabsorbed, and
eventually sent back to the bloodstream. This process is known as tubular
reabsorption.
There is also a different process, known as
tubular secretion. Weak acids, such as uric acid, are secreted into the
tubule. This is the body's way of quickly getting rid of these
acids. However, only a limited amount of acid can be secreted at any
given time. If enough of one acid is present, it will saturate the
process, and this will block the secretion of other acids. This is how a
lower amount of one acid, is able to block the secretion of larger amounts of
another acid, resulting in less of the other acid being excreted into the
urine. This is why low doses of salicylates,are
able to block excretion of uric acid.
Probenecid, being a weak acid, is also
secreted using tubular secretion. This is why salicylates can also block
probenecid. However, the amount has to be quite large to do this,
definitely not small hidden amounts. This is why people who take
uricosuric drugs, are not told that they need to avoid small sources of
salicylates. On the other hand, Dr. St. Amand believes that small amounts
can block guaifenesin.
As an aside, it should be point out that
guaifenesin itself is not secreted into the kidneys. Guaifenesin is not
an acid, but is slightly basic. However, guaifenesin is almost totally
metabolized by the liver, and the metabolites are excreted in the urine.
Guaifenesin's major metabolite is beta-(2-methoxyphenoxy) lactic acid.
Lactic acid is similar in strength to uric acid, and competes with uric acid
for tubular secretion. And the medical literature states that lactic
acidosis, a buildup of lactic acid in the body, can be caused by taking
salicylates. Thus, it's likely that guaifenesin's lactic acid metabolite
is handled by tubular secretion.
However, as previously noted, it still takes
a fair amount of salicylates to block a uricosuric drug, such as
probenecid. Even if guaifenesin is weaker than probenecid, we still know
that guaifenesin can block uric acid, and uric acid itself isn't that
weak. It still takes a fair amount of salicylates to block uric acid, so
we can deduce that we need a similar amount of salicylates to block
guaifenesin. This amount is very unlikely to occur without taking
medicine that contains salicylates. Many studies in the 1990s have been
done to study the amount of urinary salicylates that exist in people not taking
salicylate medication, and they all have shown extremely low amounts of urinary
salicylates:
Additionally, studies
from the 1990s have shown that the salicylate content in foods, herbs, and
spices, is much lower than was found in previous studies.
Unfortunately, many web pages which discuss salicylates, only refer to the
earlier studies, and thus distort the true level of salicylates.
However, even if a person was somehow
exposed to a hidden amount of salicylates, an amount large enough to block
guaifenesin, then these same salicylates should also be large enough to block
uric acid. This would then result in lower urinary uric acid levels.
It is this fact that Dr. Bennett uses as one
his reasons why the patients in the guaifenesin study, were not exposed to
enough salicylates to block guaifenesin. Had they been so, they should
have had lower than normal urinary uric acid levels. However, 24 hour
urinary tests, before and during their guaifenesin treatment, were always about
500mg. The normal range is 250-750mg, so they were just about average.
Now, if the patients were not exposed to
salicylates, and the guaifenesin wasn't blocked, shouldn't their urinary uric
acid increase, due to the uricosuric effect of guaifenesin? Not necessarily
so. Uricosuric drugs have to reach a threshold dose before they are able
to block enough reabsorption of the uric acid in the proximal tubule, in order
to create a uricosuric effect.
What is the effective dose of guaifenesin
necessary to exhibit the uricosuric effect? Unfortunately, the only study
that were conducted on this effect, was done so decades ago, and only used pure
guaifenesin, rather than the sustained release form that was used in the
Bennett study:
In that study, people were given 600mg doses
every 2 hours for 6 hours, for a total of 1800mg. The uricosuric effect
was noticable, but not deemed high enough to be of clinical use. At a
much lower dose, i.e. 600mg sustained release over 12 hours, which was the dose
used by the guaifenesin study, there might be little or no uricosuric effect.
However, what the guaifenesin study did
show, was a noticable increase in calcium excretion in the guaifenesin group
vs. the placebo. See:
http://www.myalgia.com/guaif2.htm
This may be significant, because there have
been cases of people developing kidney stones after taking large quantities of
cough medicine containing guaifenesin:
Analysis of the kidney stones found an
insoluble salt of the guaifenesin metabolite combined with calcium. If
anyone does experience mineral excretion from taking guaifenesin, it might be
due to the formation of such insoluble salts. Additionally, guaifenesin
is metabolized into acids, which are excreted in the urine. This would
increase the raise the acid level of the urine, and increased acidity is associated with increased calcium
excretion.
In any event, there is little proof that
salicylates in small amounts can totally block guaifenesin in the
kidneys. On the other hand, there is the possibility that people with
fibromyalgia are being directly affected by salicylates, and that any benefits
from avoiding salicylates might have nothing to do with guaifenesin. In
large enough doses, salicylates significantly inhibit oxidative
phosphorylation, the process that creates ATP. ATP is source of energy
for the body, and ATP levels has been shown to be low in people with
fibromyalgia. Whether people are exposed to high enough levels for this
effect to be noticed is unknown.
However, even small amounts of salicylates
are believed to be capable of causing problems in some people. This
condition is known as salicylate sensitivity. Sensitivity and side
effects from salicylates have long been claimed by many people to be able to
affect many different health problems. While many of these claims lack
proper studies, a well documented sensitivity is known to exist in people with
asthma and chronic sinusitis. Aspirin sensitive asthma is not only a
reality, but it affects a very significant amount of people with asthma,
especially those who also have allergies. This is significant, since many
people with fibromyalgia also have asthma, sinus problems, and allergies.
One of the main reasons for aspirin sensitivity, is that salicylates cause an
increase in a class of chemical known as leukotrienes. Leukotrienes are
known to cause inflammation, vasoconstriction, and pain. People who are
senstivity to salicylates, may either produce more leukotrienes, or are
sensitive to their effects, and that could be why some people feel better when
they avoid salicylates. People with asthma, who are aspirin sensitive,
are often helped by taking drugs like Singulair, which block some of the
effects of leukotrienes.
Aspirin sensitivity may also be related to aspirin's effect on
platelets. Aspirin is usually known to reduce platelet
activity. However, when aspirin is introduced to platelets from aspirin
sensitive asthmatics, the platelets become more activated. This appears
to be due to aspirin's ability to inhibit cyclooxygenase. In these
people, salicylate sensivity could therefore be adversely affecting people with
fibromyalgia, and blocking the anticoagulant effect of guaifenesin, which will
be discussed later.
Salicylate sensitivity has also been associated with low levels
of glutathione-peroxidase activity. This may be significant, as some
people believe that chronic fatigue syndrome is partially due to low levels of
glutathione, and many people with fibromyalgia also have CFS. Some people
with CFS have found that taking whey supplements help them, and whey contains
amino acids that increase glutathione production. Therefore, perhaps low
glutathione levels might make some people with fibromyalgia likely to be
sensitive to salicylates, and avoiding them would help to alleviate
fibromyalgia symptoms.
By the way, even if people with asthma and
sinus problems aren't aspirin sensitive, they might be helped on the
guaifenesin protocol from the well known expectorant effect of
guaifenesin. Many
people with fibromyalgia have some form of sleep disordered breathing, such
as apnea, without realizing it. Apnea
problems have been found to be significantly undiagnosed in many women, due to
poor diagnosis, as women often present different symptoms than men. Also, there is the incorrect belief that
apnea is mainly found in men. Relieving congestion
would not only improve sleep, but it would also help to avoid sinus infections,
both effects which could help to relieve fibromyalgia symptoms.
Salicylates can also block Vitamin K. This may be
important for some people with fibromyalgia, as easy bruising is a common
symptom in some people with fibromyalgia, and a vitamin K deficiency could
cause this. However, Vitamin K does much more than this. It
is also a significant antioxidant, controls insulin release, and is important
in protecting osteoporosis. Additionally, vitamin K reduces IL-6, an inflammatory
cytokine, which some people theorize places a role in creating fibromyalgia
pain. Vitamin K deficiencies have also been linked to mitral valve
prolapse and hypermobility, both conditions which also commonly overlap in some
people with fibromyalgia. Therefore, reducing salicylates may be helping
some people with fibromyalgia by increasing levels of vitamin K.
Perhaps even more important, salicylates are known to cause hypoglycemia in some people.
This is important, since many people with fibromyalgia that Dr. St. Amand
treats, also have hypoglycemia, and their fibromyalgia symptoms are often
greatly affected, simply by going on a hypoglycemic diet. Additionally,
Dr. St. Amand has said he has treated many children with fibromyalgia, and
children are more likely to experience hypoglycemia due to salicylates, than
adults.
In any event, avoiding salicylates can have
a wide range of effects on the body, and therefore it's impossible to tell what
is the result of avoiding salicylates, without proper lab tests or
studies. Additionally, perhaps avoiding salicylates, causes people to
avoid other substances that might be affecting them. This leads into our
next section.
Many herbs and supplements, which contain
significant amounts of salicylates, also contain high amounts of a family of
substances known as phenols. Salicylates are related to phenols, as
salicylic acid is a phenolic acid. If one adheres to a salicylate free
regimen, one will likely reduce one's intake of phenols, and phenols themselves
have their own effects. This might explain why certain supplements, such
as quercetin and peppermint oil, which are high in phenols, yet are not known
to contain salicylates, are on the list of supplements to avoid by Dr. St.
Amand. Either it's poor research on his part, or he has seen people have
reactions to these supplements.
One of the most commonly known phenols in
foods are flavonoids, and several lab studies have shown that flavonoids do have anti-thyroid effects This is
important, because hypothyroid disorders can often lead to fibromyalgia, and
normalizing thyroid levels other helps to treat or resolve fibromyalgia
symptoms Soy flavonoids has been best studied, with regard to this
effect While this property may not have a direct effect on thyroid levels
in the average person, there is a concern that it may be a significant effect
for people who have other contributing factors that would lead to a thyroid
problem, such as low levels of iodine, or high level of thyroid
antibodies.
Also, this effect has only been studied on
the original flavonoids themselves. But once ingested, flavonoids do not
always stay in their original form. Flavonoids are mostly metabolized via
a process known as sulfation, where they are combined with sulfur. This
results in phenolic metabolites, which may not have any anti-thyroid effects.
So any such effects, would be dependent on how quickly the phenols are
metabolized by sulfation. The rate of sulfation is dependent on several
factors, one of them being the availability of inorganic sulfate.
A low level of sulfur, would lead to a lower rate of sulfation, leading to
increased levels of phenols in the body. And as shall be seen in a
minute, there are many factors in fibromyalgia that could lead to low sulfur
levels.
On the other hand, lab studies show that phenolic acids, which are related to phenols, also have an
effect on thyroid levels. Salicylic acid, being a phenolic acid, may
therefore have a similar effect. And in fact, studies have shown that 2 forms of salicylate medicines, given to humans, have the
ability to lower serum thyroid levels. In those studies, it was found
that salicylates compete in the serum with thyroid hormones, for binding to
serum protein. This directly affects thyroid levels. Supplements and
other organic sources, that contain salicylates, may cause this
effect. This could be true, even if the amount of salicylates is
small. This is because, other similar acting phenolic acids, are often
found together with salicylates, and together they may cause a significant
effect.
Since the sulfation process requires sulfur,
a high rate of sulfation could, in theory, contribute to a lack of
sulfur. And a lack of sulfur can lead to symptoms that are commonly
present in fibromyalgia, such as joint problems, skin disorders, and immune
disfunctions. Sulfur baths and spas are an age old remedy for such
problems, and in fact one study has shown sulfur baths to have a positive effect on
fibromyalgia. Plus, many people with fibromyalgia take supplements
that contain high amounts of sulfate, such as whey, MSM, SAMe, and glucosamine
sulfate. Several researchers have expressed the belief that the benefits
from such supplements, may actually be from the sulfate itself:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11436179
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12623294
But while phenols themselves may not
significantly lower sulfur levels, there are factors that might be present in
some people, that have the ability to lower sulfur levels, by increasing
urinary sulfate excretion Vitamin D, T3 thyroid hormone, and growth
hormones, are all substances which are found low in some people with
fibromyalgia, and a lack of any of them can result in increased urinary sulfate
excretion.
Additionally, although salicylates
themselves do not appreciably require sulfur to be metabolized, one lab study
has shown that salicylic acid can increase urinary sulfate excretion.
Unfortunately, this effect has not been studied humans, to see how significant
it is.
Sulfur is necessary for many processes in
the body, so that a lack of it is likely to have some effect on fibromyalgia.
In fact, since sulfur is especially well known for providing proper connective
tissue health, it's possible that the lumps which Dr. St. Amand feels in
fibromyalgia patients, could actually be a disorder related to a lack of
sulfur.
There are other possible clues that sulfur
could be a problem in fibromyalgia. Many people with fibromyalgia find
benefits from hypoglycemic or low carbohydrate diets, which are high in
protein. While there are a number of possible reasons for this, perhaps
one reason is because of the increased levels of sulfates derived from the
amino acids. In particular, sulfate is mainly derived from the amino acid
cysteine. However, this process depends on the cysteine dioxygenase
enzyme, and in some individuals, the activity of this enzyme is
decreased. Of particular note to people with fibromyalgia, is that
autoimmune or inflammatory conditions, such as rheumatoid arthritis and lupus,
can cause decreased activity of this enzyme, and thus decreased sulfate levels.
This appears to be due to the fact that certain cytokines directly influences the enzyme's activity.
Cytokines are inflammatory substances which are elevated in RA and lupus and
other autoimmune conditions, conditions often found in combination with
fibromyalgia. People who have such problems, might require other means to
raise their sulfur levels.
Additionally, tylenol is one of the well
known drugs that is metabolized by sulfation, and it definitely has been found
to lower serum sulfate levels. Since many people with fibromyalgia are
either taking tylenol, or drugs that contain tylenol such as ultracet and
vicodin, these people may need extra sulfate. Guaifenesin's analgesic
effects may help people to decrease the use of pain killers containing tylenol,
and thus may indirectly be helping sulfur levels.
Phenols aren't the only ingredients which
are commonly found in combination with salicylates. There are others that
may be able to reduce the effectiveness of the guaifenesin treatment.
Several clues indicate this might be happening. People who are salicylate
sensitive, must also avoid foods that contain significant amounts of
salicylates. However, patients on the guaifenesin treatment,
are told that no special diet is required, as "the
liver adds glycine to the small amount of salicylates contained in food plants,
and this process prevents guaifenesin from blocking." Instead,
they are only told to avoid supplements and topical sources of
salicylates. The theory is that supplements contain higher amounts of salicylates
than food, which would then overwhelm the liver. Or, in the case of
topicals, the salicylates would directly enter the bloodstream, and be more
likely to bypass the liver. But even if these sources introduce more
salicylates to the body, the liver should still be able to properly metabolize
them. A study using a single dose of 600mg of aspirin,
has shown that the majority of the salicylate was metabolized into the glycine
conjugate, salicyluric acid. Only at higher doses, is the glycine
metabolic process saturated, at which point substantial amounts of other forms
of salicylates will appear.
But more importantly, it's salicyluric acid,
the form of salicylate combined with glycine, and not other forms of
salicylates (such as salicylic acid), that is mainly excreted by the
kidneys. For example, the following quote is from a study where different
forms of salicylates were tested, to see if any of them might renally compete
with a carboxylate drug:
Renal elimination plays a minor role in the elimination of
salicylic acid (<16%), and hence the potential for competing with the carboxylate
via the renal tubular secretory pathway is low. In contrast, renal
excretion plays a significant role in the elimination of salicyluric
acid (~60%).
So this seems to be totally at odds with Dr.
St Amand's claim that salicyluric acid, the form of salicylate that is
conjugated with glycine is less likely to cause blocking effects than other
forms. Because it is that form of salicylate that is more likely to be
the one that would compete with guaifenesin. So what's the real story
here? Is this another case of misinformation? Perhaps, but perhaps
not. One alternative explanation for why salicylates in foods are not a
problem, is that the amount of salicylates is simply too low to be a problem.
On the other hand, as I previously noted,
studies on the major form of salicylate in lotions, i.e. octyl salicylate, have
shown that very little of it is absorbed through the skin. So how is it
that some people claim that salicylates in these products can block
guaifenesin's effects, yet salicylates in food are not able to do so? One
answer is found by looking at the other ingredients that are found in such
lotions..
In topical sources, you will often find
additives that contain benozic acid. Benzoate compounds are extremely
common in topical products, oral products such as toothpaste, and also
processed foods (jams, juices, non yeast bakery products), and sodas.
They are used as both preservatives and aromatics. But benzoates can be
absorbed through the skin. And benzoates are metabolized by the same
glycination process that salicylates are, which is why they can end up competing with each other for
glycine conjugation, which lowers their rates of metabolization. This
would then prolong the time that salicylates would be circulating in the body.
Alternatively, people could be reacting
directly to the benzoates. Sensitivity to benzoates has been reported by
people who have salicylate sensitivity. In fact, there have even been
cases where benzoates by themselves have been reported to cause symptoms
such as joint pain, headaches, and concentration problems.
Additionally, cinnamic acid and its
derivates, which are converted by the body to benzoates, are also commonly
found in topicals and aromatic products.
People on guaifenesin are told to avoid
flavonoid supplements, as they are believed to contain salicylates.
However, such substances also contain both benzoic and cinnamic derivatives:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11996210
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10589442
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10752646
And just as the salicylate metabolites are
subjected to tubular secretion in the kidneys, so are the benzoate metabolites,
i.e. hippuric acid and its derivatives. In fact,
probenecid itself contains benzoic acid, being that its chemical name is
p-[Dipropylsulfamoyl]benzoic acid. And even more interesting, salicylic
acid is 2-Hydroxybenzoic acid! So it's surprising that no one has considered
that benzoates might be also be problematic. If one believes that
salicylates can block the effects of guaifenesin at the kidneys, one could
easily theorize that benzoates have a similar effect.
But it's also quite possible that any adverse effects caused by these
chemcials, could be solely due to the fact that they share the same path of
metabolization in the liver, rather than any effects they might have on the
kidneys. Both salicylates and benozates can decrease the available amount
of glycine in the liver. Glycine is an important amino acid, with regard
to carbohydrate metabolism, as it regulates gluconeogenesis in the liver, one
the processes which controls blood glucose levels. A reduction of glycine
can lead to inhibited carbohydrate metabolism and hypoglycemia. Perhaps
this is why, as previously mentioned, there have been cases of salicylates
causing hypoglycemic symptoms.
In addition, one study has shown that hypoglycemic effects from
salicylates, could possibly be due to salicyl Coa.
Salicyl Coa is the intermediate form of salicylate, which salicylates are first
transformed into, before they are conjugated with glycine. With
insufficient glycine, there would then be an excess of salicylyl Coa, which
could be the reason for the disrupted carbohydrate metabolism.
These possible hypoglycemic effects could be
significant, considering that Dr. St. Amand has claimed that a large percentage
of people with fibromyalgia have some form of hypoglycemia, and that these
people can't successfully be treated with guaifenesin, unless the hypoglycemia
is also untreated. But the hypoglycemia could be due to the effects of
salicylates and benzoates. These chemicals could be the reason why some
people have hypoglycemia, while others don't, or why some people are very
sensitive to salicylates, while others are not. It may not be a
coincidence that Dr. St. Amand states that salicylates and hypoglycemia are the
2 main reasons why the guaifenesin treatment may fail. They may, in fact,
be one and the same problem.
But I don't think it's likely that people
are being exposed to high enough levels of salicylates, for hypoglycemia to
solely occur due to them. I suspect it's more likely that it's a
combination of salicylates, and other chemicals, such as benzoate
compounds. Benzoates are not just found in foods and topical sources, but
in many other products we are exposed to. And beyond that, there are
many petrochemicals, such as xlyene, tolunene, and other benzenes, that many of
us are exposed to on a daily basis, without us knowing it, that are also
processed by glycination. Which is why some people have theorized that
these chemicals are a significant reason why so many people have a problem in
metabolizing carbohydrates. An
overload of such chemicals would deplete glycine, and allow such chemicals to
circulate longer in the body, causing other adverse effects. And the lack
of glycine could also lead to low oxidation levels, a condition which has been proposed as a trigger for
fibromyalgia, given that some people with fibromyalgia have low levels of
antioxidants.
If you avoid products that contain
salicylate additives, you are likely to also avoid some benzoate
additives. I.e., many salicylate free products are also fragrance free,
which means that aromatic benozate compounds may also be removed And if
you go on a hypoglycemic diet, you will also lower the amount of natural
benzoic and quinic acids that you ingest. Is this just a coincidence, or
a meaningful observation?
It could be, that the benefit of avoiding
salicylates, may have nothing to do with a possible interaction between
salicylates and guaifenesin. Instead, the benefit could be due to the
reduction of detrimental effects, which are directly being caused by
salicylates and similar substances.
Avoiding salicylates and other possible
chemicals and substances, taking guaifenesin, and going on Dr. St. Amand's
hypoglycemic (or other healthy) diet, may have a combined effect which could be
significant, and which could lead to beneficial effects on fibromyalgia, but in
a different way than Dr. St. Amand theorizes. It may have nothing to do
with any effects on the kidneys.
Guaifenesin has another
effect that might be useful for some people with fibromyalgia. It has a known anticoagulant effect, And
interestingly, both of the previous uricosuric drugs that Dr. St. Amand used
for fibromyalgia, i.e. anturane and probenecid, also have an anticoagulant
effect. This effect is relevant, because it has been found that some
people with CFS/FMS have hypercoagulant activity, and initial studies have
shown some success with using heparin and other anticoagulant drugs.
The anticoagulant effect was first noticed in 1994 by a Dr. John Couvaras, an
infertility doctor, who began using heparin for fertility problems, and
discovered that it helped many symptoms of his patients who also had CFS and
fibromyalgia. Perhaps not so coincidentally, guaifenesin is also known to
have the ability to increase fertility (originally it was thought that this
effect from guaifenesin was due to thinning of cervical mucus. But
guaifenesin has not been found to have a direct effect on thinning mucus,
but instead simply stimulates mucus glands to allow more mucus to flow,
possibly by irritating gastric linings. This effect is not likely to
occur in the cervix, because little if any guaifenesin could appear
there. Plus, it's the thinning of the mucus which is important, not
increased mucus flow. Thinning mucus occurs due to a raise in estrogen
levels, and coincidentally estrogen inhibits platetlet aggregation.)
There are several reasons given as to
possibly why anticoagulants have helped some people. But there is one
specific effect that might be very relevant for fibromyalgia. In a recent
study on fibromyalgia, it's been found that some fibromyalgia symptoms coorelate
with lower levels of serum serotonin and higher levels of plasma
serotonin. See:
But platelet activation, which causes
platelet aggregation, also causes the release of serotonin, resulting in high
plasma serotonin In addition, only in the last few years has it been
recognized that serotonin influences many other problems, such as migraines,
hypoglycemia, asthma, Raynaud's, and IBS, all conditions which are associated
with fibromyalgia. Some of these conditions are exacerbated due to
serotonin's ability to cause constriction. However, Dr. Couvaras has said
that migraines, irritable bowel syndrome, and pelvic pain, all went away when
he put his patients on heparin. Interestingly, Dr. St. Amand has also
claimed that guaifenesin is able to treat many different conditions. An
imbalance of serotonin in the blood could be the link that connects all these
conditions.
Hypoglycemia is one of the more interesting
conditions related to serotonin, as it is especially common in fibromyalgia. It
is so common, that Dr. St. Amand himself regularly prescribes a diet for
hypoglycemia to many of his patients, and it is often an integral part of his
treatment in combination with guaifenesin.
However, hypoglycemia can be influenced by a
serotonin release, as serotonin has been shown to increase insulin levels.
Not only that, but platelet aggregation sensitivity is increased due to
hypoglycemia. Thus, this is one possible explanation of why
hypoglycemia is so common. (As an aside, so many people have remarked how
helpful the diet is, that anyone considering going on the guaifenesin protocol
and the diet, might want to first try the diet alone, in order to be able to
tell which effects are occurring from diet, and which effects are from the
guaifenesin.)
Other commonly seen conditions also have a
serotonin link. For example, plasma serotinin in celiac patients has been found to be
elevated. Problems associated with blood pressure, such as Neurally Mediated Hypotension, are
also influenced by serotonin.
In addition, platelet activity causes a
release of other substances that might be affecting fibromyalgia. For
example, ATP is also released, and this might be the cause of reduced levels of
ATP found in red blood cells of people with fibromyalgia.
Both of the previous uricosuric drugs used
by Dr. St. Amand, anturane and probenecid, also affect platelet activity.
Anturane (sulphinpyrazone) is well known for having
antiplatelet activity. Probenecid's effect is a bit different. It's
able to block a number of different aggregating agents. And its main effect may
be due to its ability to inactivate thrombin, which is the cause of platelet
activation which leads to the secretion of serotonin from the serum to the
plasma. See the following studies:
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8865538&dopt=Abstract
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=23532&dopt=Abstract
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2474820&dopt=Abstract
But what's more, is that an anticoagulant
effect might be the reason for the increased phosphate excretion. The
clue to this possibility is a recent report of a patient being treated with
probenecid for calcinosis:
According to most studies, probenecid does
not cause phosphate excretion in either non-gout or gout patients.
However, there are several reports in the medical literature of it
occurring. But they are so rare, that whenever a case occurs, its reported
in a medical journal. In the above report, the patient had Juvenile
Dermatomyositis which led to calcinosis, a condition where calcium is
abnormally deposited around bones, causing severely limited mobility. The
patient also had hyperphosphatemia, and probenecid was able to reverse this
condition by increasing phosphate excretion, and this led to reversing the
calcinosis.
However, it's possible that the
hyperphosphatemia seen in this patient was due to a drug that she was taking,
which was Cyclosporin A. This drug is known to cause platelet aggregation
and high plasma serotonin levels:
http://www.sums.ac.ir/~ijms/9834/fardaee9834.html
This paper mentions that impaired renal
functioning and reduced renal plasma flow also occur with this drug. The
impaired renal functioning could lead to phosphate retention. If an
anticoagulant could improve renal flow, then theoretically this could cause
increased phosphate excretion.
And there is possible proof that the
phosphate excretion from probenecid is due to an effect other than the
uricosuric effect. Here is a study of an earlier case of probenecid being
successfully used for calcinosis:
In that case, phoshate excretion occurred
even without a significant increase in uric acid excretion. In other
words, the two effects might be unrelated.
This would also explain the puzzle of why
uricosuric drugs produce increased uric acid excretion in normal people, yet
phosphate excretion does not occur. They are two separate effects, and the
phosphate excretion would only occur in people who had impaired platelet
functioning.
But it should be pointed out that not all
anticoagulants affect the impaired renal functioning which is caused by
platelet aggregation. This is not surprising, as there are several different pathways involved in platelet aggregation
Thus, different drugs inhibit aggregation in different
ways. In the following study, renal impairment was induced by endotoxin,
a platelet growth factor which causes aggregation. In high enough doses,
endotoxin is able to cause reduced phosphate excretion. Heparin had no
effect on the renal impairment, while aspirin was able to restore proper renal
functioning: