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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 claimed at the time that he had 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. This was true, 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. My intent is not to discourage anyone from following this treatment plan. Indeed, because I found scientific proof of why it works, some people have actually started the treatment, because of reading my web page. My intent, however, is to use known scientific facts, to explain why the treatment helps some people.

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, one study (unfortunately no longer on the web) showed that people with fibromyalgia who had higher pain levels, were less likely to have flares than those with lower pain levels. This possibly could be due to the fact that in response to pain, the body produces natural opioids. This is why that when people are exposed to a painful stimulus, "people actually tend to experience less pain the more they are exposed to it". Thus, If a person is experiencing a higher constant pain level, those natural opioids might block or dampen further flare ups. Therefore, 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. Sadly though, many people don’t get any better at all on guaifenesin, but actually get worse. But because they are told that this is an expected effect of the treatment, some people have avoided seeking out other treatments, and suffered needlessly, due to the belief that these symptoms represent a good thing. Besides which, the cycling theory doesn’t provide a scientific reason why a person who feel worse by the release of phosphate deposits. Such deposits 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 negative symptous.

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 from an old web page of Dr. St. Amand’s, "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. Additionally, 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. Dr. St. Amand believes these are 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.

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. 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.”

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 North America became aware of the guaiac tree, due to the fact that they were looking for remedies to treat untreatable diseases, such as syphilis. Basically, they were looking for a way to make money. They discovered that the local natives were using extracts of the guaiac tree for medicinal properties, and so they tested it on syphilis. The extracts were able to treat the back pain related to syphilis, so they believed that it could therefore treat syphilis. Thus, for a long time, it was more well known for treating syphilis, than rheumatism. The fact that guaifenesin has a history of treating various ailments, supports the theory that it has a more general analgesic effect, rather than a specific effect that only treats fibromyalgia. So it's no wonder that people such as Gregory Penniston, a chiropractor who designed the GuaiLife form of guaifenesin, markets it for a very wide range of pain conditions, such as pelvic pain, Ehlers-Danlos Syndrome and restless leg syndrome, among others.

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.

Can Med Assoc J. 1970 Sep 12;103(5):473-83 AUTHORS: Garcia DA, Yendt ER (No abstract available in MEDLINE)

Additionally, other studies have confirmed that probenecid does not increase urinary phosphate excretion, such as the following:

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=809224&dopt=Abstract

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. The ability of the body to excrete excess phosphate, does not occur until a significant loss of kidney functioning occurs. For example, chronic kidney disease (CKD), does not result in a significant increase in serum phosphate levels, until stage 4 of the disease is reached.

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. 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. According to this article that he wrote: http://www.psha-inc.com/guai-support/Vulvodynia.htm

"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, for many people, fibromyalgia is not a progessive disease. It is true that some people do progressively get worse, but this could be due to the fact that they are not getting proper treatment, or that they have a secondary condition that is undiagnosed. And the fact that some people people develop fibromyalgia in a very short period of time, while in others it develops slowly, starting from any age, shows the wide variability of the disease. If a genetic flaw in the excretion of minerals was the cause of fibromyalgia, it is unlikely that one would not see such wide differences in patients.

Besides, 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.

Indeed, a recent 2013 study on ATP levels in fibromyalgia and non-fibromyalgia patient groups, showed that “no significant group differences existed with respect to inorganic phosphate”. And while they did find decreased levels of ATP, they stated that “the content and function of mitochondria decreases with physical inactivity”, and that this “would support an explanation of our findings of lower absolute concentrations of ATP and PCr in FMS may be due to inactivity.” Again, this supports the theory that the decreased ATP levels, may actually be the result of inactivity, caused by fibromyalgia pain, rather than the reduced ATP levels being the cause of the fibromyalgia pain.

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 US population. Not only is our daily intake low, but we eat a diet which increases the demand for magnesium. And unfortunately, urinary magnesium loss can be increased by many factors, both physical and emotional. Magnesium loss increases in the presence of certain hormones. Stress can greatly increase magnesium loss. Even loud noises can extra magnesium loss. One article on the web goes so far as to say that that almost everyone is the United States is at least marginally deficient in magnesium. So there is an excellent chance that a person with fibromyalgia has a magnesium deficiency. But since people with fibromyalgia often have high levels of stress, and a disrupted hormonal system, they are more likely to be candidates for magnesium deficiency. Plus, sleep deprivation has been shown to cause lower magnesium levels:

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9068914&dopt=Abstract

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:

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1384353&dopt=Abstract

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.

What Your Doctor Never Told You About Salicylates

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:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9110565

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8901795

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12944546



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:

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4617771&dopt=Abstract

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:

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10414721&dopt=Abstract

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.

Salicylates, Phenols, Thyroid, and Sulfur

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.

Salicylates, Benzoates, and Hypoglycemia

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's Anticoagulant Effect

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:

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11203736&dopt=Abstract

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:

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11361202&dopt=Abstract

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:

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9360503&dopt=Abstract

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:

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1667536&dopt=Abstract

Heparin is strictly an anticoagulant, while aspirin is an antiplatelet drug. This study theorized that only antiplatelet drugs could reverse the renal impairment caused by platelet aggregation, but perhaps the real reason is how the kidneys handle the drugs. Drugs such as uricosuric drugs and salicylates are actively secreted into the kidneys. Thus, uricosuric drugs might be the only anticoagulant drugs that are able to reverse all the affects of platelet aggregation.

What is causing the platelet aggregation? There are many possible reasons. A magnesium deficiency can be the cause. Another interesting possibility is that low levels of certain antioxidants factors, glutathione and thiols, can also be the cause. This is interesting because some people with fibromyalgia and CFS appear to have this condition, and people have found benefit from taking supplements that increase glutathione, such as special forms of whey. Elevated blood homocysteine levels is also a possible cause. This can be due to a B12 deficiency, and many people with CFS and fibromyalgia find benefit from taking B12 shots. Homocysteine levels are also increased in hypothyroidism, and hypothyroidism is commonly found in fibromyalgia patients. Estrogen may be a factor in women, since it's known to inhibit platelet aggregation. Fibromyalgia is more likely to occur in older women, when estrogen levels are decreasing. One study showed lowered basal levels of estrogen in women with fibromyalgia. Another study showed that fibromyalgia symptoms were worse during part of the cycle with the lowest level of estrogen. Certain infections, such as candida, can increase platelet activity, as platetets secrete toxins against infections. Lyme disease might also increase platelet aggregation.

It's quite possible that a number of factors can be increasing platelet aggregation. This is true in other conditions, such as diabetes, where platelet aggregation exists, and different treatments have been found to be useful, One treatment of specific interest is the use of amino acids which have been found to be low in diabetes. Taurine and arginine have been successfully used to reduce platelet aggregation. Since amino acid levels have been found to abnormal in both fibromyalgia and CFS, this is another possible factor.



However, even if platelet aggregation or coagulation problems exist in people with fibromyalgia, this would not necessarily mean that the problem is worse enough to impair renal functioning. If that was the case, then decreased phosphate excretion would be noted in patients with fibromyalgia. Not only is this not true, but people with fibromyalgia have found benefit from guaifenesin without observing any increased phosphate excretion.



If platelet activity is a factor in fibromyalgia, then how is it that other drugs and supplements for fibromyalgia are also effective, yet they don't have any effect on platelet activity? The answer is that coincidentally (or perhaps not), most other drugs and supplements for fibromyalgia do inhibit platelet aggregation. All of the following have some affect on platelet activity: Some antidepressants, especially tricyclics, benzodiazepines such as xanax and valium, antihistamines such as benadryl, anesthetics such as procaine, supplements such as MSM, ginko, pycnogenol, quercetin, and bromelain, magnesium, B12 (homocysteine increases platelet aggregation), whey (treats glutathione deficiency, which causes platelet aggregation), some amino acids such as taurine and arginine, and relaxin (presently experimentally used for fibromyalgia). Thus, like guaifenesin, all of these substances are recommended for use for fibromyalgia, but they also have some ability to inhibit platelet aggregation

In fact, one could hypothesize that some of the people in the guaifenesin study, who did not see any benefit from guaifenesin, might have already been taking a supplement or medicine that inhibited platelet activation, and thus were not affected by the addition of guaifenesin. This hypothesis gains further strength from the fact that Dr. St. Amand recommends to people to avoid most supplements, because he feels they are not necessary, so that his own patients would be less likely to be exposed to such remedies. Additionally, many of the supplements that inhibit platelet activation, may contain traces of salicylates, so they are avoided by people taking guaifenesin. The fact that both guaifenesin and many salicylate containing supplements are able to inhibit platelet aggregation is not simply a coincidence. Both guaifenesin and many of these supplements are derived from the skins and barks of plants, so they are likely to have similar effects. However, guaifenesin is now artifically produced, rather than being naturally derived, so it doesn't have the traces of salicylates that the other supplements might have.

Regardless of whether the anticoagulant theory is correct, people should be aware of this effect from guaifenesin, as many other drugs and supplements also have anticoagulant effects. The combination of several such drugs could causes side effects. Too much of an anti-platelet effect can destroy platelets, resulting in a much larger release of serotonin and histamine. Also, if guaifenesin doesn't help your platelet aggregation problem, it could be that you need a different type of anticoagulant, as platelet activation is caused by several different effects. Additionally, guaifenesin's effect is dependent on how long it stays in the blood stream. However, guaifenesin is rapidly metabolized and removed from the blood, so that it doesn't necessarily make for the best anticoagulant drug. And it also has other effects which are not found in other anticoagulants.

So what are the lumps that Dr. St. Amand claims to find in his patients?

One of the main diagnostic tools which Dr. St. Amand uses to determine if a patient is correctly responding to guaifenesin, is by examining lumps which he detects on a patient. He maps the body for such lumps. While the definition of fibromyalgia includes the presence of tender points in the body, these points are not necessarily lumpy. Plus, Dr. St. Amand finds many more lumps than the number of known tender points. They literally are all over the body, not just on muscles, but also on tendons and ligaments. Such lumps are not described by any other fibromyalgia researcher, and are not a part of the description of fibromyalgia. It's perplexing that Dr. St. Amands finds these "lesions" (as he often refers to them), while no other fibromyalgia researcher has found any such abnormalities that are specific to fibromyalgia.

Some fibromyalgia researchers used to wonder if perhaps there were major abnormalities in the muscles that could be the reason for the pain. However, no major differences could be found that would be responsible for the pain. Therefore, they no longer believe that the primary cause of fibromyalgia originates from the muscles themselves, but in the neurological and immune system. Any abnormalities found in muscles and tissues surrounding them are believed to be secondary effects. Thus, any changes in the muscles do not necessarily reflect whether the primary cause of fibromyalgia is being treated.

And as an aside, even by Dr. St. Amand's own theory, he believes that these lumps are secondary to the source of fibromyalgia pain. Because he doesn't actually believe that the lumps are "phosphate deposits". This might surprise the many people who use guaifenesin, and who talk about such deposits. He believes that the excess phosphate is actually stored in all the cells of the body. The lumps are simply areas where excess calcium has been dragged into cells by the excess phosphate, causing constriction of the tissues. They aren't even necessarily painful. Dr. St. Amand only uses them as gauge to determine if the phosphate is "clearing". They by themselves aren't the source of fibromyalgia pain. And anecdotally, I've spoken with people who have taken guaifenesin for over a year, and had all their lumps reduced, creating a clear map, yet their level of fibromyalgia pain was still quite high.



But this doesn't quite make sense. Because areas of constriction, means areas of lower blood flow, and Dr. St. Amand has often said that tissues with lower blood flow, should clear more slowly. Phosphate in the other areas of the body, i.e. brain and the immune system, where the true source of fibromyalgia pain comes from, should actually clear first. The lumps should be the last areas to clear.

So what exactly are these lumps? Could they be myofascial trigger points or knots in the muscles? Possibly. However, Dr. St. Amand has stated he does not feel for areas which are painful or tender, but which are swollen to the touch. Thus, if they are swollen, another possible explaination is that they are related to edema, or water retention. E