The MTHFR – SAMe Connection and Fibromyalgia

Stuck on Acronyms?

From the heading, one might think we’re taken with acronyms.  Perhaps, in some way we are, because to say the names of the enzymes and compounds these acronyms represent is a feat in itself. Nevertheless, we’ll brave it here for your edification and tell you about a vital connection between the enzyme methylenetetrahydrofolate reductase and s-adenosylmethionine, a critical compound used in the body to regulate more than 200 enzymes.  Now you know why we use acronyms.

The MTHFR gene produces an enzyme called methylenetetrahydrofolate reductase, used by the body to convert one form of folate into the most usable form of folate for every cell in the body.  Folic acid, by itself, is useless to the body – it is ineffective and does nothing until it is transformed through various enzymes into a form that is useable, that is methyltetrahydrofolate, or, more commonly expressed in its shortened form, methylfolate.

Methylfolate is a Key Compound …

The function of methylfolate in the body is to help create neurotransmitters in the brain.  It is neurotransmitters that allow us to think, sleep, flee from danger, learn, and myriad other capabilities and functions.  If methylfolate levels are low, then so are neurotransmitters, and the end result can be conditions such as addictive behavior, depression, anxiety, ADHD, insomnia, and other issues.

… And, So is S-Adenosylmethionine (SAMe)

Along with helping to create neurotransmitters, methylfolate allows the body to make a compound that is critical to its function, s-adenosylmethionine, also known as SAMe.  SAMe helps regulate more than 200 enzymes in the body and is second only to ATP (adenosine triphosphate), the body’s power unit, in importance.  Without ATP the body dies and without SAMe, the body ceases to function as well.  A decrease in SAMe puts a person at higher risk for infertility, cancer, thrombosis and many other dysfunctions and illnesses, including chronic pain and fibromyalgia.

The question now becomes, how do SAMe and MTHFR end up in the same sentence?  The answer to that question is that is it very common for the MTHFR gene to not work to capacity because half the population (one in two people) has an area in the MTHFR gene that has an incorrect DNA base – called a polymorphism.  Poly means “many” and morphic means “shape”, which means that when an MTHFR gene has a polymorphism, the enzyme it produces has an altered shape.  This difference in shape means the function of the MTHFR enzyme is reduced which, in turn, causes a decreased neurotransmitter function and decreases SAMe production.  As we’ve learned, that is detrimental to the body’s well-being.

So, What Does All of this Mean to YOU?

A person who is suffering with fibromyalgia syndrome (FMS) deals constantly with pain and depression.  SAMe has been used in Europe for decades as a prescribed treatment for pain, depression and the effects of diseases, including FMS.  There is now good evidence that SAMe is as effective as NSAID painkillers, like ibuprofen and others, in the treatment of osteoarthritis pain, without the side effects that drugs cause.

SAMe has also been used as an effective agent against depression for people with MS and other disorders.  Some studies have found that SAMe might work as well as tricyclic antidepressants in relieving symptoms.  There is also strong evidence to support the use of SAMe as means of helping alleviate the pain of fibromyalgia, including the pain from migraines, muscle pain and back pain that is often associated with FMS.

How Much is Too Much?

There is no standard dosage established for taking SAMe supplementation at this point.  However, for depression, many studies indicated that between 400-1,600 milligrams daily is sufficient.  That is a big spread and it is always important to have the dosage recommended by a naturopathic or medical practitioner.  It is never a good idea to self-medicate. 

Is SAMe For YOU?

SAMe has been deemed a relatively safe compound to ingest.  However, there are cases where it is not appropriate to use the supplement.  As always, we recommend you check with your doctor before you start using SAMe supplements.  It may not be safe for people suffering with bipolar disorder or diabetes.  It may also interact negatively with drugs that a person may be taking.

Savella, the brand name for milnacipran HCL,  received U.S. Food and Drug Administration (FDA) approval in 2009.  Savella, an antidepressant from the selective serotonin and norepinephrine reuptake inhibitor (SSNRI) class. The drug is being produced by Forest Laboratories in New York City, as licensed by Cypress Bioscience in San Diego.

SSNRIs help neurons, or nerve cells, in the brain, to communicate with each other through the use of serotonin and norepinephrine, which are neurotransmitters. These neurotransmitters have major impact on the regulation of both mood and pain perception.

Up until then, there were only two drugs available as specific therapy for the treatment of fibromyalgia. One of these two drugs is Cymbalta, which is produced by Eli Lilly and is both an antidepressant and a pain reliever. The other drug is Lyrica, a drug produced by Pfizer. Lyrica works to control pain and seizures. Savella’s producers have announced that the new drug will be made available to U.S. pharmacies by March of this year (2009).

The American College of Rheumatology claims that the number of U.S. fibromyalgia sufferers occupies 4% of the total population. Scientists have yet to pinpoint the cause of this mysterious condition, but it becomes clearer every day that both heredity and long-term stress may be factors.

The Journal of the American Medical Association (JAMA) published the results of a study showing that traditional antidepressants like Savella reduce many of the symptoms of fibromyalgia. Marketed as Ixel and Toledomin, milnacipran (Savella) is already approved for use in many countries throughout South America, Asia, and Europe.

Rae Marie Gleason, the executive director of the National Fibromyalgia Association, a nonprofit organization located in Anaheim, California feels that none of the three drugs approved for fibromyalgia treatment, Cymbalta, Lyrica, and now Savella, provide total relief from symptoms or effect a reduction of symptoms in all patients. Gleason comments, “It’s definitely a step in the right direction, but it’s not the final answer,” and believes that researchers must continue to press on in their research, in particular in areas such as “combination treatments [combining medication with counseling and exercise] and other medicines that might come on board.”

The Experts Speak

Big News

Big news is in the cards for those with fibromyalgia syndrome (FMS), a chronic ailment characterized by chronic widespread pain, fatigue, sleep disturbances, and depression. A new drug received U.S. Food and Drug Administration (FDA) approval on January 14, 2009, lending hope for some relief for the 4% of Americans afflicted with the condition. The New York City-based Forest Laboratories, Inc., and its licensor, Cypress Bioscience, located in San Diego, California announced the approval of their drug, Savella (milnacipran HCI), a selective serotonin and norepinephrine dual reuptake inhibitor (SSNRI) for the management of fibromyalgia syndrome.

Deemed Safe

Savella has been deemed both safe and effective after undergoing two U.S. phase III trials with the help of more than 2000 fibromyalgia sufferers as participants. The studies demonstrated that doses of 100 or 200 mg. of Savella per day gave patients significant improvement in terms of pain reduction and other fibromyalgia-associated symptoms. Forest Laboratories and Cypress Bioscience believe their prescription product will be available in pharmacies by March of 2009.

Dr. Daniel Clauw, a University of Michigan professor of anesthesiology and medicine (rheumatology) comments, “Fibromyalgia is a complicated chronic pain condition, so it is important that physicians and patients have access to treatments that have been shown to help manage the symptoms that define the experience of fibromyalgia. The introduction of Savella is important because it is the first drug approved to treat the symptoms of fibromyalgia using a composite responder analysis.”

Primary Endpoint

The chairman and CEO of Cypress Bioscience, Jay D. Kranzler, MD, PhD, elaborates, “Savella is the product of a unique clinical development program, one that considered a patient to be a responder to therapy only if they demonstrated concurrent clinically significant changes in multiple aspects of their fibromyalgia, including pain, patient global assessment and physical function. Savella is the only product approved for the management of fibromyalgia that used this complete responder analysis as its primary endpoint.”

Forest Laboratories chairman and chief executive officer Howard Solomon had this to say about the new drug, “We and our partner Cypress Bioscience are very pleased to receive marketing approval for Savella, following a first-cycle review, from the FDA. Fibromyalgia is a chronic and often debilitating condition with a significant need for new therapies. Savella is a valuable new treatment for patients afflicted with fibromyalgia. Its effectiveness was evaluated based upon the multiple symptoms included in the responder analysis.”

Crucial Approval

The original producer of milnacipran, Pierre Fabre Laboratories, is thrilled about the news. Chief executive officer of Pierre Fabre SA emphasized that, “This approval is crucial for Pierre Fabre Laboratories as milnacipran is one of the flagship products of our portfolio and represents another product of Pierre Fabre research registered in the United States.”

New Drug Highlights

A great many people are excited about Savella: sufferers of fibromyalgia, their families, loved ones, employers, and physicians. But while the FDA approval has generated excitement, some are skeptical, and wonder if the drug is really safe and effective. There’s some validity to being cautious about a new addition to the pharmacists’ stock of drugs to treat fibromyalgia, but there’s not much point to being worried and concerned. It makes more sense to study up and find out on your own if Savella is worth trying. The manufacturers believe the drug will be on the pharmacists’ shelves in March 2009, so now is a good time to look at the issues and come to some conclusions.

No Lab Tests

The nature of fibromyalgia is that it eludes any standard measuring process for obtaining conclusions about a worsening or an improvement of the patients’ symptoms. There aren’t really any laboratory tests, for example, that indicate the patients’ status regarding their pain and fatigue. Physicians must rely in heavy measure on what their patients have to say about their own symptoms.

Perhaps this is why the clinical development program for trials on Savella was designed in a unique manner which revolved around the patients’ assessments of their own symptoms. For these trials it was deemed necessary that individual patients show improvement in their symptoms according to a numbered scale. The patients’ input in how they felt was considered to be crucial to the analysis of the medication. To this end, patients rated their own wellbeing with regard to three different issues: impressions of pain according to a visual analog scale, global assessments or impressions of any change in general wellbeing, as well as any progress made in terms of physical function.

Significant Improvement

In the course of the two U.S. Phase III clinical trials on Savella, 2,084 patients took part with 1,460 of them using Savella, and another 624 of them taking a placebo. A significant improvement was seen in those patients who took the medication as opposed to those treated with the placebo. The first of these trials lasted 6 months, and the second trial lasted a total of 3 months.

In each of the two studies, the majority of the patients being treated with either 100 mg. or 200 mg. per day of Savella (as opposed to those treated with the placebo) reported a 30% reduction in pain and described their condition as either “very much improved” or “much improved” after three months of treatment. The vast majority of those participants in the Savella treatment group achieved improvement in their levels of pain, physical functioning, and patient global assessment meeting the primary endpoint or goals of the trials. In both trials, some patients who were self-described as “much” or “very much” improved achieved a measure of pain reduction within the very first week of treatment.

Well Tolerated

The clinical trials appear to have given ample demonstration that Savella is both safe and easy to tolerate. However, the long-term effects of Savella are outside the parameters of these short-term studies. The main adverse reaction to the drug was found to be nausea. Other common reactions to the medication during the clinical trials included: constipation, hot flashes, excess sweating, vomiting, palpitations, increased heart rate, dry mouth, and hypertension. In general, these reactions were reported as mild or moderate in nature.

Inexpensive Relief

For some fibromyalgia sufferers, the pain is so bad, they find themselves incapacitated, spending most of their time lying on the couch or in bed. Just accepting a hug from a child or spouse causes intense discomfort. But a clinical trial begun in the spring of 2008 has participants rejoining the human race. One woman from the Stanford University School of Medicine trial has found enough relief to enable her to go back to the workplace where she does interior decoration.  She even managed to take the lead in a fundraising project at her daughters’ school. “I am really, really good,” said Tara Campbell. “Having said that, I’m still not one hundred percent. I’m still not that person I was before.”

Off-Label Use

Lucky Tara Campbell was one of only 10 participants in a beginning research study for women with fibromyalgia. The Stanford study was carried out over a period of 14 weeks with the purpose of testing an off-label use for a drug known as naltrexone. Naltrexone’s traditional use is as a treatment for opioid addiction, but has been found to relieve pain and fatigue in low doses. In general, 30% of the women in the trial found low dose naltrexone more effective than the placebo. This is according to the results posted to the April 17, 2009 online journal, Pain Medicine.

Senior author of the study, Sean Mackey, MD, PhD, an associate professor of anesthesia and chief of Stanford University Medical Center’s pain management division said, “Patients’ reactions were really quite profound,” and noted that many participants made the decision to stop taking their other medications. Others, like Tara, found themselves at last able to return to the workplace. There was an overall marked improvement in quality of life for these fibromyalgia sufferers.

In spite of these encouraging results, Mackey and colleagues are still hesitant to recommend the drug at this early stage of testing. Mackey expressed the fact that he and his team are excited about the results of the trial, but believe that longer studies with more patients are necessary for any kind of conclusion about the effectiveness of low dose naltrexone to be formed. To this end, the researchers are moving onward with a 16-week trial for 30 participants.

A Bargain

The report at Pain Medicine stated that this first study is important because there aren’t many medications on the market to treat fibromyalgia symptoms and also because low dose naltrexone is a bargain at a cost of some $40 per month. Low dose naltrexone also carries few side effects. Some of the participants described very graphic, lifelike dreams while taking the medication.

Fibromyalgia is still fighting its reputation as a controversial diagnosis. The condition is characterized by chronic muscle pain and fatigue. Those in the medical community on the side of treating the condition believe it may affect as many as 4% of the overall population. Lead author of the study, Jarred Younger, PhD, who teaches anesthesia and pain management at Stanford said, “The symptoms of fibromyalgia are commonly seen in a number of other diseases, and there is no well-established and objective blood test to confirm the diagnosis. In the meantime, new treatments that work particularly well for fibromyalgia go a long way toward validating the usefulness of the diagnosis.”

Restless legs syndrome (RLS) is a condition that often coexists with fibromyalgia syndrome (FMS) and is a major cause of sleep disturbances such as insomnia. The condition can prove difficult to treat and researchers are always on the lookout for new avenues of treatment for the debilitating syndrome which affects one in ten adults.

RLS Relief

Now, a drug that is in wide use for the treatment of seizures and anxiety has been found to give relief for sufferers of RLS. The off-label use of pregabalin appears to give restless legs syndrome sufferers a better night’s rest, claim the researchers of a recent study. This new trial was carried out over a 12 week period and involved 58 RLS patients. Out of the 58, 30 participants were treated with pregabalin, and the other 28 received a placebo. The researchers performed sleep studies at the beginning and at the conclusion of the clinical trial.

The research team discovered that almost two-thirds of those participants in the pregabalin group were symptom-free during the course of the trial. In those patients in the pregabalin group who remained symptomatic, there was still an improvement in symptoms in up to 66% while taking pregabalin, while 29% of those in the group taking the placebo said their symptoms had worsened.

Those taking pregabalin had a better night’s rest with the drug. The study demonstrated that the pregabalin group spent the most time in Stage 3 sleep, also known as slow wave or deep sleep. This same group was seen to spend less time in the lighter stages of sleep known as Stages 1 and 2 as opposed to those participants receiving the placebo.

Adequate Sleep

Study author Diego Garcia-Borreguero, MD, the director of the Madrid, Spain-based Sleep Research Institute said, “Since RLS symptoms get worse at night, it’s difficult for people with RLS to get adequate sleep. However, our findings show pregabalin helped people get more deep sleep.”

Garcia-Borreguero added that since pregabalin is well-tolerated, it may prove a practical alternative to treatments in current use for RLS and that in addition to this benefit, the drug brings about a significant improvement in sleep quality. Pregabalin is already approved for use in fibromyalgia, epilepsy, general anxiety, and nerve pain.

The symptoms of restless legs syndrome include a continuous urge to move the legs, often accompanied by uncomfortable tingling, numbness, or burning sensations. The symptoms worsen when the patient is at rest, and only a bit of short-lived relief is found when the patient resumes activity. RLS is worse at night and symptoms tend to be progressive.