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| July 2007 eNews Alert |
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Now that Lyrica (pregabalin) is FDA-approved for treating fibromyalgia pain, you may be wondering: What’s next on the horizon? Chances are, Cymbalta (duloxetine) will be the next FDA-indicated drug for FMS, although the manufacturer has recently experienced setbacks. This new type of antidepressant was released on the market about two years ago, and many fibromyalgia syndrome-chronic fatigue syndrome/myalgic encephalopathy (FMS/ME) patients are already taking it to treat their pain and fatigue. A survey of our Members in 2006 rated Cymbalta as their fifth most useful medication. Like most antidepressants, Cymbalta increases serotonin in the central nervous system, but it also raises the levels of another pain/fatigue-fighter, norepinephrine. Perhaps more interesting is the ongoing trial to get Xyrem (sodium oxybate, a derivative of GHB) approved for FMS to promote sleep. Xyrem is already FDA-approved for patients with the sleep disorder narcolepsy. And for patients who encounter too many side effects from Lyrica or don’t receive enough symptom relief, a preliminary study using a low dose of Lyrica plus Seroquel (quetiapine) may interest you. |
In this eNews Alert:
Reader-Friendly Version This eNews Alert is available for viewing and printing in a larger size. Click here to view. |
| Lyrica/Seroquel Combo Therapy |
Being able to use one medication to treat FMS would be ideal but may be unrealistic given the wide range of symptoms most patients experience. A doctor in Spain and her research team are studying a combination of medications when taken in small doses may treat several FMS symptoms. The combination includes Lyrica for pain and Seroquel for other FMS symptoms. Please visit the Latest News section of our website to read about this study (or just print it out). |
| FDA Regs: How many patients are tested? |
Now that Lyrica is FDA-approved for FMS and more drugs are being tested, you may be wondering: How long does it take for the FDA to approve a drug, and how many patients need to be tested for a particular medical condition? The process often takes about seven years, testing 1,200 to 3,000 patients. If the drug is already on the market, it can be fast-tracked through the FDA for a new indicated use in two to three years, which was the case for Lyrica. Although a large number of patients are tested, it often represents just a tiny percentage of people with a given medical condition. This is especially the case with FMS/ME in which 3-5% of the general population has this condition. For a drug to be FDA-approved for a specific medical use (even if it is already on the market for another condition), the process begins with a Phase I trial involving 20-80 patients to evaluate safety, effective dose ranges, and identify side effects. This trial is typically initiated by one investigator at one treatment center. Assuming the results are favorable, a Phase II trial involving about 200 patients is performed with the same goals in mind as the Phase I trial. However, this second study usually involves multiple treatment centers across the United States to include a more diverse population of patients that can be studied by more than one investigator. Ideally, the Phase II trial is successful and it identifies the most effective dose with the least amount of side effects. When the FDA gives a drug company the go-ahead to begin Phase III trials, this is a very promising sign that the drug might be approved for the condition or patient population being tested. Roughly 1,000 to 3,000 patients are evaluated in Phase III trials to confirm the drug’s effectiveness, safety profile, and common side effects. Often 50-100 treatment centers are involved. This FDA phase may consist of a short-term, placebo-controlled trial (two to three months) and then a six- to twelve-month trial to determine if the drug maintains its effectiveness in the long-term. Favorable results from the Phase III trials could result in the FDA’s permission to release the drug onto the prescription market or approve it for a new indicated use. After a medication is FDA-approved, the drug company must perform Phase IV trials to provide additional information to prescribing physicians. If the drug is new (i.e., it has not already been FDA-approved for another indicated use), some physicians may wait until the Phase IV trial results are published before they feel confident enough to prescribe the drug to a large number of their patients. |
| Phase III Xyrem Trials |
No doubt about it, the use of Xyrem is controversial—it’s the prescription brand name of GHB (gamma-hydroxybutyrate), known as the date-rape drug. Yet, despite the drug’s reputation on the streets, one must consider Xyrem’s potential to help millions of people with FMS, and possibly CFS/ME. Xyrem increases deep level sleep, it raises pain-fighting neurotransmitters and opioids in the central nervous system, and it increases growth hormone, which is substantially low in people with FMS but needed for tissue repair.* Can science win out against controversy? Apparently, yes because the drug is now in Phase III clinical trials. During 2004-2005, Xyrem was tested in 20 treatment centers in the United States. This Phase II trial involved 188 FMS patients and evaluated three different doses to determine which one worked best. More importantly, the FDA required that the drug not only improve sleep and reduce fatigue in FMS, but it also had to significantly improve pain ... and it did by an average of 35%. Now Xyrem is being tested at 105 treatment centers in 31 states. During the first part of Phase III testing, 1,050 patients will either be given a placebo or Xyrem for a duration of 14 weeks. Then patients who respond favorably or those who took the placebo will be given an opportunity to take Xyrem for nine and one-half months (this is the second part of the Phase III testing). If you are interested in becoming a study participant, here are a few of the key requirements:
Want to learn more about the Xyrem trials and treatment center locations? There are two different website listings for the first part of the Xyrem Phase III trial (placebo-controlled). You can click on the following two links to read more:
To find out if you are near a treatment center for the nine and one-half month study, click here. Note that some of the locations are not yet recruiting for this part of the study (probably because they have not completed the first part). If you have CFS/ME (but do not meet the criteria for FMS) and you live in New Jersey, you may be interested in the Phase I trial on Xyrem. Details can be found on the government’s Clinical Trials site by clicking here. Recruiting is almost done, but this study documents that Xyrem is being evaluated for CFS/ME patients as well. *Pardi D, Black J. CNS Drugs 20(12):993-1018, 2006. |
| Carnitine Trial for FMS |
| Carol Beals, M.D., of Lansing, MI, says that blood levels of carnitine are low in more than 50% of her FMS/ME patients and that the prescription grade of this supplement (Carnitor) reduces the symptom of fatigue (see the April 2007 issue of Fibromyalgia Network Journal).This could leave you wondering about the answer to three questions:
These and other questions were answered by a research team in Italy that conducted a ten-week, placebo-controlled, seven-center trial of carnitine involving 102 FMS patients.1 The authors of this current study point to findings of low carnitine in the muscles of FMS patients despite normal blood levels.2 This may explain why a deficiency of this nutrient strongly affects the muscles, producing many symptoms of FMS, such as muscle weakness, fatigue, and exercise intolerance. Carnitine plays an important role in producing energy by pulling fatty acids into the cell’s mitochondria that can be burned as fuel. The mitochondria’s primary function is to produce energy for the cell. Carnitine may also benefit FMS patients by transporting toxic waste out of cells so that irritating chemicals do not accumulate, leading to pain and muscle dysfunction. Half of the FMS patients (52) received a placebo and the other half (50) received acetyl-L-carnitine (or ALC). ALC and L-carnitine are both available as over-the-counter supplements, but the ALC form is better absorbed by the intestines and more efficiently crosses the blood-brain barrier to aid the mitochondria in the brain. Participants had to go off all medications for pain, such as opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and antidepressants that are often used in low doses for pain. Due to the fact that half of the patients could be placed on a placebo without the benefit of their other FMS medications, the authors did not want to extend the trial beyond ten weeks. To help reduce the time needed to see improvements from the ALC, patients received intramuscular injections daily (500 mg of ALC or placebo) for the first two weeks of the study in addition to taking two capsules daily (500 mg ALC or placebo). After the first two weeks, patients went to a regimen of three capsules per day (each containing 500 mg of ALC or placebo) for the next eight weeks of the study. Muscle pain was the most significantly improved symptom with ALC, not fatigue. Several pain measures were used, all showing an average benefit of 20%. Overall, perceptions of general health and mental well-being also improved. Patients took about eight to ten weeks to demonstrate significant relief of pain. However, it is not known how much longer it would have taken to reap the same success had the patients not undergone intramuscular injections the first two weeks. A separate study using ALC to treat the pain of diabetic neuropathy (1,000 mg three times daily) showed significant reductions in pain at the 26-week mark, and pain levels continued to decrease throughout the 52-week study.3 This is double the dose used in the FMS study, and side effect symptoms of nausea, vomiting, abdominal cramps, diarrhea, and a “fishy” body odor are much more likely to occur. The estimated cost of taking 500 mg capsules of ALC three times per day starts at $16.50 per month. What about dietary sources of carnitine? Healthy people should be able to make all of the carnitine they need from two amino acids found in protein: methionine and lysine. Small amounts of carnitine occur in animal products such as meat, fish, poultry, and milk. The most concentrated source is red meat, but you will only get about 300 mg from an eight ounce steak. Although there is no recommended daily requirement for carnitine, it is an essential nutrient for muscle function. It is readily available at the health food stores, it has the potential to reduce your pain by 20%, and you can always back down on dosage if you encounter any side effects. If you are concerned about the purity of the supplement, talk to your doctor about prescription oral tablets of Carnitor (covered by most insurance companies for the diagnosis of fatigue). Other than the cost of this supplement, what do you have to lose? 1. Rossini M, et al. Clin Exp Rheumatology 25:182-8, 2007. |
| Brain Findings Linked to Pain |
| The widespread nature of FMS pain and the presence of so many different symptoms provides a strong argument in which the symptoms stem from malfunctions in the brain. In the July 2007 Journal we described a brain imaging study that showed a significant loss of gray matter in the pain processing areas for people with FMS as compared to healthy controls. The possibility that loss of gray matter is linked to low dopamine levels in the brains of people with FMS was alluded to, and just-published research will help clarify the role of dopamine in the upcoming October Journal. After the current issue was sent to the printers, another interesting brain imaging study was published. The authors demonstrated that reduced blood flow to the right thalamus (and to a lesser extent the left thalamus) correlated with the amount of pain the FMS subjects were experiencing.* The thalami play an important role in the processing of pain-related signals entering the brain. The study involved 19 FMS patients and 25 healthy, pain-free controls. Participants filled out questionnaires to assess symptoms of depression, anxiety, and beliefs about their level of control over their pain. Previous reports in chronic pain patients show that when patients feel they have no control over their pain, they usually have a worse prognosis (trying to stay hopeful and optimistic will work in your favor). Then immediately prior to undergoing the brain imaging procedure, patients were asked to rate their pain on a scale from one to ten. In other words, this was a measure of the clinical pain they felt at the time their brain was being imaged. The higher the patient’s clinical pain rating, the more dramatic their reduction in blood flow to the thalami. In addition, more substantial reductions in thalami blood flow were observed in patients who believed that only their doctor could help relieve their pain. What about signs of anxiety or depression? These two symptoms did not influence the brain imaging findings. Taking all of these factors into account, the authors believe their brain imaging results are clinically relevant to the disease severity of FMS rather than random or unrelated findings. As more imaging studies are published to document the brains’ involvement in FMS, the credibility of people with this disease will improve and more effective therapies targeting the abnormalities in brain function will be developed. * Sundgren PC, et al. Acad Radiol 14:839-46, 2007. |
Substantial progress is certainly being made to test new and existing medications for treating FMS/ME. The participants in these clinical trials are to be commended because it takes a brave patient to go off all medications to aid investigators who are testing new treatments for FMS/ME. The willing nature and the sacrifices made by thousands of patients involved in the FDA trials are the very reasons why advances are being made. Your participation is appreciated! Even if you cannot take part in a clinical trial, you can help us by participating in a one-question survey (it’s an extremely important question). Please click here to give us your input. Wishing you better health, Kristin Thorson & the Staff of FM Network |
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