August 2003 AFSA Update
Special Update Edition

Below are the topics of all the sections in the Special Update Edition. Just click on any of the topics and this will take you to the beginning of that section.

• Nine Years at a Glance
• Objective Tests to Validate Your Pain
• The Neuroscience of FMS Pain (Includes Dr. Larson's Mast Cell Theory)
• Neuroendocrine Findings
• Brain Imaging Studies
• What's Driving Your Symptoms?
• Treatment Trials

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Nine Years at a Glance

AFSA has officially reached the million dollar mark in contributions! We have provided a steady supply of seed money for new and experienced investigators for nine years. Twenty-three projects have been funded and we are making a substantial impact on research progress in the field of fibromyalgia syndrome (FMS) and overlapping conditions such as chronic fatigue syndrome (CFS). It takes tremendous effort to recruit applicants who have a strong sense of what is patient-relevant, and who have the skills to accomplish the proposed project, but this is only one facet of our job.

While our primary focus is to fund research on FMS/CFS, our responsibilities to our donors extend beyond the distribution of award monies. Not only do we feel compelled to describe the details of each project funded, but AFSA is, and will continue to be, accountable for explaining the progress and results of previously funded studies. This is an implied promise to you, our contributor, that AFSA will follow through on every award made ... not just to the point of each project's completion, but also beyond. As you read through this Special Update Edition, you will learn how many of the investigators who have been funded by AFSA are thriving in this field of study. They have become the mentors of a new generation of researchers interested in helping you.

FMS afflicts millions of people, but an elite group of roughly 3,500 people (mostly patients) have fueled the success of AFSA in recent years. As one of AFSA's donors, we want you to feel an immense sense of accomplishment. The many milestones that AFSA has achieved are all due to your generosity. Our volunteer staff, along with our donors and funded researchers, work as a larger, more empowered team to advance the scientific understanding of FMS/CFS.

The existing treatments for FMS/CFS leave much to be desired, but as you read this Update, please note that the projects funded by AFSA are opening up new avenues of thinking, with the next step being the investigation of novel therapeutic approaches. Although most of these new pharmacological concepts will require additional seed money, we hope that you will find them worth pursuing so that someday soon you will truly feel better.

Naturally, you are entitled to ask: Why doesn't the pharmaceutical industry or NIH foot the bill for new interventions for FMS? This is a great question! Over the years, I have discovered that most drug companies don't have FMS in mind for their new products, although there is some glimmer of hope in this area. The drug companies will require more research data to convince them that investing in FMS treatment trials will payoff. As for NIH, many researchers have informed me that the "drug treatment" section of their grant proposals were axed. This is because the NIH expects pharmaceutical companies to pick up the tab, rather than the taxpayers. There are also substances naturally produced by the body that can't be patented, and therefore, no one wants to take the first step in developing them for FMS. For example, a substance produced in the brain called gamma hydroxybutyrate (GHB), enhances slow-wave sleep, doubles growth hormone secretion during the night in healthy humans, and blocks activation of the pain amplifying NMDA receptors. These are all great properties for a potential drug to treat FMS, but GHB is a regulated drug. Until more research is conducted on this substance, it will not be prescribed to FMS patients. If this situation weren't bad enough, the NIH has recently decided to cut back on its FMS/CFS awards so that it can allocate more funds to what they consider more "worthy" diseases, such as AIDS and cancer.

The information contained in this special edition is fresh and reported for the first time. With AFSA being the only charity that funds research on your illness, we understand that this places a hefty burden on you. Rest assured that you will be the first to learn about new breakthroughs funded by AFSA. As a donor, your opinions about how contibutions should be spent are welcome. It is my sincere hope that nine years from now I will be writing to you about highly effective treatments for FMS/CFS, and that AFSA will no longer be reliant upon your support!

Best wishes to all.

Kristin Thorson
Founder and President

[Back to Table of Contents]

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Objective Tests to Validate Your Pain

One must be able to effectively measure the pain of FMS in order to determine the impact of exercise or other therapeutic interventions. This may seem like an obvious concept and goal, but its implementation in FMS has always been a challenge. At the October 2002 American College of Rheumatology (ACR) meeting, AFSA-funded researcher Roland Staud, M.D., explained that one of the primary interests of his research team at the University of Florida in Gainesville is to be able to explain the pain of FMS. He estimates that tender points account for roughly 9% of an FMS patient's pain at any given time. In fact, most patients meet all 18 of the prerequisite tender points, so there is a ceiling effect when using tender points as a measure of pain. They are helpful for diagnostic purposes and they validate that a person has widespread pain, but they really don't provide an accurate measure of a person's pain level.

At the American Pain Society meeting in March of 2003, Staud presented a protocol for measuring pain that enables him to determine 49% of a fibromyalgia patient's pain at any given time.¹ This is by far much better than the 9% afforded by tender point scores! An important ingredient of the protocol involves the measurement of "second pain" or what is commonly called windup.

To fully understand the implications of Staud's previous work in assessing the impact of exercise, as well as his more recently published studies that evaluate medications, it is essential to understand windup. In fact, measurements of windup and similar objective pain tests are rapidly becoming the gold standard in FMS research. Gone are the days when study participants are simply checked for tender points and asked to rate their pain from one to ten ... so it is essential that you understand the new way of doing research. Instead of getting weighed down by the intricacies of neuroscience, just imagine yourself in the driver's seat at a busy intersection.

There are two main types of fibers in your body that transmit information to your brain about a painful stimulus in your peripheral tissues. You have your high-speed "carpool express lanes" that are A-delta fibers carrying information to your brain instantaneously about a particular stimulus. These fibers help you react quickly to potential dangers, such as withdrawing your hand from a hot surface. You also have fibers that transmit signals at much slower velocities (like cars in slow moving school zones), roughly one-tenth the speed, and they are called C-fibers. These fibers are thought to be more important in the process of windup and chronic pain states such as FMS. If you apply a heat stimulus to the hand, a person can actually feel the arrival of the two inputs to their central nervous system. It may take a bit of training on the part of the technician and the patient, but first pain (A-delta fiber inputs) can be distinguished from second pain (C-fiber inputs).

"The mechanisms that lead to chronic pain are clearly related to spinal cord mechanisms," says Staud. Indeed, another AFSA-funded researcher, Serge Marchand, Ph.D., of the University of Sherbrooke in Canada, has uncovered a defect in the diffuse noxious inhibitory control (DNIC) system that is designed to tone down pain at the spinal cord level. Staud and Marchand use different pain test procedures, but their conclusions converge: the spinal cord mechanisms in FMS patients don't work well.

The spinal cord is where the NMDA receptors and the wide dynamic range neurons reside. When the NMDA receptors are activated by incoming signals, they have the capability of amplifying pain. Also, if the pain lingers (like cars at a traffic accident), the wide dynamic range neurons can pick up the signal and transmit it to regions nearby in the spinal cord. It is similar to the situation when a traffic accident occurs on a southbound highway and the northbound travelers slow down to take a look at what is going on. Lanes traveling both north and south become congested and even the side roads become backed up with traffic. While this is an oversimplification of what happens when the NMDA receptors and the wide dynamic range neurons become involved, it forms a basis to explain how regional pain can lead to body-wide central pain. And once this widespread pain syndrome gets going, it has the ability to cause changes in the way the body processes pain (in this analogy, drivers avoid the highway altogether and begin taking the side roads). So far, scientists have not figured out how to undo these unwanted changes in the spinal cord that work to perpetuate the pain.

Although the above processes explain how the spinal cord can amplify pain (as symbolized by the traffic congestion and the sprawling detour routes), there are opposing mechanisms at the level of the spinal cord to minimize your pain. Noxious inputs can turn on the production of endogenous (internally produced) opioids to tone down the impact of the signal. This can also cause the release of noradrenaline, serotonin, GABA, or endorphins (natural intrinsic morphine) into the spinal region to reduce the sensation of pain. The problem that Staud alludes to in FMS is that the pain-amplifying or pain-facilitating systems in the spinal cord may be overpowering the pain-relieving mechanisms, and this can lead to a situation of central pain, more specifically, FMS and increased windup.

Using the analogy of cars, highways, 2-way and 4-way stop signs, yield signs, green lights, and side streets, the windup concept is illustrated in the Car Analogy Diagram (the PDF file of the diagram can be downloaded below). As the slow velocity C-fiber inputs arrive at the spinal cord, they may pile up like a traffic jam and lead to an added pain effect. Of course, in healthy humans, this pile up of pain would be promptly relieved by the body's production of opioids and other pain relievers in the spinal cord. This backlog of pain signals can be measured objectively as windup (temporal summation) and it is the additive potential for pain signals to cause enhanced pain. In the car analogy, this means a greater backlog of cars on the C-fiber Highway and side streets during a period of time because "temporal" is related to time.

The most wonderful aspect about the measurements of windup (temporal summation of pain) and DNIC activity (spatial summation of pain) is that neither are invasive test procedures. Marchand's experiments are designed to directly measure DNIC activity and the details of his work will be described later. Suffice it to say, all that is needed to measure what is happening within the spinal cord is an external extremity, such as a hand or arm. No invasive methods, injection of dyes or expensive imaging equipment is needed ... just well-trained technicians and roughly $7,000 worth of equipment that is set up by researchers who know what they are doing (e.g., Drs. Staud and Marchand).

Exercise Increases Windup in FMS Patients

In June of 1999, AFSA funded Staud $30,000 to show that exercise increases windup in patients with FMS, which may explain why you ache all over after too much exertion. The project, The Effect of Graded Exercise on Temporal Summation of Second Pain (Windup) in Patients with Fibromyalgia Syndrome, was successfully completed and published in the peer-reviewed literature for others to read.²

Exercise has always been touted as something that makes people feel great, such as the "runner's high" experienced by athletes. This is in direct opposition to the claims by FMS patients who say that their symptoms flare after too much exertion. So the focus of this study was to objectively assess pain before and after exercise by using windup as an indicator of what is happening at the level of the spinal cord. Please refer to the diagram of the car analogy, and to the table at the end of this section which summarizes the study and its findings.

Click here for the Car Analogy Diagram (PDF)

"Exercise activates opiate and noradrenergic systems in proportion to the magnitude and duration of the exercise," writes Staud and coworkers in his published report on the AFSA-funded project. These endogenous pain-relieving systems should reduce the intensity of painful sensations, and using this logic, exercise should reduce pain sensitivity. Yet, there is a twist to the situation. Short-term acute stress is known to trigger the pain-relieving system, but chronic stress increases pain sensitivity (which may be a similar situation to persistent FMS pain). So Staud's study was designed to look at the effects of maximal exercise on pain sensitivity in healthy pain-free control subjects and patients with FMS.

The study design directly compared the effects of strenuous exercise on clinical pain and on the additive effects of second pain (windup or temporal summation) when exposed to a repetitive experimental pain stimulus. The working hypothesis was that the endogenous inhibitory systems designed to control pain would not be effectively mobilized by exercise in patients with FMS. In other words, a pile up of pain signal inputs, such as the traffic jam analogy, was expected to be measured as increased windup in the FMS test group. In addition, it was hypothesized that the effects of exercise in patients with FMS would cause an exacerbation of clinical pain (how patients said they felt).

Remember, it is second pain that arrives by the slow-velocity C-fibers; first pain is ten times faster. With second pain arriving in such a delayed fashion, if one undergoes a process that causes repeat stimulation (such as exercise or repeat stimulus testing), then the spinal cord mechanisms will not get a break from the inputs. The repeated inputs to the spinal cord will continue to add up or build up to what is called temporal summation or windup (again, visualize this as a pile up of cars in heavy traffic, except here we are dealing with a pile up of C-fiber inputs). The effects of first pain will likely vanish immediately, so that the A-Delta fibers are not the focus of the study's measurements. If the pain stimulus interval is at least 3 seconds apart, Staud's group found that second pain on the "C-fiber Highway" vanishes in healthy control subjects.³ Remember, it is first pain that usually vanishes and second pain has the potential to linger if the amplifying systems in the spinal cord are turned on (i.e., the NMDA receptors) and/or the pain-relieving systems are not activated (i.e., release of the body's opioids and other substances) ... which is the hypothetical case for FMS.

Providing a repetitive pain stimulus (varying from 2 to 5 seconds apart) before and after exercise, Staud and coworkers were able to determine the degree to which the endogenous inhibitory mechansims pitched in to moderate the pain produced by a 15-minute exercise program (both mild and strenuous intensities were tested). Ratings of repetitive painful stimuli after exercise were also measured for each group (healthy and FMS subjects) to determine how the two groups felt between 1.5 and 10 minutes after the exercise program.

In the healthy individuals, the endogenous inhibitory mechanisms appear to have been activated because exercise significantly reduced their pain when given repetitive heat stimulus testing to their hand 1.5 minutes and 10 minutes after exercise. The endogenous opioid effects were most apparent soon after exercise (the post-exercise test 1.5 minutes later), but it also reduced pain up to 10 minutes following exercise. This "feel great" finding was more substantial after the subjects performed strenuous exercise, but it also occurred to a lesser degree after mild exercise (performed on a different day). This means that the endogenous pain-inhibitory system was working well in healthy subjects to keep the traffic moving swiftly so that pain signals didn't "pile up" to amplify the pain. In other words, they didn't lead to problems of windup.

There was no difference between healthy males and healthy females on the improvements in pain threshold and no detection of windup when their hand was subjected to a repeat heat stimulus at 3 second intervals or greater. This is important to note because it means that this test of windup is not influenced by gender. But when it came to FMS patients, the findings were completely different.

Baseline testing of both pain-free and FMS patients confirmed Staud's previous finding that FMS patients have increased pain at rest that can be objectively measured as windup or temporal summation. "In addition," write the authors, "temporal summation was evident for subjects with FMS at slower repetition rates than for pain-free subjects." This means that the closer the interval for the painful heat stimuli, the greater the differences detected between healthy pain-free subjects and FMS patients.

Now, what about the results of testing after exercise? As already mentioned, exercise in healthy subjects caused an activation of the pain-relieving opioid system, even for mild exercise. For the most part, the opposite effect occurred in patients with FMS; the endogenous inhibitory system was either not activated or it was overpowered by the pain-facilitating system (e.g., activations of the NMDAs). Exercise caused an exacerbation of pain in FMS patients, and more importantly, it led to increased windup or temporal summation of pain, which can be measured objectively.

Asking Dr. Staud about the most crucial point made by his study on exercise, he says, "The important information from this research included the fact that exercise does not attenuate windup (or temporal summation of pain) compared to normal pain-free controls, but it increases windup. This finding emphasizes abnormal pain mechanisms in FMS and may explain the increased pain sensitivity that FMS patients experience with exercise."

The AFSA-funded pilot study not only won an award at the 2001 American Pain Society meeting, but also enabled Staud (along with his colleagues Charles Vierck, Ph.D., and Donald Price, Ph.D.) to receive funding from NIH to further his work to objectively measure windup in FMS patients receiving dextromethorphan and fentanyl. Dextromethorphan is a weak NMDA receptor antagonist and fentanyl is a mu-acting opioid agonist (acts like an opioid), which is the key ingredient in the Duragesic Patch.

The findings by Staud on these two drugs were presented at the ACR meeting in October of 2002. Preliminary work was published this year in PAIN as well as in abstract form at the 2002 ACR and 2003 APS meetings.^4,5,6 Staud found that both dextromethorphan and fentanyl (tested individually) were each effective in reducing windup in patients with FMS. Although the results were only obtained with one-time dosing of each drug, the results are promising and Staud hopes to expand his studies to longer-term treatment trials in patients with FMS.

Windup/Temporal Summation

• Temporal relates to time
• Summation is additive effect
• Measures ability of pain-processing systems in spinal cord to handle a repetitive stream of noxious inputs produced at timed intervals
• Windup (temporal summation) is the additive effect of the repeat stimuli; it's detected as an increase in pain sensation with time (as the stimuli continue to be applied).
• Healthy individuals do not detect any increase in pain with repeat stimuli at 3 second intervals or greater; their pain-inhibitory system works to obliterate the pain
• If repeat stimulus is generated at intervals less than every 3 seconds, healthy individuals begin to experience windup (it's painful and they tell the pain tester to stop the stimuli).
• Windup effects are independent of gender–the response is the same for healthy males and healthy females.
• FMS patients have increased windup at rest (the repeat noxious stimuli, even when spread out to every 5 seconds, becomes very painful to FMS patients).
• AFTER EXERCISE (funded by AFSA)
  • Healthy subjects: stimulates endogenous pain-relieving system and produces a "feel great" effect that can be measured as increased pain threshold
    
  • FMS patients: The pain-inhibitory system is not adequately activated, leading to activation of the pain-facilitating system. Result: increased windup (more so than at rest), patients experience enhanced pain with repeat stimulus testing.
• AFTER FENTANYL (funded by NIH)
  
  • Fentanyl is an opioid-like substance and the active ingredient in the Duragesic Patch; administration reduced windup, presumably by aiding the pain-inhibitory system.
• AFTER DEXTROMETHORPHAN (funded by NIH)
  
  • Dextromethorphan is an NMDA receptor antagonist; administration reduced windup, presumably by minimizing the pain-facilitating system.

Diffuse Noxious Inhibitory Control (DNIC) System
... it's the pain "traffic controller" in the spinal cord

So far, we have discussed the body's response to a repetitive painful stimulus to look at its additive effect on a person's pain. In the pain literature this additive effect with time (like the cars piling up) is called temporal summation or windup. In healthy people, windup is not much of a problem because the C-fiber signals arriving at their spinal cord activate the pain-relieving or diffuse noxious inhibitory control (DNIC) system (opioids, noradrenaline, etc.). The pain-facilitating or amplifying system (i.e., NMDAs) is not activated. So healthy humans handle the signals as they arrive, and nothing accumulates to cause problems. Yet, preliminary findings from an AFSA-funded project indicate that the system doesn't work like this in people with FMS. Now, in order to fully appreciate the research by Serge Marchand, Ph.D., another AFSA-funded investigator, it is important to grasp the concept of spatial summation.

Spatial summation of pain is related to the amount of surface area stimulated. The greater the surface area stimulated, the greater the pain intensity one should feel based on pure intuition. However, the body has a DNIC system that operates by sending inhibitory signals from higher centers in the brain stem, down into the spinal cord and it can inhibit pain signals or filter them out before they reach the pain-processing centers in the brain.

How does the DNIC system actually work? When the C-fiber signals arrive in the central nervous system, it poors out endogenously produced opioids, noradrenaline, serotonin, and GABA. These substance originate in the brain stem and then work in the spinal cord. The DNIC is the pain-relieving system already described in the previous sections on windup. Opposing the DNIC are the pain-facilitating (or amplifying) abilities of the NMDA receptors and wide dynamic range neurons. Of course, substances that activate the NMDAs would also be part of this pain-facilitating system, such as substance P, nerve growth factor, and excitatory amino acids. The involvement of the excitatory amino acids is unclear, but both substance P and nerve growth factor are greatly increased in the spinal fluid of patients with FMS.

So once again, we have the two opposing pain-inhibitory and pain-facilitory systems, but one of the basic goals of the AFSA-funded project was to measure the subject's response to increasing the amount of surface area exposed to a heat stimulus. In June of 2000, AFSA awarded $49,407 to co-investigators Serge Marchand, Ph.D., and Pierre Arsenault, M.D., Ph.D., for a multi-faceted project entitled: The Role of DNIC in FMS Pain and Treatment. Marchand and Arsenault were at the University of Quebec, but have since moved to the University of Sherbrooke where Marchand is chairman of the chair in pain neuroscience.

The first aim of the AFSA project was to validate that DNIC function could be accurately tested in healthy men and women, and to provide a larger comparison group of healthy controls. This portion of the project was published in 2002.⁷ The second aim of the project was to test the DNIC of people with FMS and another group of patients with low back pain (a regional pain syndrome). This part of the study is also completed has been presented at the IASP meeting (Julien et al., 2002).⁸ It is now in preparation for publication. The third aim of the study involved a treatment trial using Effexor-ER, in which the DNIC of FMS patients was tested before and after an eight-week trial period. Effexor-ER increases the central nervous system levels of serotonin and noradrenaline, although its impact on serotonin is more substantial. This final portion of the project is now completed and it's being written up for formal publication.⁹

Instead of using a thermal tapping on the hand (as in Staud's work), Marchand's experiments use a bath of circulating water maintained at a specified temperature. He evaluates the effects of what happens when a person increases the amount of their arm submerged into the bath. Remember, that intuitively, one would expect that the greater the amount of the arm submerged (greater surface area), the greater the person's pain intensity rating. If you look at the generalized diagram below, the line for the healthy controls should be a straight diagonal line, increasing upward with increased amount of arm submerged. However, this is not what Marchand found. In healthy people, their DNIC system is activated to provide pain relief despite being subjected to a greater surface area of pain stimulus.

How does the term spatial summation come into play? It is the additive effect of pain unpleasantness when one's arm is submerged in either a hot or cold water bath stimulus (see diagram). If the DNIC system kicks in, as it does for healthy individuals, there isn't much spatial summation because the pain intensity plateaus off. The situation is different for FMS, in which the pain intensity continues to increase as greater portions of the arm are submerged. This causes increased spatial summation, which mathematically is the area under the curve in the graph.

Marchand was kind enough to share with AFSA contributors the role that his funding by AFSA has played in his career, that of new FMS researchers working with him, how the results should lead to a better understanding of FMS, and generate other exciting areas of interest.

What the award meant to us:
Writing grant proposals is a time-consuming task, but it is a necessary step for pursuing a career as a researcher. So whenever a charity, such as AFSA, awards money for a project that a researcher is interested in performing, it has special meaning. First, it proves that a group of people, in this case those affected by the chronic symptoms of FMS/CFS, believe in our work. It is of special importance to us to know that we have the support of the people that we are hoping to help with our investigations. Second, being funded by an organization that employs a formal grant review process consistsing of many of the leading researchers in the field signifies to us that we are judged to have the capacity to perform the proposed project, collect the necessary data to seek larger sums of money from other granting institutions, and to guarantee that the development of our understanding of FMS/CFS proceeds with the goal of better treatments in the long run. Finally, grants from charitable associations are treatment oriented; they provide researchers with the ability to perform studies that will have clinical implications (i.e., patient-relevance).

What it enabled us to do:
With the grant from AFSA, we were able to collect enough data to have results for thirteen medical conference presentations, one paper published,⁷ and two papers in the preparation stage.^8,9 In parallel with our AFSA-related work, we began researching the role of sex hormones in pain, because we believe that they are related to our interest in understanding more about the pain mechanisms involved in patients with FMS. We recently published one paper on this topic,¹⁰ and we have several projects ongoing.^11,12,13

A good measurement of the interest of a research team for a particular topic is directly related to the number of graduate students working on a project related to that topic. We have one PhD student investigating the role of endogenous pain modulation in fibromyalgia (Nancy Julien) and one PhD student doing fundamental research in animals on the role of sex hormones (Isabelle Gaumond). We have one more student starting his PhD on the role of sex hormones in human pain (Itachi Falanga). An MSc student has just joined our team to look at the differences, as well as the similarities, between the chronic pain mechanisms involved in fibromyalgia, low back pain, and irritable bowel syndrome (Yannick Tousignant-Laflamme). We also have a colleague (Jacques Charest) supervising a student (Claire Beaudry) who is obtaining her master's degree on the role of adapted physical activity on pain in people with FMS. As one can easily see, we are in the process of expanding our research in the field of understanding the neurophysiological mechanisms of fibromyalgia by enlarging our team of researchers interested in helping individuals with FMS.

Project Results; Future Directions

Spatial summation and pain
A model using spatial summation as a way to objectively measure the role of the endogenous pain modulation systems in healthy men and women has already been published.⁷ We have just submitted the next paper in which we demonstrate that FMS pain is related to a deficit of the endogenous pain-inhibitory mechanisms (the DNIC system) while chronic low back pain is not. These results may explain why the pain of FMS is diffuse rather than regional in nature. A deficit of the diffuse noxious inhibitory control (DNIC) systems can lead to heightened pain sensitization (hyperalgesia) and pain following non-painful stimulation (allodynia). Understanding the role of a deficitive DNIC system in fibromyalgia as well as the impact of supplementing the neurotransmitters involved in this system, such as serotonin (5HT), noradrenaline (NA) and endogenous opioids (this includes such compounds as endorphins and enkephalins - ENK ), would help in the development of more effective treatments. In addition, our spatial summation model enables us to test the effect that these agents have on the DNIC system in people with FMS.

Differences and similarities between fibromyalgia, chronic low back pain, irritable bowel syndrome (IBS), and depression.
The goal of this AFSA-related project is to identify the specifics of FMS mechanisms by studying different aspects of the neurophysiology of pain in patient groups that share some symptoms with FMS. They all suffer with chronic pain and/or depression to varying degrees, and in some cases they also exhibit diffuse pain (such as FMS and IBS). Nancy Julien, M.Sc., is completing her PhD work on this topic and has just submitted a paper to be considered for publication.⁸ Yannick Tousigant-Laflamme, PT, has joined our team and will be doing his MSc on this subject as well. Comparing the different pathologies involved in these conditions will permit us to better understand them and should lead to the development of specific treatments based on mechanisms rather than solely on symptoms.

Treatment with Effexor: DNIC Function and Clinical Symptoms of FMS
The DNIC system uses endogenously produced opioids, serotonin, noradrenaline, GABA, and other pain-fighting substances to tone down the noxious inputs at the level of the spinal cord. Given that low serotonin and noradrenaline levels have been reported in the spinal fluid of patients with FMS, it makes sense to test the effectiveness of a drug that raises the central nervous system levels of these two substances. Effexor primarily increases serotonin (5HT), but it mildly elevates noradrenaline (NA) levels as well.

An elaborate 9-week, blinded and placebo controlled trial of Effexor in patients with FMS was just completed. The cross-over design meant that all 25 FMS patients were tested on the Effexor and the placebo (just a sugar pill in this case). Throughout the study period at set intervals, the DNIC function (or spatial summation) was evaluated for each patient. We are now at a point where we have a massive amount of data to analyze. We wish to take a careful look at who responded to the Effexor and if their response correlated with changes in their objectively measured DNIC function, or spatial summation. Naturally, we will be evaluating the dosage most commonly taken by patients and the most frequent side effects reported. Our goal is to be able to correlate as much of our data to clinical improvements, since the primary objective of our ever-expanding research team is to find out how to help chronic pain and FMS patients feel better.¹⁰

The role of sex hormones
Several arguments implicate sex hormones in pain perception and in the development of some chronic pain conditions. Many studies demonstrate that pain thresholds vary across the menstrual cycle in women (higher threshold in follicular phase).^14,15,16 In other words, women experience less pain during the first half of their cycle which is dominated by estrogen. Greater pain levels are usually experienced in the second half of the cycle, which is dominated by progesterone. Moreover, the onset or the remission of some chronic pain conditions varies across lifetime; boys and girls have the same pain thresholds and the same prevalence of pain conditions before puberty.¹⁷ Furthermore, women present an increase in pain thresholds and increased levels of analgesia during pregnancy.^18,19 Finally, it is well established that receptors for sex hormones have a wide distribution in the central nervous system where they can modulate the pain-transmitting pathways and/or endogenous pain-inhibitory systems, such as DNIC.^20,21,22 Isabelle Gaumond, M.Sc., of our research teams has shown that in rats, both female and male sex hormones modulate pain perception and that female sex hormones seem to play a pro-nociceptive (pain-facilitating) role while male sex hormones appear to play a protective or pain-inhibitory role.¹⁰ Isabelle Gaumond is now a PhD student and will continue her investigation of the role of sex hormones in relation to various structures in the brain that could be playing a pain-modulating role. She will also employ brain imaging techniques (MRI) in her research projects. Our new PhD student, Itachi Falanga, M.Sc., will continue to work on the role of sex hormones as they relate to pain in humans.

The results of these projects will help improve our understanding of the role of sex hormones and pain, as well as the relation between sex hormones and certain neurotransmitters implicated in fibromyalgia (5HT, NA, ENK). These results could lead to the development of combined hormone therapy with pharmacological treatments in FMS.

DNIC Function/Spatial Summation

• Spatial relates to surface area
• Summation is additive effect
  
• Spatial summation is the additive effect of increasing exposure to hot or cold water stimulus
  
• Intuitively: the greater the surface area exposed to the hot/cold temperature, the greater the perceived pain intensity
  
• DNIC Influence: As increasing surface area is exposed to painful hot/cold water, the DNIC system minimizes pain intensity by pouring out opioids, serotonin, noradrenaline, etc.
  
• Healthy individuals (both male and females) exhibit the DNIC influence
  
• AFSA-FUNDED
  - DNIC in healthy people similar to low back pain (regional pain syndrome) but not FMS patients (diffuse pain syndrome), in preperation
  - Impact of Effexor (serotonergic, noradrenergic drug) on FMS pain and DNIC response, data being analyzed for publication
  
• RELATED RESEARCH
  • The DNIC system may be more pronounced in healthy males as opposed to females because it is likely influenced by hormones such as testosterone.
  • An animal study recently coauthored by Isabelle Gaumond, Ph.D., indicates that testosterone may have a protective pain effect, while female hormones, estrogen and progesterone, exert more of a pain-facilitory effect (in other words, making the pain worse). This may help explain the female predominance of painful disorders. Fortunately, this study supports the concept that the problem may not be caused by the structure of the central nervous system, but rather, the way the hormones influence the nervous system's response to painful stimuli. In other words, female rats whose ovaries have been removed can be placed on testosterone and their pain responses will mimic those of male rats.
  • Human studies using hormonal manipulation to minimize pain are in the planning stage.

Conclusion

There is no question in my mind, or that of my colleagues and students, that the AFSA grant played a significant role in starting our research in FMS. Your support is well appreciated, and will lead to advances in both the fundamental and clinical research aspects of fibromyalgia.

References

1. Staud R, Robinson M, Price DE, Vierck C: Central Sensitization Predicts Clinical Pain in Fibromyalgia. J of Pain 4(2 suppl 1):8, #667, 2003.
2. Vierck CJ, Staud R, Price DD, Cannon RL, Mauderli AP, Martin AD: The effect of maximal exercise on temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. J of Pain 2(6):334-344, 2001.
3. Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD: Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 91(1-2):165-175, 2001.
4. Staud R, Robinson ME, Vierck CJ, Price DD: Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 101:167-174, 2003.
5. Staud R, Robinson ME, Mauderli AP, Cannon RL, Vierck CJ, Price DD: Opioids modulate the enhanced temporal summation of second pain of fibromyalgia patients. Arthritis & Rheum 46(9 suppl):S396,#1027, 2002.
6. Staud R, Robinson M, Mauderli A, Cannon R, Vierck C, Price D: Dextromethorphan Attenuates Thermal Wind-Up of Fibromyalgia Patients. J of Pain 4(2 suppl 1):20, #667, 2003.
7. Marchand S, Arsenault P: Spatial summation for pain perception: interaction of inhibitory and excitatory mechanisms. Pain 95(3):201-206, 2002.
8. Julien N, Arsenault P, Marchand S: Spatial Summation in Pain Perception: Deficits of endogenous pain inhibition in fibromyalgia but not in low-back pain. IASP, San Diego, 782-P52, 2002.
9. Julien N, Arsenault P, Marchand: Overview of Fibromyalgia Treatments. American Pain Society, Phoenix, AZ, April 2001. For more details, see Web site at: www.afsafund.org.
10. Gaumond I, Arsenault P, Marchand S: The role of sex hormones on formalin-induced nociceptive responses. Brain Research 958(1):139-145, 2002.
11. Gaumond I, Arsenault P, Marchand S: The role of sex hormones supplementation in male and female rats on nociceptive responses. American Pain Society, Atlanta, GA, November 1-4, 2000.
12. Gaumond I, Arsenault P, Jasmin P, Marchand S: The role of sex hormones in rat nociceptive responses. Society for Neuroscience Abstracts, New Orleans, LA, November 4-9, 2000.
13. Gaumond I, Arsenault P, Marchand S: Stress induced analgesia: Sex hormones specificity on noradrenergic and serotoninergic brainstem neurons. IASP, San Diego, August, 2002.
14. Berkley KJ: Sex differences in pain. Behav Brain Science 20(3):371-380,1997.
15. Fillingim RB, Maixner W, Girdler SS, Light KC, Harris MB, Sheps DS, Mason GA: Ischemic but not thermal pain sensitivity varies across the menstrual cycle. Psychosom Med 59(5):512-520, 1997.
16. Riley JL, Robinson ME, Wise EA, Price DD: A meta-analytic review of pain perception across the menstrual cycle. Pain 81(3):225-235, 1999.
17. Robinson JE, Short RV: Changes in breast sensitivity at puberty, during the menstrual cycle, and at parturition. British Med Journal 1(6070):1188-1191, 1977.
18. Cogan R, Spinnato JA: Pain and discomfort thresholds in late pregnancy. Pain 27(1):63-68, 1986.
19. Gintzler AR: Ovarian sex steroids activated antinociceptive systems and reveal gender-specific mechanisms. Sex, Gender and Pain. Fillingim RB (Ed.). Vol. 17, pp. 89-108, Seattle, 2000.
20. Aloisi AM: Sensory effects of gonadal hormones. Sex, Gender and Pain. Fillingim RB (Ed.). Vol. 17, pp. 7-24, Seattle, 2000.
21. Amandusson A, Hallbeck M, Hermanson O, Blomqvist A: Estrogen-induced alterations of spinal cord enkephalin gene expression. Pain 83(2):243-248, 1999.
22. Smith SS: Female sex steroid hormones: from receptors to networks to performance—actions on the sensorimotor system. Prog Neurobiol 44(1):55-86,1994.

[Back to Table of Contents]

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The Neuroscience of FMS Pain (Includes Dr. Larson's Mast Cell Theory)

Wouldn't it be nice if every neurochemical abnormality in FMS was known and all researchers had to do was figure out a way to fix them? We aren't to that point yet ... but scientists are working hard to reach this goal. At a March 2003 meeting on pain, neuroscientist Alice Larson, Ph.D., described a potential model for FMS. Her model, described below, takes into account every neurochemical abnormality known in this condition, as well as the variety of symptoms. Larson's model is complex, but for any patient that lives and breathes with this illness, this should come as no surprise! There is nothing easy about FMS, but it is reassuring to read about the tenacity with which the researchers in the field are masterminding theories and developing hypotheses that would not have been conceivable ten years ago.

The field of neuroscience and its relationship to FMS pain is rapidly expanding. As you read about the studies performed by Drs. Larson, Russell, Stewart and Jasmin, you will note that their AFSA-funded projects played an important role in the developing theories pertaining to the neuroscience of FMS pain. There are still many avenues to be pursued, as is evident from Larson's speech, but progress is being made and the groundwork for effective therapies is being constructed!

A Possible Cause of Fibromyalgia
Based on speech by Alice Larson, Ph.D., University of Minnesota Focus on Pain meeting, March 9, 2003 in Orlando, Florida

If one were to develop a research model to explain what is happening in FMS (even if it is just on paper), it must account for many essential factors that occur in this condition. For example, the pain is chronic, and yet, Larson says that most of the models used by scientists for testing pain are for acute pain scenarios. The results found by these models can't be extrapolated to FMS. Another problem that makes developing a model for FMS difficult: "Pain is just one component."

Elaborating on the other components of FMS, Larson says exacerbation of symptoms by stress, as well as triggering the onset of FMS by trauma, surgery, or infections (all of them stressors), can make it more difficult to conceptualize a model for FMS. The cause of the pain is always described by patients as coming from the muscles and yet there doesn't appear to be any damage to the muscles. Even at the characteristic tender points, there appears to be no tissue damage. The tender points also happen to occur in areas of the body where there is very little innervation (not many nerve fibers in the region). "This is a big paradox," says Larson, because one would expect that areas with lots of nerve endings should generate more pain. "Another facet that is paradoxical about FMS is that it is symmetrical, and that hints at the fact that it is probably centrally mediated." Sleep disorders are also common in FMS, which again points to the fact that this is not just a pain syndrome.

Essentials for an FMS Model:

• Serotonin and tryptophan low in blood
  
• Dynorphin elevated in spinal fluid
  
• Threefold increase in spinal fluid substance P
  
• Fourfold increase in spinal fluid NGF
  
• Widespread hyperalgesia or enhanced pain sensitivity
  
• Symptoms exacerbated by stressors
  
• No obvious tissue damage
  
• Symmetrically located tender points
  
• Sleep disorder
  
• High female predominance
  
• Symptoms influenced by sex hormones
  
• Altered blood flow to the thalamus in response to stimuli

Biochemical Factors

Before describing her model, which is basically a description of the processes that may be causing FMS, Larson first identified a number of biochemical factors that are already known about this condition. After all, any conceptual model for FMS would have to account for these abnormalities. Serotonin and its precursor, tryptophan, are low in the blood of patients with FMS. Dynorphin, an opioid compound that alleviates pain in low concentrations but produces pain at high concentrations, is elevated in the spinal fluid of people with FMS.¹ Several different investigators have reported elevated levels of substance P in the spinal fluid of individuals with FMS. Larson points to this finding as being the first objective indication "that this is a painful disorder and not something that is in the patient's mind." Although she talks about FMS as being centrally mediated, she is referring to the brain structures and certainly not the mind. "Fibromyalgia is in my mind because I am thinking about it, but it is in the patient's brain. That's an important distinction!"

Going back to substance P, how and why is it elevated in the spinal fluid of FMS patients? "We knew that substance P was elevated, but there was no tissue damage at the tender points, so where was this substance P coming from?" posed Larson. "Usually, when you have tissue damage, nerve growth factor (NGF) is synthesized in the area of the tissue damage or trauma. Then the NGF molecules are transported back to the cell body (located alongside the spinal cord) and the presence of NGF causes enhanced synthesis of substance P in the spinal fluid. But this can't be happening if there is no obvious tissue damage in the periphery. So, our hypothesis was that the NGF was already elevated centrally" (e.g., in the spinal fluid).

Larson's initial involvement in FMS research centered around testing her hypothesis that NGF was elevated in the spinal fluid of patients with this condition. She knew from prior studies that NGF increased pain sensitivity (hyperalgesia) and speculated that this may be the problem within the spinal fluid of patients with FMS. Larson's published results indicated that her hunch was correct.² NGF in the spinal fluid of healthy control subjects was compared to patients with "primary FMS" (no other medical problems besides the FMS or what researchers call primary FMS). The primary FMS patient group had a fourfold increase in NGF. But it's known that roughly 30% of patients with lupus and rheumatoid arthritis also have the widespread pain of fibromyalgia that tends to develop "secondary" to or after the onset of these other autoimmune conditions. Do these patients with "secondary FMS" also have elevated NGF in their spinal fluid? Larson separated the two FMS patient groups into primary and secondary FMS, and found that the NGF levels in the "secondary" group were the same as those of the healthy controls; they were normal. What does this tell us? "It just means that there may be a different etiology (cause) for the fibromyalgia in the secondary FMS group."

"What could possibly be the source of elevated NGF in primary FMS?" asks Larson. Of equal importance, one has to wonder: Does the elevated NGF cause the elevation in substance P and the other symptoms seen in people with FMS? Providing answers to these essential questions was the main focus of Larson's AFSA-funded project awarded in 1998. Larson administered NGF into the spinal fluid of mice and then measured their responses to a number of tests. For example, she looked at tail flick latencies, which is the time it takes for a mouse to respond to a thermal stimulation of the tail. After the infusion of NGF, the mice responded much quicker and this hypersensitivity state lasted for several days. Further details of the AFSA-funded study are provided in the article that follows. Suffice it to say, elevated NGF in the spinal fluid does cause hyperalgesia, but the situation is much more complex.

"We could have just administered NGF to our mice and said, ‘This is our model for fibromyalgia' because it produces hyperalgesia," claims Larson. But as she has already pointed out, FMS is not just a pain sensitivity problem—it is so much more. Further evaluation of the mice revealed that stress did not intensify their pain, they did not exhibit any evidence of a sleep disorder, and they did not have any of the other symptoms often associated with FMS in humans. Basically, Larson was successful in generating a chronic pain model, but it was not a model for FMS. Many of the associated symptoms of FMS were missing and the presence of elevated NGF in the spinal fluid could not be explained. Ordinarily, NGF is generated in the periphery when there is damage to the tissues, and then it is transported back to the spinal fluid by the neurons that are in the area of the tissue trauma. Yet, significant tissue damage is not seen in patients with primary FMS, so this ruled out peripheral NGF as the cause of the syndrome. (In fact, Larson's research casts doubt on the strongly held notion that elevated levels of substance P and NGF cause FMS. These substances likely play a role in generating the symptoms of FMS, but something else is causing their elevated production.)

What if the "damage" occurred within the central nervous system? This would produce elevated NGF in the spinal fluid. However, Larson says that situations that could cause a significant elevation of NGF would have to be very dramatic, such as meningitis, and this just is not seen in FMS patients. Spinal stenosis (a narrowing of the spinal canal caused by disk or vertebrae impingement) could possibly contribute to a small fraction of people with FMS, but certainly not all of them. Something else has to be causing the elevations of NGF.

Mast Cells in the Thalamus

After performing an extensive literature search, Larson says she was "excited when she ran across the fact that there are cells within the central nervous system (CNS) that can synthesize NGF. Those are mast cells." Mast cells are usually located in areas of inflammation or allergic reactions. They are created from bone marrow and shipped out to the tissues as part of the immune response system and Larson says, "You don't think of mast cells as being in the CNS." She adds that because their function in the CNS is not understood, it is easy to overlook them.

As it turns out, the mast cells aren't just scattered randomly throughout the CNS; they are concentrated in the thalamus. This would make sense for FMS. The thalamus influences the function of the hypothalamic-pituitary-adrenal (HPA) axis, which is one of the body's primary stress response systems. The thalamus is also involved in pain transmission, sleep modulation, and many different sensory pathways such as hearing and vision. When pain signals travel up the spinal cord neurons en route to the brain, they arrive at the thalamus (via the spinal-thalamic tracts) and from there, the signal is relayed by the thalamus to various parts of the cortex. The thalamus appears to be the area where there are problems in FMS, and this just happens to be where the NGF-producing mast cells are located in the mammals studied thus far.

The location of the mast cells appears to be consistent with FMS findings, but what about the elevated levels of substance P in the spinal fluid? Is there a link between the mast cells in the thalamus and elevations in substance P? As it turns out, the substance P-containing fibers that are known to transmit pain can also attract mast cells like a magnet attracts iron particles. In addition, substance P is known to "degranulate" or break mast cells apart. This happens when the mast cells are activated (by the substance P) and it causes a release of their contents, which in turn, leads to inflammation and histamine buildup in the region. It's also important to note, mast cells are not like white blood cells, which get activated, become degranulated, and then they are history. Mast cells degranulate in the presence of substance P, but then they often turn around and resynthesize their granular contents, and they are back in action. They go through this process countless times and have a relatively long life in the body.

The foregoing explanation of how mast cells operate, especially when activated by substance P, is well-documented for mast cells in the peripheral tissues. Yet, FMS is a problem within the CNS, where substance P and NGF are elevated. Not as much is known about how masts cells operate in the thalamus, but Larson hypothesizes that it is similar to that in the periphery. In other words, substance P causes degranulation (or a bursting) of mast cells in the periphery, so substance P is thought to exert the same effect on the mast cells in the thalamus. With an abundant supply of substance P in the spinal fluid (threefold elevation in FMS), it may be able to cause continual degranulation of mast cells in the thalamus and trigger a cascade of symptoms ... possibly FMS.

How Does the Theory Hold Up?

In order for the thalamic mast cell hypothesis to hold up, these cells need to respond in a fashion that mimics the clinical symptoms and findings in people with FMS. First, it is known that these cells produce NGF, which can then trigger the production of substance P. This could account for the elevated levels of these two compounds in the spinal fluid of FMS patients. Secondly, as Larson presented her model, she addressed the following six factors: (1) symptoms triggered and/or made worse by stressors, (2) gender differences to explain the high female predominance, (3) hormonal influence (women with FMS anecdotally claim that symptoms are worse during the second half of their menses cycle), (4) blood flow changes in the thalamus, (5) modulation of sleep function (sleep is often disturbed in people with FMS), and most important of all, (6) modulation of pain. A brief rundown of how each factor fits into the model is provided in the paragraphs that follow.

Mast cells are most commonly known to rush to the site of parasitic infections and places where allergic reactions occur. This automatic response to these types of stressors causes mast cell degranulation (e.g., breaking apart to expose their guts) and a series of immunologic reactions, such as inflammation and histamine release. But this is just one of many different ways in which mast cells are linked to stressors. "What a lot of people don't know," says Larson, "is that stressors that activate the HPA-axis, which then causes the release of corticotropin-releasing hormone (CRH), are very active on mast cells and can cause their degranulation." Another molecule that has recently been discovered, called urocortin, is even more potent than CRH in its ability to cause mast cell degranulation during stressful situations. Larson cautions that stress is often misinterpreted. It is not just tightened muscles or feeling distraught; stress is a chemical reaction that can activate many diseases, such as psoriasis (and other skin disorders), interstitial cystitis, and irritable bowel syndrome. In the case of FMS, Larson's theory is that this chemical reaction and release of CRH or urocortin is occurring in the brain's thalamus.

If the mast cells in the thalamus play a causative role in FMS, then one would expect differences in them between the genders because FMS is far more prevalent in women. Comparing males to females, the number of mast cells in the thalamus of mice were the same. However, mast cells tend to aggregate in certain areas within the thalamus, and this is where the differences between the genders became apparent. Larson found three specific areas in the thalamus of female mice where the mast cells congregated, and this pattern was not found in males. In fact, in one of the areas, there were absolutely no mast cells in the male mice (comparing 15 male mice to 16 females). These areas happen to be important for pain transmission as well as communication between the spinal cord neurons and the thalamus. So the dramatic difference in mast cell distribution between the genders may help account for the higher prevalence of women with FMS pain.

What about hormonal influences? Based on several elaborate studies done by Larson, she found that estrogen tended to recruit mast cells to specific areas in the thalamus and progesterone caused their degranulation. The degranulation causes an immunologic response—not in the peripheral tissues but rather, in the thalamus (the center of the brain).

Do mast cells play a role in blood flow? Yes. Mast cells have been studied in cancer research because they enhance the blood flow to the area of the tumor. Without sufficient oxygen and nutrients, the tumor would die. Looking at this from a different perspective, from the thalamus in the brain where the mast cells in patients with FMS are hypothesized to play a causative role, these cells may cause a change in blood flow. Pain signals carrying substance P could degranulate them and reduce their ability to enhance blood flow. This corresponds to studies by Laurence Bradley, Ph.D., (another AFSA-funded researcher), showing that pain stimuli significantly alter blood flow in the thalamus in people with FMS.

The mast cells in the thalamus secrete NGF and they degranulate when substance P-containing neurons terminate in the thalamus. This occurs during situations of stress and pain, making the pain worse. It also has ramifications for disturbing sleep. "Histamine is a major compound in mast cells," says Larson, "and it is released upon degranulation. Histamine is a stimulant in the CNS; it causes arousal." So stress can modulate both pain and sleep in Larson's model, which mimics what happens in FMS.

Future Studies

How do substance P, NGF, dynorphin and serotonin affect mast cells in the thalamus to actually cause FMS? Can an animal model be generated from this hypothetical "paper" model? These are two of the many questions that Larson plans to answer in her studies over the next five years. She also hopes to answer relevant questions about pain transmission in fibromyalgia as well as clarify the role that these stress- and hormone-sensitive mast cells in the thalamus might be playing.

FMS: Chronic Effects of NGF in the Spinal Cord

In 1998, Alice A. Larson, Ph.D., Professor of Pharmacology and Neuroscience at the University of Minnesota, was awarded a grant to study the effects of infusing NGF into the spinal fluid of mice to determine if this might generate a good animal model for FMS. The funding by AFSA was just the beginning of a very ambitious and much-needed study to better understand the role that chronically elevated levels of nerve growth factor (NGF) play in the development and perpetuation of the symptoms of FMS. Indeed, patients with FMS have an elevation of both NGF and substance P (SP) in their spinal fluid. Based upon the knowledge that NGF could cause elevations of SP and increase pain, Larson hypothesized that mice with artificially elevated levels of NGF could serve as an animal model for people with FMS. Upon hearing the mind-boggling presentation by Larson at the "Focus on Pain" meeting in Orlando, FL, one could certainly state that the AFSA project conducted by Larson was the start of many good studies to come!

"Our grant from the American Fibromyalgia Syndrome Association, entitled Fibromyalgia: Chronic Effects of NGF in the Spinal Cord, was pivotal in generating the preliminary data that was necessary to obtain our current funding from the National Institutes of Health (NIH)," says Larson. "This award, entitled Role of Neurotrophins in an Animal Model of Fibromyalgia, focuses on the role of NGF in the spinal fluid of patients with fibromyalgia. Our approach is to correlate various conditions in animals that may produce a long-term hyperalgesia (enhanced pain sensitive state) with changes in growth factors, targeting muscle pain and gender-dependent differences as important variables."

During the speech in Orlando, Larson indicates that while chronic infusion with NGF generated a model for chronic pain or hyperalgesia, it was not FMS. This is an important distinction because Larson explains that FMS is more than just having enhanced pain perception! There are problems with sleep, cognition, modulation of symptoms by stress (including infections and physical exertion), gender differences (any model would have to explain why FMS occurs more often in females), and a number of other variables that make fibromyalgia a syndrome.

Larson generated rather surprising data with her small-scale AFSA study and the NIH funding allowed for her to confirm her findings and expand the scope of her work. The actions of SP are not so straight forward. SP splits into two types of metabolites or compounds: one that is thought to relieve pain, called SP(1-7), and one that is thought to be the cause of all of the pain problems produced by SP, called the C-metabolite. In a report by Larson and colleagues, the actions of SP are not so simplistic.³ The "good" metabolite under most conditions relieves pain, but not always. Also, newly designed drugs that block SP (NK₁ receptor antagonists) don't obliterate pain, but are involved in hyperalgesia. These drugs are soon going to be available on the market and have already been tested in an AFSA-funded study conducted by Luc Jasmin, M.D., Ph.D. The bottom line: they will boost the action of opioids, but they won't be the panacea for treating FMS (see Jasmin's project description). Another avenue of investigation involves cloning the SP(1-7) receptor to capitalize on the pain-relieving aspects of SP(1-7) type of molecules. John Stewart, Ph.D., is already working on an AFSA-funded study with this goal in mind.

In addition to the work outlined at the Orlando meeting, Larson is also involved in studying another interesting compound, kainic acid. It is not produced in humans, but kainic acid can be easily tested in mice to determine if similar compounds that activate the same receptor may be somehow involved in FMS pain. "One of the papers that has resulted from this work was done in collaboration with Dr. Luc Jasmin, another researcher who has been funded by AFSA," says Larson. "These studies focus on the long-term hyperalgesic effect of kainic acid, a compound that can be used to selectively study certain excitatory amino acid receptors that are hypothesized to be involved in FMS pain.⁴ We had previously shown that kainic acid produces a persistent hyperalgesia in both rats and mice when injected under the skin.⁵ In collaboration with Jasmin, we have now found that this effect is likely mediated by an action on the vagus nerve." Larson also found that activation of the kainic acid receptors interfered with morphine's effectiveness to reduce pain in mice. Mice that lack noradrenaline also tend not to respond as well to morphine analgesia, as indicated by Dr. Jasmin's work.

What does this mean? Larson explains that "excitatory amino acids (EAAs) are molecules normally found inside all cells where they are used for protein synthesis. When cells burst, as during tissue damage or mast cell degranulation, EAAs are released into the surrounding tissues where they can interact with EAA receptors on the cells that they come into contact with. The receptors are located on the surface of neurons and the EAA or kainic acid molecules interact with these receptors like a lock and key fit. This activity on a specific type of EAA receptors, in this case the kainic acid receptors on the vagus nerve, is what we think causes hyperalgesia. The vagus nerve is important because it carries autonomic information from the gut, heart, immune system, etc. It regulates autonomic function (which is not working well in patients with FMS) and the vagus nerve also carries appropriate reflex information.

"This study may have relevance to fibromyalgia as many FMS patients have inflammatory conditions in the GI tract where the vagus nerve projects. Wounds are known to contain elevated concentrations of excitatory amino acids that could mimic the action of kainic acid. Our ongoing studies are examining the fiber type that is involved in the hyperalgesic condition produced by kainic acid."

As part of Larson's work on EAAs, she found evidence for increased production of nitric oxide (NO) in the spinal fluid of people with FMS and credited AFSA for providing partial funding assistance.⁶ "Molecules similar to kainic acid and activated NMDA receptors in the spinal fluid can both induce NO synthesis," says Larson. "We measured a variety of amino acids in these spinal fluid samples of patients to see what picture emerged" (citruline, an amino acid that is co-produced along with NO, was elevated). Although a small pilot study by Laurence Bradley, Ph.D., shows that NO is elevated in the blood of FMS patients, this molecule in the periphery does not perform the same functions as it does in the CNS where it is involved in pain transmission. "Peripheral NO," says Larson, "is involved in vasodilation of the vasculature and does not reflect the same pool of NO as that in the central nervous ystem."

Summing up the meaning of her AFSA grant and how it has influenced her research, Larson says: "The success of the award from AFSA cannot be measured merely in publications at this time. Most of the work that resulted from that study is not yet published, but is being extended by our ongoing work funded by NIH. We have a mixture of some promising data as well as surprises that have led to even more questions about the basic assumptions that prevail in the pain literature. For example, for many years, we have assumed that because SP is released in the spinal cord in response to pain transmission, it must be important in the mediation of this sensation. Now, of course, we know that this data is correlational only and that acute pain is not influenced by compounds that antagonize SP (such as the neurokinin-1 or NK₁ receptor antagonists). In fact, it is the enhanced pain (hyperalgesia) experienced during chronic pain conditions that is attenuated by these compounds.

"Based on our recent findings, it would appear that the role of SP is merely modulatory. This raises the question, what is the role of the elevated SP found in the spinal fluid of patients with fibromyalgia? While the mediation of hyperalgesia may be the simple and widely accepted answer, we have recently found that the metabolites of SP are able to increase the density and distribution of the SP receptor (NK₁) in the rat spinal cord.³ This suggests that the release and accumulation of SP metabolites during pain transmission ‘feeds forward' and promotes the synthesis of sites that serve to modulate pain transmission. While this in and of itself is not remarkable, it is noteworthy that this increase in production of NK₁ sites occurs simultaneously with the development of an antinociceptive (analgesic/pain-relieving in humans) condition when tested in these same rats. If SP interacting with NK₁ sites is important in hyperalgesia, one would predict the exact opposite.

"You can see how this work, done simultaneously with the AFSA project, put our whole interpretation of the relationship between NGF, SP and the metabolites of SP in question. Our results from the AFSA study did not clarify the issue, so we decided not to publish at that time to avoid cluttering the literature with mere data, but to try to continue work to discover a likely interpretation of our findings. So we used the data from the AFSA study to procure an NIH award to further our work to look for more conclusive answers regarding the role of NGF and its relationship to SP. (As mentioned, a portion of our findings now appear in print.³)

"I'm afraid that the answers are not as simple as we had originally thought. What does all this mean to patient who are suffering with fibromyalgia? I'm ever hopeful that when the maze appears to be the most convoluted, that we may be nearing the center, a point from which the whole pattern may unravel. Having been sufficiently perplexed with our results over the past few years, I wrote a review of the research in the field in the hopes of finding a lead that we may have originally missed.⁷ During this process we have come across many possible ‘suspects' that we are now more fully investigating. So, while perplexing data may at first appear to be a setback, it has served to redirect our efforts, perhaps to a more fruitful direction. I hope this summary helps to put our recent publications in perspective.

The Role of Zinc in FMS Pain

Beginning in 1997, I. Jon Russell, M.D., Ph.D., at the University of Texas in San Antonio, initiated a pilot study to investigate the possible role of zinc, a trace mineral, in the production of FMS pain as well as other symptoms. Why look at zinc? It is known to be essential for the development of the central nervous system, its largest concentration in adult humans is found in the brain's hippocampus (the primary region being investigated by Patrick Wood, M.D., – see Brain Imaging section), and this element is known to be involved in both memory and pain transmission.⁸ In addition, zinc may help block the activation of the NMDA receptors in the spinal cord that are thought to be responsible for magnifying the pain of FMS. Zinc also appears to play an assistive role in the development of persistent pain (hyperalgesia) that is caused by the activation of kainic acid receptors.⁹ Ordinarily, kainic acid receptors are not activated, but a just-published study by Alice Larson, Ph.D., points to the possibility that this pain-producing mechanism may be important in the development of chronic pain, such as FMS.⁴ Certainly, the role of zinc is not clear-cut. A deficiency could explain some of the pain in FMS, but too much zinc could create problems as well.

Russell conducted an investigational study to determine if patients with FMS might be deficient in zinc. He hypothesized that if patients were low in zinc, that this could explain some of their symptoms, particularly pain. Given that zinc is found in numerous areas in the body, one can't simply take a blood sample to get an accurate reading on a person's zinc stores. This meant that Russell had to perform a short "loading test" in which 30 FMS patients and 30 healthy matched controls were given a specified amount of zinc to take during a 48-hour period. He measured plasma zinc values before and after the loading test. The increase in the amount of plasma zinc levels is a rough estimate of the zinc nutritional status of the study participants (both the FMS patients and the healthy subjects). In other words, the greater the increase in the plasma zinc level, the greater the suspected zinc deficiency.

At the October 1999 meeting of the American College of Rheumatology, Russell presented the preliminary findings of his AFSA-funded study. He did find that people in the FMS group were more likely to have a larger increase in their plasma zinc levels during the loading test, compared to healthy control subjects. Naturally, one might ask if lower-than-normal zinc levels may play a role in the painful symptoms of FMS, but the answer is complex. Dr. Russell kindly provided an answer to this question in a report to AFSA and it is reprinted below to help you understand the complicated dynamics of the situation.

Are fibromyalgia patients zinc deficient?

"This is a difficult question because deficiency of zinc in the medical literature has taken so many different clinical forms. Severe deficiency in children has resulted in growth retardation and a number of other developmental abnormalities. In adults, a recognized manifestation can be loss of smell and taste. Fibromyalgia patients do not typically complain of loss of taste or smell. Perhaps zinc deficiency in the presence of some other abnormality, such as high substance P, can result in more pain than loss of taste and smell. The literature is replete with controversy about zinc deficiency because its levels are usually measured in the blood. Blood zinc levels are highly regulated and may be normal in spite of chronic total body deficiency. It seems likely that this question will require considerable additional study to clarify it with confidence. The first step would be to repeat the present study with a comparable or larger number of subjects, using a larger exposure to zinc. The goals would be to confirm zinc deficiency at the onset, estimate the magnitude of the total body deficit of zinc, replace zinc by dietary supplementation until the deficit has been normalized, and monitor carefully to determine whether the painful symptoms respond to zinc replacement."

Russell also points out that while he tested plasma zinc levels (before and after the 48-hour zinc loading period) the spinal fluid levels in patients may produce different information. "The abnormality may be even more dramatic in the spinal fluid as is the substance P," says Russell. This study has generated interesting findings but only a small number of individuals were tested and it was conducted on a short-term loading basis. It would be unwise to advise patients to take zinc because the effects (and side effects) on its chronic, daily use remain to be determined. Still, the results of this project can serve as an important basis for future investigations.

Cloning a Receptor for New Drug Development

In 1998, AFSA received an application that proposed something entirely different from the other proposals received so far in the organization's history: cloning a "pain-relieving" receptor for developing a new FMS/CFS drug. The applicant, John Stewart, Ph.D., of the University of Colorado Medical School in Denver, proposed the cloning of the receptor for one of the metabolites of substance P (SP). SP is a pain transmitter in the central nervous system and its threefold increase in the spinal fluid of patients with FMS has been measured by four different research laboratories. Original work by Stewart demonstrated that in the brain, SP is split into two major compounds: one that causes pain (the C-metabolite) and one that in many cases may relieve pain (SP(1-7) or the N-metabolite). NGF is also involved and the situation is more complicated than initially thought. A diagram of the process is illustrated below.

Rodent studies by Stewart and AFSA-funded researcher Alice Larson, Ph.D., indicated that SP(1-7) can produce substantial pain relief. The results depend upon the type of test used and the information cannot be "perfectly" extrapolated to humans. Still, the pain-producing effects of the C-metabolite, and the possibility that drugs acting on the SP(1-7) receptor could cause substantial pain relief, begs two important questions: (1) Why hasn't the pharmaceutical industry developed a drug to block the "bad" pain-producing metabolite of SP, and (2) Why haven't they focused on the potential "good" metabolite, SP(1-7)? The situation isn't simple.

At least three major drug companies have developed their own patented version of an SP receptor blocker (referred to as a neurokinin receptor antagonist, or an NK₁ drug). First, the NK₁ receptor had to be cloned, and then the drug industry developed compounds to block its action. After several years of trying to demonstrate the pain-relieving effects of NK₁ receptor blocking drugs, the outcome has been disappointing. The only glimmer of hope in this area came from AFSA-funded researcher Luc Jasmin, M.D., Ph.D., who was able to demonstrate in mice that the NK₁ drugs may work exceptionally well in relieving FMS pain—as long as the medication is used in conjunction with an opiate (at least a low dose) and a drug that boosts the levels of noradrenaline (there are many meds that do this). Jasmin's phenomenal work in mice still needs to be replicated in patients with FMS once the NK₁ drugs reach the marketplace at the end of 2003. However, it is a major breakthrough that was made possible with funding assistance from AFSA. Despite Jasmin's accomplishments, patients may face two potential obstacles: (1) the inability to convince their physician to prescribe an opiate on a regular basis and (2) the undesirable side effects that limit the use of opiates in many patients.

Stewart is working on an entirely different approach to combat the elevated SP problem. He is cloning the SP(1-7) receptor so that novel drugs that either block (turn off) or bind (turn on) this receptor can be studied. This means developing drugs that are completely different from the NK1 class of medications. SP breaks down into its "bad" metabolite that produces pain, and its "good" metabolite that relieves pain in certain situations. While the drug industry has been focused on trying to block the "bad" metabolite known to produce pain, Stewart is working to clone the receptor for the "good" metabolite SP(1-7) that relieves pain.

This is a tedious, high-tech process, but Stewart has a proven track record. His previous work has led to the discovery of compounds that may produce new drugs to treat cancer. One of his compounds is in development at the National Cancer Institute for lung cancer. Stewart is well on his way to developing the SP(1-7) receptor clone, but this is not a project that can be rushed. He has evidence that the rat brain has the "message" (mRNA) for the SP(1-7) receptor among its thousands of messenger RNAs. He fractionated total mRNA into a library of 400 fractions and is now testing each one in order to find the correct clone and determine the exact chemical structure of the receptor.

Stewart reports that he is well into the receptor testing phase–more than halfway through the project. Once completed, he will determine the exact amino acid sequence of the SP(1-7) receptor, and will seek additional funding from the NIH for developing a bio-active drug to treat FMS/CFS pain ... just as he has done before in the field of cancer.

Commenting on the importance of his work, Stewart says: "Completion of this project will open a novel and very exciting pathway for the development of new fibromyalgia drugs that will not produce the unwanted side effects of any of the currently available medications. Using the new molecular tools developed in this AFSA-funded project, we will be able to discover new drugs to treat other serious illnesses as well, such as Parkinson's and Alzheimer's diseases."

While the forgoing discussion explains the science behind Stewart's award, his answers to a few additional questions will enable you to fully understand why this grant is so important.

What has AFSA's award meant to you?
It has been the key to letting me work on this project I have wanted to do for many years. Three years ago I made a deal with my department chairman. I told him that I would accept early retirement but continued to teach (I have 130 med students!), as long as he would let me use the funds otherwise paid to me in salary to hire people for the lab. Thus, we have salary funds for the two people working on the project, but we still needed outside funds for supplies for the project to proceed. This arrangement means that we can accomplish much more with the limited AFSA funds, since we don't have to pay salaries out of the award ... and it also allows me to oversee a project that I have been interested in doing for several years.

What is it enabling you to accomplish that you may not have been able to do otherwise?
Since so few people believed in us about the analgesic action of SP, there is no way I could have otherwise received the funds needed. I am very grateful to AFSA for making this important project possible.

How will patients benefit from your study once it is completed and what new avenues of research will result from it?
Although new drug development is a lengthy process, eventually there will be a totally new class of analgesics to help treat patients with FMS based on this work. Since these new agents, such as SP(1-7) receptor antagonists, will work by a mechanism totally distinct from those of current analgesics, they should provide excellent complements to existing drugs for pain control.

Blocking Substance P ... Will it Work?

Drugs that block the pain-transmitting action of substance P will soon be on the market. The natural question is: Will they be effective at taming the pain of FMS? Pain neuroscience researcher Luc Jasmin, M.D., Ph.D., at the University of California in San Francisco, had the daunting task of determining how substance P blockers (called NK₁ receptor antagonists), noradrenaline and opioids might work together, or individually, to treat chronic pain. Jasmin already had an NIH grant to look at the effects of short-term depletion of noradrenaline (NA) in mice. He found that this led to elevated levels of substance P in the central nervous system and enhanced pain sensitivity. In other words, it seemed as though Jasmin had developed a "temporary" model for FMS, but a more stable model was needed in order to test the effects of different drug interactions.

"The June 2001 AFSA award was essential for conducting our study on mice that lack NA," says Jasmin. These mice had a genetic abnormality that interfered with their ability to manufacture NA, so they represented a more "stable" model. Commenting further, Jasmin says, "This study, entitled Noradrenaline Deficient Mice as a Model for Fibromyalgia, was entirely supported by AFSA funding and would not have been done without this support. The results are key to our scientific understanding of the role of NA in pain, in the control of substance P release, and in opioid analgesia."

One primary study that examines the impact of NA on the development of substance P-related pain and responsiveness to morphine in mice has already been published (supported in part by AFSA).^10,11 Jasmin and his colleague, Peter Ohara, Ph.D., found that these specially bred mice, which lacked NA and had elevated levels of substance P in their central nervous system, had a reduced analgesic response to morphine. In other words, these mice did not respond as well to opioids as they should have. In many ways, these mice were similar to humans with FMS.

Patients with FMS have been shown to have low levels of NA and elevated levels of substance P in their spinal fluid. They also have low pain thresholds and while patients do respond to opioids, this class of drugs doesn't come close to eradicating the pain. Given this situation that tends to parallel the NA deficient mice, Jasmin looked for ways to improve their pain thresholds as well as their responsiveness to opioids. His intent was to search for treatment methods that might be useful for FMS.

Jasmin found that there were two different ways to enhance the pain-relieving effects of opioids. One way was to increase the central nervous system level of NA (many tricyclic antidepressants do this, i.e., amitriptyline). NA works by inhibiting the release of substance P, which can lessen a person's pain. Yet, drugs that raise NA levels don't provide nearly enough pain relief. This may be explained by Jasmin's second finding: that NK₁ receptor antagonists worked just as well as NA to raise pain thresholds in the mouse and restore the efficacy of morphine.

"Reestablishment of morphine efficacy by NK₁ antagonists," says Jasmin, "indicates that substance P is released despite the presence of morphine." This means that when NA is low and substance P is high (a situation found in FMS patients), morphine and other mu-opioid agonists will not be as effective as they ought to be. Jasmin proposed that substance P and opioids have opposite effects on pain; the former works to increase pain while the latter works to diminish it.

One implication of Jasmin's work is that the soon-to-be-released NK₁ drugs may play an essential role in the treatment of FMS, but not by themselves. The greatest benefit of NK₁ meds may be achieved when they are used in combination with opioids as well as drugs that raise the level of NA in the central nervous system. Since Ultram (tramadol) works as a mild opioid and increases NA (along with serotonin), Ultram plus NK₁ receptor antagonists may prove highly effective in treating FMS. It is also possible that NA-elevating drugs that also reduce substance P may work well in conjunction with NK₁ agents. Zanaflex (tizanidine) would be such an agent and it has been shown in a small drug trial to reduce substance P in the spinal fluid of patients with FMS. This drug also displays muscle relaxant properties, which patients with muscle pain may find beneficial.

Based on Jasmin's work with NA-deficient mice, the interactions of substance P, opioids, NA, and NK₁ drugs (which work to block substance P) can be summed up in the accompanying diagram. Opioids and substance P produce opposite effects on pain. In conditions in which substance P is elevated (e.g., FMS), the "pain balance" can be restored by increasing NA and/or adding an NK₁ antagonist. As you can see, Jasmin's findings open the door to multiple approaches that may be beneficial in targeting FMS-like pain.

Delving further into NA's role in chronic pain, Jasmin's studies in mice establish that a dysregulation of NA transmission can lead to chronic pain. In addition, Jasmin's NIH-funded experiment that temporarily blocked the action of NA-producing neurons with a chemical agent served to confirm the results of the AFSA-funded study with NA-deficient mice. Part of this work was recently published in Journal of Comparative Neurology.¹² "Overall," says Jasmin, "the role of NA in chronic pain is a much more subtle one than previously thought, based on other types of short-term or acute pain models."

"The take home message," according to Jasmin, "is that, in contrast to previous suggestions that NA is a necessary neurotransmitter of the endogenous pain-inhibitory system, our results indicate that NA contributes minimally to determining one's pain threshold." He also found that the pain-fighting effects of NA work in conjunction with opioids and substance P blocking drugs, as already discussed above.

"One of the most important implications for patients," says Jasmin, "is that this works demystifies some of the obscure concepts of pain. Despite its subtle role, NA exerts some very specific functions that can improve our understanding of pain, allow us to design new treatments, and more importantly, show how a single defective neurotransmitter can be responsible for a number of apparently unrelated disorders. A decrease in NA leads to a lowered pain threshold, sleep, memory, hypothalamic-pituitary-adrenal (HPA) axis regulation and autonomic dysfunction. Doesn't this sound similar to FMS?"

Jasmin is using the studies carried out with AFSA funding, as well as his larger NIH study, to provide the basis for a new NIH grant application. His work with NA-deficient mice will be followed up by studying the contribution of NA to the pain-relieving effect of antidepressants (which raise the central nervous system levels of NA and/or serotonin and are often prescribed for patients with FMS). "Below is the summary of a proposal recently sent to NIH," says Jasmin, "to give you insight on where we are headed with regards to future studies:"

"Because antidepressants (ADs) are among the few drugs that effectively, although moderately, treat chronic pain, there is a great need to understand their precise mechanism of action in order to improve their analgesic efficacy. ADs work by decreasing the sensory and emotional components of pain. The neurotransmitter noradrenaline (NA) is essential to both components. AD's analgesic effects likely depend on NA acting in different brain areas, yet the contribution of specific brain areas remains largely unknown. Take for example, the cerebral cortex, the structure that forms the outer shell of the brain (see the diagram in the Brain Imaging section). It seems likely that the cortex is the target for the analgesic action of ADs, since studies have shown that reduced NA in the brain's cortex leads to increased pain. Other brain structures that appear more closely linked to the anti-anxiety effect of ADs are the hypothalamus and amygdala. These two structures are part of the limbic system in the brain and they receive inputs from the thalamus. In these two areas, ADs induce changes in gene expression as well as alter the response of neurons expressing corticotropin-releasing hormone (CRH). CRH is a key neuro-hormone that controls the body's of stress responses by acting through the HPA system. It is unclear if NA is involved in this process and this needs to be explored.

"The guiding hypothesis of our proposal is that NA in the cerebral cortex is essential to the pain-relieving effect of ADs, implying that chronic pain and non-responsiveness to treatment involve a lack of cortical NA. In other words, animal models as well as patients with FMS should theoretically have low NA levels in the cortex region of their brain. As it is not uncommon for anxiety to complicate chronic pain, we will identify which brain areas NA acts as an analgesic and which brain areas it acts mostly to relieve anxiety. Because part of the analgesic effects of ADs is believed to depend on opiates, we will also test whether the synergistic effect of combining ADs and opiates is dependent on NA. As a correlative, we will determine if ADs alter specific molecular markers in the hypothalamus and amygdala."

References

1. Laughlin TM, Larson AA, Wilcox GL. J Pharmacol Exp Ther 299(1):6-11, 2001.
   
2. Giovengio SL, Russell IJ, Larson AA. J Rheumatology 26(7):1564-9, 1999.
   
3. Velazquez RA, et al. Eur J Neuroscience 16: 229-241, 2002.
   
4. Tien et al. Pain 102(1-2):39-49, 2003.
   
5. Giovengo SL, et al. Pain 83: 347-358, 1999.
   
6. Larson AA, et al. Pain 87(2):201-11, 2000.
   
7. Larson AA and Kovacs KJ. Current Pain Headache Rep 5: 338-346, 2001.
   
8. Velazquez RA, Cai Y, Shi Q, Larson AA: The distribution of zinc selenite and expression of metallothionein-III mRNA in the spinal cord and dorsal root ganglia of the rat suggest a role for zinc in sensory transmission. J Neuroscience 19(6):2288-2300, 1999.
   
9. Larson AA, Giovengo SL, Shi Q, Velazquez RA, Kovacs KJ: Zinc in the extracellular area of the central nervous system is necessary for the development of kainic acid-induced persistent hyperalgesia in mice. PAIN 86:177-184, 2000.
   
10. Jasmin L, et al, PNAS 2002; 99(2):1029-1034.
    Downloadable free at: www.pnas.org/cgi/content/abstract/99/2/1029
    
11. Hill R, PNAS 2002; 99(2):549-551.
    Downloadable free at: www.pnas.org/cgi/content/full/99/2/549
12. Jasmin L, et al. J Comp Neurol 460:38-55, 2003.

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Neuroendocrine Findings

In the early to mid-nineties, researchers raised the question about whether FMS (as well as CFS) might be a neuroendocrine condition. Abnormalities in the hormonal secretions from the pituitary gland had been uncovered. For example, Leslie Crofford, M.D., of the University of Michigan in Ann Arbor, found abnormalities in the stress response mechanisms involving the hypothalamic-pituitary-adrenal (HPA) system. Robert Bennett, M.D., of OHSU in Portland, found that one-third of FMS patients met the criteria for adult growth hormone deficiency syndrome. Daniel Clauw, M.D., previously at Georgetown, but now at University of Michigan in Ann Arbor, was interested in testing a neurological system that interacted with the HPA axis called the autonomic nervous system (ANS).

As you can see from the diagram below, both hormones and neurotransmitters are involved in the regulation of the ANS and the same holds true for the HPA system. That is why this section is called Neuroendocrine Findings and the results obtained by two AFSA-funded researchers are described in this section.

Melatonin in Patients with FMS and CFS

The rheumatologist and principal investigator Leslie Crofford, M.D., collaborated in 1996 with another neuroendocrine scientist, Ania Korszun, M.D., Ph.D., in a successful project to determine whether the abnormalities in cortisol production were due to problems with melatonin production. The results were subsequently published in the Journal of Rheumatology in December of 1999.¹ An overview of the study findings and an explanation of their significance are provided by Crofford below.

"Our study was the first on circadian phase of patients with FMS and/or CFS. Our findings have subsequently been confirmed by a research team at Harvard, whose published report appeared in 2001.² Melatonin is involved in synchronizing the circadian (24-hour) rhythms controlled by the brain by acting as an interface with environmental cues such as the light-dark cycle. When your eyes see light in the morning, this shuts off the production of melatonin by the pineal gland in the brain. In situations where desynchronization of biological rhythms occur (e.g., jet lag or people working odd shifts), symptoms of fatigue, cognitive dysfunction, and depression can occur. Some of the neuroendocrine hormones that are disturbed in FMS and CFS, particularly the stress hormone cortisol, have a strong circadian rhythm. Therefore, we asked whether there was evidence of desynchronization of the melatonin and cortisol rhythms that might provide clues to the neuroendocrine biology of FMS and CFS. In other words, perhaps an abnormally low or out-of-sync production of melatonin might be at least partially responsible for some of the symptoms of these two overlapping syndromes.

"In the study funded by AFSA, we asked whether the level of melatonin was altered and we also looked to see if its production was out of rhythm from that of cortisol in patients with FMS and/or CFS. We found that melatonin and cortisol rhythms did not differ significantly with respect to their phase in patients with FMS or CFS compared with controls subjects, although the time between peaks of these two hormones was longer in patients than controls. Furthermore, rather than lower melatonin levels, patients with FMS, but not those who only met the criteria for CFS had higher melatonin levels during the overnight peak. Taken together, we conclude that the symptoms of FMS are not related to circadian phase shift nor a deficiency of melatonin.

"The lack of significant circadian phase shift in FMS was later confirmed by Gail Adler, M.D., Ph.D., at Harvard University.² This study looked at three measures throughout a 40-hour period: melatonin in the blood, cortisol in the blood, and core body temperature. Actigraphs (devices placed on the wrist to monitor movement) and a controlled diet were also implemented. Comparing the circadian rhythms of cortisol, melatonin, core body temperature, and sleep/wake data from the actigraphs, the authors also concluded that symptoms of fatigue, sleep disturbances, and cognitive dysfunction were not caused by abnormalities in the body's circadian rhythm.

"Nevertheless, melatonin as a sleep inducing agent may still be helpful in some patients with FMS and CFS. This issue has not been examined directly in a controlled clinical trial, although a small uncontrolled trial implied that some patients benefited from this therapy for reasons that can't be explained by circadian rhythm or insufficient melatonin secretion.³ Melatonin possesses hypnotic properties and it may simply be acting in such a manner for FMS or CFS patients who are likely to have a sleep disorder or problems falling asleep.

"The AFSA funding provided data that assisted me with the renewal of our team's NIH-funded grant to further examine the neuroendocrine biology in patients with FMS. The melatonin study allowed us to exclude circadian phase shift as the cause of the neuroendocrine alterations, which is very important to our understanding of this perplexing condition. We have now completed a detailed analysis of the pulsatile secretion of two components of the stress axis, ACTH and cortisol. Furthermore, we have completed a study of the responsiveness and resiliency of the HPA stress system. It appears that the stress response defects in FMS patients are at the level of resiliency (that is, how rapidly the HPA axis re-sets itself after activation). We are continuing to try to understand why this is the case and how these problems may be corrected therapeutically.

"Understanding the biology of FMS patients helps in several ways. New knowledge that demonstrates biological causes of FMS symptoms assists patients and their physicians to more fully understand FMS. We have also used our research program to train young investigators in Rheumatology, Neurology, and Cognitive Psychology.

"I hope your donors will recognize that their contributions have allowed investigators to make incredible progress. In the last two years, three large pharmaceutical companies have performed multicenter randomized controlled clinical trial in patients with FMS – a major milestone. We are now working with the FDA to determine what kinds of studies would be needed for a product to have a specific indication for the treatment of FMS (not yet accomplished) that should encourage development of new and effective treatments. It is my belief that the next five years will bring treatments that will spur an educational effort directed towards primary care physicians enabling more rapid diagnosis and treatment. I am very excited about the opportunities this creates for improving the quality of life for FMS patients. AFSA should be very proud of its funding accomplishments over the past nine years!"

Autonomic Function in FMS and CFS

The autonomic nervous system (ANS) is another one of the body's neuroendocrine systems that interacts with the hypothalamus as well as the adrenal glands—two ways in which its function is linked to that of the HPA axis. Due to the interconnection between the ANS and the HPA axis, both play a role in the body's stress response mechanisms. Stress, when used to explain the actions of these systems, takes on a broader meaning that goes beyond what people think of as mental stress or worrying. Any type of challenge to the body is considered a stressor, such as an infectious agent, exercise, physical trauma, noxious odors/chemicals, or the mere stress of changing posture from sitting to standing.

How your body responds to a given challenge may alter your heart rate, breathing, digestive process and many other systems. Fortunately, you don't have to consciously think about these changes because your ANS automatically takes control of the needed modifications. Catecholamines, such as epinephrine and norepinephrine, play an important role in controlling the function of the ANS (they are also commonly called adrenaline and noradrenaline (NA), the terms used in Dr. Jasmin's work). The point is, increases or decreases in these two neuro-hormonal substances may reflect the activation of the ANS, and they have been the subject of much research in the field of FMS. Not only does NA play a role in helping to regulate the body's stress response mechanisms, but NA is also an important neurotransmitter in the pain-inhibitory system (see the AFSA-funded studies performed by Drs. Staud and Marchand).

In 1995, when Dr. Clauw was funded by AFSA, no previous researcher had looked at the ANS function in terms of NA levels in the blood or measured the balance between the two branches of the ANS: the sympathetic and the parasympathetic. The symptom of lightheadedness corresponding to a rapid drop in blood pressure during tilt-table testing had been documented to occur in a subgroup of teenagers with CFS, but the mechanisms by which this and other "dysautonomia" type symptoms occurred was far from understood. So Clauw used the AFSA award to better understand the tilt-table phenomenon. He also used Holter monitors, which are portable 24-hour EKG measuring devices, to look at the neuro-transmission of the heart and he measured the blood levels of neuropeptide Y. This latter substance is a long-acting, more stable form of noradrenaline.

The results of Clauw's AFSA project were presented at the 1996 ACR meeting. To date, many researchers have made similar observations that the ANS is not functioning properly in people with FMS and CFS. In addition, the ability of various stressors to activate the ANS in patients was the subject of research presented at the 2002 ACR meeting by Clauw. He found that the levels of the catecholamines (epinephrine and NA) were higher than the healthy controls for all test periods in the study. When FMS and CFS patients were subjected to intense physical exercise, the normal rise in catecholamine levels was significantly less in patients who met the CFS criteria (with or without meeting the tender point criteria for FMS). Clauw also showed that decreased heart rate variability (HRV) exists in patients with FMS, CFS and Gulf War Illness (GWI), but that this marker for dysautonomia is mostly found in women, not men. Could this be a gender phenomenon? It's possible and emphasizes the importance of taking gender into consideration when analyzing research data.

So, what role do neuroendocrine findings play in the symptoms, as well as the cause of, FMS and CFS? Clauw says, "It is more likely that the abnormalities in HPA and autonomic function are predisposing factors. Or, they could be due to the illness itself (e.g., from problems of deconditioning or chronic pain) rather than the cause of the symptoms."

Clauw was the first investigator funded by AFSA, and at that time, funds from the government were very limited for studying FMS/CFS. Reflecting back on his AFSA award, Clauw provided the following answers to various questions:

What did your award mean to you?
It was the first funding I ever received specifically for studying fibromyalgia.

What did it enable you to accomplish?
It allowed our group to collect pilot data that served as the basis for several successful Department of Defense (DoD) grant applications. (Why the DoD? Clauw was one of the first researchers to recognize the strong overlap between FMS and GWI, and this allowed him to advance the science of both conditions!)

What do you consider the greatest area of benefit from your work?
Although the AFSA grant has not led to specific improvements in patient care, it certainly led to a better understanding of how the autonomic nervous system functions in patients with FMS.

What new avenues of research resulted from your AFSA award?
Our group now has considerable federal funding to study FMS and other related conditions, and the AFSA grant was critical in allowing us to collect the pilot data that served as the basis for many of those applications.

Chemical Intolerance

Chemical sensitivities or intolerance to odors, medications, foods and other substances are common symptoms for most FMS patients. Iris Bell, M.D., Ph.D., of the University of Arizona in Tucson, was awarded by AFSA in 1999 to look at the mechanisms by which toxins may be causing an activation of the CNS, which in turn, could exacerbate the symptoms of FMS/CFS. Bell evaluated three groups: (1) FMS patients with chemical intolerance, or CI, (2) FMS patients without CI, and (3) healthy individuals. Bell's previous research shows that CI is a marker for heightened neural sensitization and hypothesized that this could be occurring in patients with FMS, especially with their elevated spinal fluid levels of SP and NGF.

What is neural sensitization? Bell describes this as the progressive amplification of a given response when repeatedly exposed to the same chemical stimulus. In the AFSA-funded project, participants were exposed to a concentrated sucrose (sugar) syrup three times, roughly one week apart. Then one week later, subjects were given a placebo (pure water). They were also evaluated at baseline, before they ingested the sucrose. Each study participant underwent blood tests and filled out questionnaires to assess diet, symptoms, sugar cravings, mood, and other factors during the two weeks preceding the baseline evaluation. Before, during and after the sucrose administration, Bell measured each person's brain electrical activity using a computerized electroencephalogram (EEG). An EEG measures brain wave frequencies through the placement of electrodes on the scalp at 16 specified locations. Each location correlates with brain structures.

Bell observed several abnormalities in FMS patients that seemed accentuated by the presence of CI, and she published two reports on the study.^4,5 FMS patients had substantially lower resting blood sugar levels and higher carbohydrate cravings than the controls. When exposed repeatedly to sucrose, patients also exhibited increased alpha wave activity in the front midline areas of the cortex, as measured by EEG. Alpha waves slow down the function of the brain, interfering with cognition and other CNS processes. Based on her AFSA project, Bell received an NIH grant to look at the impact of diet, biofeedback and odor (aromatherapy) on FMS symptoms, EEG, and ANS function (e.g., heart rate variability).

References

1. Korszun A, et al. Melatonin Levels in Women with FMS and CFS. J Rheumatology 26(12):2675-80, 1999.
2. Klerman EB, et al. Circadiam Rhythms Of Women with FMS. J Clin Endocrinology Metabolism 86:1034-39, 2001.
3. Citera G, et al. The Effect of Melatonin in Patients with FMS: A Pilot Study. Clin Rheumatology 19(1):9-13, 2000.
4. Bell IR, et al. Concomitant Environmental CI Modifies the Neurobehavioral Presentation of Women with FMS. JCFS 9(1/2):3-19, 2001.
5. Bell IR, et al. EEG Beta 1 Oscillation and Sucrose Sensitization in FMS with CI. Intern J Neuroscience 108:31-43, 2001.

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Brain Imaging Studies

AFSA has funded four studies involving the use of brain imaging techniques. Two projects were awarded to Laurence Bradley, Ph.D., of University of Alabama at Birmingham (UAB). Bradley used SPECT (single-photon-emission computed tomography) in combination with MRI to analyze blood flow to various regions in the brain. The SPECT scanner detects the blood flow while the MRI allows Bradley to accurately identify the location in the brain where abnormalities in blood flow are detected. Muhammad Yunus, M.D., of the University of Illinois College of Medicine in Peoria, used a different imaging technique, called PET (positron emission tomography) in an effort to try to pinpoint the location of brain dysfunction and potentially the neurotransmitters involved (see Web site for details). The forth study was awarded to Patrick Wood, M.D., at LSU in Shreveport, to use yet a different technique called proton MRS, and this happens to be the most recent project funded by AFSA.

Each imaging study was designed to provide different insights into the brain malfunction of patients with FMS. AFSA and its funded investigators have held strongly to the belief that FMS (as well as CFS) is linked to serious abnormalities in brain function. Identifying these defects as well as showing that they are not caused by depression or mood states is a challenge. Fortunately, experience and improvements in brain imaging techniques are proving to be beneficial to researchers in this field. An update on the brain imaging findings funded by AFSA is provided below.

Pain Sensitivity Real ... and made worse by anxiety

It may just appear that FMS patients are hypersensitive to pain, but Bradley confirmed the enhanced pain perception in patients. He used random, blinded testing of pressure stimuli and found that the pain threshold of FMS patients is roughly one-half of the value for healthy pain-free controls. Low pain thresholds are real! He also discovered that when individuals with FMS were exposed to a random set of either painful or nonpainful stimuli, the brain blood flow (as measured objectively by SPECT scans) indicated that the brains of patients responded differently from those of healthy controls. What does this mean? Regardless of whether the stimulus was above their pain threshold, the anxiety and anticipation of being prodded generated significant increases in blood flow to certain limbic centers in the brain, particularly those involved in pain control. The impact of being subjected to pressure stimuli was the greatest for patients who already suffered from pain-related anxiety.

This project was presented at the 2000 American College of Rheumatology meeting as well as the April 2001 American Pain Society meeting. An abstract of the preliminary findings are posted on AFSA's Web site at: www.afsafund.org. Although therapies that may reduce anxieties might help, Bradley is continuing in his efforts to identify the physiological mechanism responsible for this enhanced brain blood flow generated by the anticipation of pain.

At the October 2002 American College of Rheumatology meeting, Bradley presented data showing that resting levels of blood pressure or heart rate (two variables that might be tied to one's stress level) did not correspond to the degree of blood flow changes. Bradley is looking to evaluate other neuroendocrine factors that may be tied to the altered blood flow changes caused by anticipation of a painful stimulus. The bottom line, however, is that pinpointing the mechanisms involved will likely lead to better therapies for FMS symptoms, and not just the pain. The limbic regions that Bradley evaluated are involved in regulating sleep and aiding with cognition.

FMS Not Depression!

The award enabled doctoral student Leanne Cianfrini, M.A., to work with Bradley to complete a study in which she compared the pain responses of women with either FMS or major depressive disorder to those of healthy individuals. The pain responses included (a) pressure pain threshold levels and (b) changes in brain blood flow elicited by a 4-minute period of pressure stimulation that was tailored so that each individual would experience similar pain intensity levels. Cianfrini found that the patients with FMS produced pain responses that were substantially different from those of the patients with depression and the healthy persons. However, the depressed patients' responses were not different from those of the healthy persons. These results, which will soon be submitted for evaluation by a medical journal, strongly suggest that depressive illness alone does not alter pressure pain sensitivity or brain blood flow responses to painful pressure stimulation.

Cianfrini and Bradley believe that communicating these and similar findings to health care professionals and to patients with FMS will help reduce the extent to which the painful symptoms of FMS are inappropriately attributed solely to depression or other psychiatric disorders.

Cianfrini will soon complete her Ph.D. and continue her research on FMS, beginning with her internship training that started in 2003. To date, three AFSA awards have been made to Bradley (in conjunction with one of his doctoral students). Two of them were in the area of brain imaging, and the third one on genetics will be described in the next section. When asked about the AFSA grants, Bradley and Cianfrini provided the following comments to help explain how your contributions are working to advance research on FMS:

"It has been a great pleasure to work with AFSA over the past eight years and we greatly appreciate the opportunity to describe how patient donations to AFSA have helped us further our understanding of FMS. Our colleagues at the University of Alabama at Birmingham (UAB) include both clinical and basic scientists in the Division of Clinical Immunology and Rheumatology, the Department of Physiology and Biophysics, the Division of Neuro-Nuclear Medicine, the Medical Genetics Laboratory, and the Department of Biostatistics. We also collaborate with clinical and basic science colleagues at universities in the United States, Canada, and in Europe. In addition, several graduate students have completed their doctoral studies in our laboratory with AFSA support. These new investigators include Leslie A. Aaron, Ph.D., MPH, who is continuing her research on FMS and CFS at the University of Washington (working with Dedra Buckwald, M.D.), Kristin R. Alberts, Ph.D., who is now at Jacksonville University in Florida, and Ronald Alexander, Ph.D., who is a Major in the US Air Force.

"We have been awarded three grants from AFSA. Two of these grants have allowed us to study the extent to which depression and other mood states influence pain sensitivity and brain function in patients with FMS and the third grant allows us to produce renewable samples of DNA from consenting patients and their family members for current and future studies of genetic influences on pain sensitivity in women with FMS. These grants have contributed to our ability to compete successfully for larger research awards from the National Institutes of Health (NIH), which has supported our work since 1992. In addition, AFSA grants have provided support for studies of important FMS-related problems that could not have been examined through NIH grant mechanisms. A good example was the study performed by Cianfrini to demonstrate that FMS is not a form of depression.

"We hope this article has increased your understanding of how the AFSA research grant program has provided great help to our FMS research program and to the training of new FMS investigators in our laboratory. It is important to remember, however, that a large number of investigators have received research support from AFSA. Thus, our experience is just one example of the very positive influence of AFSA on FMS research across the United States. We wish to thank AFSA for its support and especially thank everyone in the FMS community for their contributions to the AFSA research grant program."

New Imaging Technique Shows Promise

The last study AFSA funded in November of 2002 was in the area of brain imaging. Patrick Wood, M.D., the study's principal investigator and an assistant professor of medicine at LSU in Shreveport, LA, is in the process of evaluating FMS patients using proton MRS technology. The MRS stands for magnetic resonance spectroscopy. As described in our last Update, this brain imaging tool allows scientists to measure the chemical content of various tissues within the brain, and this in turn can help explain why the brain is not functioning properly in people with FMS.

Wood is already underway with his study and is focusing his attention on the hippocampus region of the brain. This is an area within the limbic system that plays a role in memory and learning, stress inhibition, and the routing of pain signals from the spinal cord to the brain. The hippocampus communicates with several other important structures as well, such as the hypothalamus, locus coeruleus and the amygdala. So if the structural integrity of the hippocampus is disrupted in patients with FMS, this could explain many of the symptoms and drugs known to protect the hippocampus may prove beneficial.

The description of Dr. Wood's study which appeared in the November 2002 Update, prompted a number of questions about how this study might lead to treatments for FMS and possibly CFS. Understandably, patients wanted to know what these "hippocampal protective" drugs were and they wondered why we didn't list them. The problem is that there are a variety of drugs that may protect the hippocampus, but this is not the purpose for which these drugs were designed and they may operate by a variety of different mechanisms. With this in mind, we asked Dr. Wood questions pertaining to treatment rationales based on his theory that the hippocampus' integrity could be disrupted. Our questions and Wood's responses are provided for you below so that contributors may better understand the importance of this most recently funded project by AFSA.

1. Isn't the main goal of your project to provide baseline data on patients so that you (or other investigators) can then proceed with drug testing?
First of all, if we can demonstrate a difference between FMS subjects and controls with regards to the metabolite concentrations within the hippocampus, then we have theoretical justification for treating FMS patients (or, designing trials) with agents aimed at improving hippocampal function and integrity. Second, the metabolites we are measuring via MRS (especially N-acetylaspartate) are markers of neuronal function and integrity. If we can indeed prove that there is a difference in hippocampal function between FMS subjects and controls, and if (as suggested by the medical literature) the hippocampus can be positively impacted pharmacologically, then one would anticipate that these values in FMS should normalize.

2. The research paper you sent AFSA regarding the role of estrogen replacement therapy (ERT) implies that estrogen has a protective effect on the hippocampus. Doesn't this impact your study design?
Yes, there is evidence in the literature to support the role of ERT in maintaining hippocampal integrity as demonstrated by MRS. In order to ensure that low-estrogen levels in our study participants do not confound our findings, all study participants must be female and between the ages of 30 – 50 with regular menstrual cycles. (This does not mean that the data generated will not benefit men with FMS or women who are post-menopausal; the rationale for testing only premenopausal females was to minimize variability in our findings, especially since this is a small, preliminary study.)

3. You have indicated that you use drugs to decrease glutamatergic hyperactivity in order to decrease NMDA receptor activation. How do you decrease glutamatergic activity with GABA-acting agents? In other words, how does this protect hippocampal function?
It is helpful to think of many neurotransmitter systems as embodying a sort of yin-yang balance between elements. Glutamate, which binds to NMDA receptors, is the primary excitatory amino acid (the yin element of neurotransmission). GABA, then, is the inhibitory yang, which balances glutamate's excitatory influence. Excessive glutamatergic flow leads to excitatory overload by allowing toxic levels of positive ions (such as calcium) into the neuron. GABA-acting drugs allow the influx of negative ions (such as chloride) into the neuron, to offset glutamatergic excitation.

4. On your long list of potential therapies for FMS, you have beta-adrenergic receptor antagonism (lipophilic) drugs, and included in this category is the drug pindolol. This is the drug that you tested in a preliminary study involving FMS patients. Could you elaborate on why this class of drugs might work and why you selected this drug to test? Also, don't these drugs reduce blood pressure? Most patients with FMS have problems with low blood pressure and any drug that even slightly reduces blood pressure is not tolerated. Perhaps you could offer your theory on this class of medications, and a brief description of them in layman's terms?
Yes! The rational behind the use of lipophilic beta-antagonists goes something like this:

• FMS is a stress-related condition; ergo, stress-related hormones (cortisol, CRH, norepinephrine) must participate in FMS phenomena. (Stress … indeed, all of life … is chemicals.)
  
• Stress-related hormones enhance NMDA receptor activity, including norepinephrine acting at beta-adrenergic receptors within the hippocampus.
  
• NMDA receptors participate in FMS phenomena, especially pain (per Arendt-Nielsen et al., and others).
  
• Ergo, block the cycle of beta-adrenergic receptor/NMDA receptor synergy and you interfere with the phenomena in which this interaction participates, including (theoretically) stress-related pain transmission. Voila!

It is therefore also intriguing to note that propranolol, another lipophilic beta-antagonist is already used in the prophylaxis of migraine headaches, another pain disorder related in part to NMDA receptor dysfunction.

As far as the low blood pressure is concerned, the reason for this (I believe) may be derived from the work which has demonstrated excessive sympathetic activity in the context of FMS. By analogy: it was once considered anathema to give patients with congestive heart failure a beta-blocker—the rational being that they needed sympathetic tone in order to compensate for their failing hearts. As it turns out, the reason the heart is failing is that it has withstood years of sympathetic hyper-drive, which has taken its toll. It's now the standard of care to gently beta-block the patient with congestive heart failure, in order to allow the failing heart to recover sensitivity to adrenergic tone. Likewise, if we gently block adrenergic (and noradrenergic) tone in FMS patients, who have withstood years of adrenergic (i.e., sympathetic) hyper-drive, then we allow both their neurological (hippocampal) systems, as well as their cardiovascular systems (especially their baroreceptors that work to control blood pressure) to recover normal function.

5. Pro-inflammatory cytokines have been described in the literature as causing destruction of the hippocampus (apoptosis). There is a new drug under investigation called CNI-1493. It is supposed to cross the blood-brain barrier (very important) and acts like giving Valium to the activated glial cells that are pumping out these awful cytokines. What are your thoughts on these types of drugs that will soon be released for use for other conditions (rheumatoid arthritis and Crohn's disease)?
I am interested in the cytokine inhibitors, although I'm not sure to what extent cytokines play a role in the theoretical disruption of hippocampal function and integrity in FMS. Two things are noteworthy, though: IL-1b, IL-6 and TNF all participate in a feed-forward cycle in conjunction with the stress hormone, CRH, in terms of revving up the stress response. Therefore, it stands to reason that they may play a role in the etiology of stress-related disorders of all stripes. Secondly, elevated levels of circulating inflammatory cytokines (especially IL-6) have been demonstrated in patients with congestive heart failure, which have then been demonstrated to normalize following treatment with carvedilol, a lipophilic beta-antagonist used to treat congestive heart failure. (Things that make you go hmm…)

6. Is there anything you wish to add that would explain your concept of protcting hippocampal function? Also, could you provide a short description of what the hippocampus does?
The hippocampus is exquisitely sensitive to the effects of stress-related hormones, which all act (by way of various mechanism) to enhance NMDA receptor function and therefore excitatory signal flow. Excessive excitation leads to atrophy and dysfunction. Therefore, anything which interrupts the cycle of stress-related excitation has the potential to be beneficial in the context of FMS.
So, what does the hippocampus do? Consider:

• The hippocampus is fundamental to declarative memory. Hippocampal dysfunction would therefore lead to slowing of information processing, degradation of short-term memory, and errors in simple language processes (i.e., word-searching). This might serve to explain the phenomenon of fibro fog.
  
• The hippocampus provides the major inhibitory drive to stress response centers, including the central amygdala and paraventricular nucleus, as well as the locus coeruleus. Hippocampal dysfunction would then lead to an uninhibited stress response system characterized by (1) excessive CRHergic activity, and (2) sympathetic over-activity. In fact, both have been demonstrated independently in the context of FMS.
  
• The hippocampus is a center for pain signal processing, including chronic pain. The process of hippocampal nociception is an NMDA receptor-related activity. It is therefore especially intriguing that FMS pain has been demonstrated to be a NMDA receptor-mediated process (at least in part) in a majority subjects.

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What's Driving Your Symptoms

Speaking at the March 2003 American Pain Society meeting, Laurence Bradley, Ph.D., of the University of Alabama at Birmingham (UAB), provided an overview on FMS. He has evaluated pain thresholds from FMS patients in the community as well as those who attend his UAB clinic for care. "Whether we look at people from the clinic or from the community, we see widespread abnormal pain sensitivity," says Bradley. "Essentially, the pain thresholds for FMS patients are about one-half the level of the measured values for healthy controls." Bradley went on to explain that this pain sensitivity phenomenon was observed for both pressure pain stimuli and thermal pain stimuli. Also, the finding that patients have one-half of the pain threshold has been replicated by other laboratories, including the University of Michigan team involving researchers Daniel Clauw, M.D., and Richard Gracely, Ph.D.

The extensive pain sensitivity and scientific data on FMS strongly point to the likelihood that FMS is caused by abnormalities in the central nervous system's pain-processing systems. The term for this in the pain literature is central sensitization, but there is just one problem alluded to by Bradley. "If we are going to assume that central sensitization might underlie the abnormal pain sensitivity in FMS, we have to ask the question: What drives the central sensitization?" He adds, "One of the investigators who has really focused most of his attention on this problem is Haiko Sprott, M.D., from Zurich, Switzerland." The question of what is driving the central pain state involves looking at the tissues and the blood for abnormalities that could be sending a steady stream of nociceptive inputs (noxious signal transmissions) to the central nervous system.

Conceptually, a central pain state cannot thrive by itself without noxious inputs to keep it going. In this section, we describe research projects funded by AFSA that have identified abnormalities in the periphery (tissues or blood) that could be feeding the central pain state. In a manner of speaking, these factors might be involved in driving your symptoms!

Abnormalities in the Skin

In 1997 and 1998, Haiko Sprott, M.D., presented data on various abnormalities in the tissues of patients with FMS that were all extremely intriguing. This was around the time when most scientists were abandoning their search for abnormalities in the tissues to hone in on problems in the central nervous system. Sprott's initial work was not funded by AFSA, but caught the attention of our grant reviewers. For example, he also found abnormalities with the opioid receptor system in the skin of patients with FMS. The number of patients tested was small and the results needed to be confirmed on a larger scale.

In 1999, AFSA funded Sprott to expand his work on evaluating the opioid receptors in the skin of patients with FMS. His preliminary findings were described in our August 2001 Update. There are three types of opioid receptors: mu, delta and kappa. Sprott found that the kappa and the delta opioid receptors were increased in the skin of people with FMS, with the finding being most significant for the delta receptor. Despite the increased population of opioid receptors, patients with FMS still have significant levels of pain. Medications that work on the delta opioid receptor may open up a new avenue of treatments for FMS, possibly with fewer side effects because they would act on the receptors in the periphery rather than those in the central nervous system.

Sprott plans to continue his work in this area to investigate why these opioid receptors are increased in the skin of patients with FMS. Further experiments will also be needed to convince the pharmaceutical industry to create specific drugs that could target the opioid receptor anomaly found in FMS.

Recently, Sprott and coworkers published findings of elevated cytokines in the skin of people with FMS.¹ Roughly 30% had increased concentrations of interleukin-1b (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a) ... all pro-inflammatory cytokines. He hypothesizes that a subset of FMS patients are experiencing an inflammatory-like phenomenon in their tissues and that this may be why some patients respond to anti-inflammatory medicines (e.g., ibuprofen, naproxen, etc.). The possible link between the abnormality in opioid receptors and the presence of cytokines in the skin of a subset of FMS patients is an area of future research that Sprott is interested in exploring.

Sprott is a rheumatologist at the Center of Experimental Rheumatology and WHO (World Health Organization) Collaborating Center for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases. He is in the process of preparing manuscripts on his AFSA-related findings and has kindly provided feedback for our donors about the significance of his two AFSA awards:

• The two awards gave me the opportunity to investigate possible new pain mechanisms in FMS patients. This in turn will hopefully provide input to the pharmaceutical industry to develop and/or to check specific drugs for FMS patients.
• With AFSA's assistance, we were able to step into a new field in FMS research, in particular, to investigate novel pain mechanisms in this disease.
  
• Although our research is basic science in nature, we hope to identify the pain regulatory mechanisms involved in FMS. Such input will help us learn more about how the symptoms are generated and might help to develop new strategies in pain management for this patient group.
  
• As our next step, it will be important to further analyze these preliminary results, confirm them, and then determine if they are specific for FMS, or if they might also be present in other painful diseases.

Cytokines in the Blood

Traditionally, cytokines are considered in connection with autoimmune and inflammatory disease, such as rheumatoid arthritis, lupus, and Crohn's disease. Elevated cytokines are thought to be markers of immunological diseases, or that was the prevailing theory. However, in the 1990s, a few research teams reported on various immunological abnormalities in patients with FMS, including Daniel Wallace, M.D., professor at UCLA and rheumatology researcher in Los Angeles. In 1999, Wallace proposed to AFSA that various pro-inflammatory cytokines be looked at in connection with FMS.

At the same time, Linda Watkins, Ph.D., of the University of Colorado in Boulder, was conducting studies to show that elevated pro-inflammatory cytokines could lead to pathological pain states ... and possibly FMS. Recently, Watkins published a medical report explaining how cytokines are produced by the immune system's glial cells that reside in the spinal cord.² They also serve as the communicating link between the immune system and the central nervous system. When the glial cells become activated, for whatever reason, they produce pro-inflammatory cytokines. However, it can be hard to measure them because their concentration becomes diluted when they enter the general blood pool. In healthy humans, these glial cells are not activated, and therefore, don't produce pro-inflammatory cytokines.

What causes the glial cells to become activated? Watkins has been able to identify many neurochemicals capable of triggering their activation, such at NGF, SP, and NO. All of these substances are elevated in the spinal fluid of patients with FMS.

Understanding of the so-called neuro-immune link was in the early stages when Wallace submitted his proposal to AFSA. In fact, much still remains unclear. Fortunately, Wallace's findings have opened the eyes of many scientists in the field.³ Who would have thought that FMS had an immunological component and that these same substances (IL-1, IL-6, and IL-8) may be operating in the peripheral blood to feed or drive the central pain state? Wallace did back in 1999, and he has proven his "hypothesis" with excellent data generated by an AFSA-funded project. His findings were published in the July 2001 issue of Rheumatology and described in the January 2002 AFSA Update (now posted to our Web site). In addition, other investigators, such as Sprott, as well as Ali Gur, M.D., of Turkey, have also confirmed that cytokines are involved in FMS. It is unclear if they are the cause of FMS symptoms or are they the result of other problems going on in the central nervous system. However, Gur's findings have shown that the abnormalities in cytokines are associated with altered blood flow measured by SPECT analysis and that the elevation in IL-8 is strongly linked to pain intensity.^4,5

Why not shut down these nasty cytokine chemicals? Early drug development generated medicines that targeted only one cytokine, and they have to be injected either daily are bi-weekly (Kineret and Enbrel). These two drugs were made with rheumatoid arthritis in mind and probably do an okay job, but they won't help FMS patients. Not only do they target a single cytokine (IL-1 and TNF-a, respectively), they don't cross the blood-brain barrier. This oversight may not be devastating to patients with peripheral joint inflammation, such as RA, but it dramatically cripples the use of these drugs for central pathological pain states, such as FMS.

A new class of drugs, called MAP Kinase Inhibitors, are now entering the early stages of human trials for RA and Crohn's disease, and according to Watkins, they work to reduce the production of all pro-inflammatory cytokines from the glial cells. In fact, she described them at the March 2003 "Focus on Pain" conference as having a powerful calming effect on glial cells, greatly reducing their production of pro-inflammatory cytokines. But, will this new class of drugs cross the blood-brain barrier? Yes! Watkins was keen to investigate this issue (at least in rodents) over two years ago and published her results.⁶

Wallace's study was able to document elevated cytokine production very early on in the development of FMS, and this was confirmed by Gur. How early? Within the first two years of the appearance of symptoms. So drugs that quiet down the glial cells may provide an effective treatment option for patients with FMS, and possibly CFS. Wallace and Watkins are both actively trying to convince the manufacturers of MAP Kinase Inhibitors to consider testing their novel drug on patients with FMS, as well as CFS.

With the aid and friendly encouragement of Watkins, AFSA developed a "fact sheet" and approached one pharmaceutical company to determine their interest in having their newly developed drug tested in patients with FMS (the Fact Sheet is reprinted on the last four pages of this Update). Like all of the other companies, the one we approached has entered the early stages of human clinical trials and their drug is not yet FDA approved, but they are working on it. The good news is that they are willing to collaborate with AFSA, provide their drug free-of-charge for research, and complete the lengthy paperwork requirements with the FDA. However, they are a small–yet open minded–company that can't afford to pay for the trial itself. This means that AFSA must locate a qualified researcher (preferably one who is well-published) to perform a preliminary drug trial without a mega-buck stipend. AFSA's grant awards of $50,000 pale in comparison to what researchers are used to receiving from large pharmaceutical companies.

If you are a patient who is under the care of a successful rheumatology researcher, please ask them if they are interested in performing a pilot study using a MAP Kinase Inhibitor. Many rheumatologists are familiar with these drugs because they are being tested in patients with RA, and they are also most likely to have the technology to assay for cytokines because these evaluations are often performed by rheumatic disease investigators. Give them a photocopy of AFSA's Fact Sheet and let him or her know that they may contact us for more details. Unlike the rest of this Update, which is copy-protected, we encourage you to photocopy the FMS Fact Sheet for your physician ... even if they are not a researcher, they may find it informative.

Natural Pain Fighters Under Attack?

We described the pain-relieving system in the section on Tests To Validate Your Pain, and in that section, we mentioned that the body produces natural pain fighters such as endogenous opioids, endorphins, and enkephalins. According to Thomas Fasy, M.D., Ph.D., at Mount Sinai School of Medicine in New York City, there are more than 20 different compounds that would fall into the category of natural pain relievers called opioid peptides, including a recently identified compound called nocistatin. Nocistatin is made up of amino acids (that is why it is called a peptide) and has been shown to relieve pain. The site at which nocistatin works is within the spinal cord neurons, where the incoming neurons connect with the spinal neurons that relay messages to the higher centers in the central nervous system.

Fasy's first AFSA-funded project awarded in the year 1999 hypothesized that possibly one or more of these natural pain fighters might have autoantibodies that destroy them. If patients with FMS did have autoantibodies attacking their natural opioid peptides, this could explain the widespread pain, enhanced pain perception, and possibly other symptoms that might result from problems in pain-processing. In fact, the presence of autoantibodies could be one of the forces driving the central pain state of FMS.

The two major goals of Fasy's 1999 award were: (1) screen strains of mice with autoimmune diseases for the presence of autoantibodies to opioid peptides so that they could be used for human analyses, and (2) test the blood sera of 20 FMS patients and 20 matched healthy controls for the presence of autoantibodies. Fasy found one particular mouse strain that produced many different autoantibodies. He also estimated that one-third of the sera of patients with FMS had autoantibodies to nocistatin. This finding in the sera does not preclude the possibility that other autoantibodies acting on the receptors in the spinal cord may even be more problematic in a greater percentage of patients.

What can be done to compensate for these autoantibodies against nocistatin? Fasy says that there are two different types of drug therapies that may indirectly help the natural opioid pain system work more effectively. Both are still in the developmental stage but appear to be promising for FMS therapy. One class inhibits the enzymes that normally breakdown the opioid peptides, so that these pain relievers last longer. The other class acts on the enkephalin receptor to mimic the action of the pain-fighting enkephalins. Interestingly, this latter class of drugs operates on the delta opioid receptor. This approach could tie in Sprott's work, which shows an increased concentration of delta opioid receptors in the skin of FMS patients. Fasy adds that studies in rodents indicate that drugs which specifically activate the delta opioid receptor induce not only a pain-suppressing effect but also a mood-elevating effect.

Genetics

Laurence Bradley, Ph.D., provides yet another explanation of what may be driving your symptoms! "Our most recent grant from AFSA has provided a very important supplement to a new genetic-related project that is supported primarily by the NIH. The major aim of this project is to examine sensitivity to three forms of stimulation (pressure, heat, ischemic) among women with FMS (i.e., probands), healthy control women, as well as the sisters, brothers, and husbands of these women. This will allow us to determine the extent to which the male and female relatives of the proband and control women display abnormal pain sensitivity consistent with FMS. While females are being selected to minimize genetic variability, both male and female siblings which may also have FMS will be evaluated. A second aim of the study is to determine the frequency with which a specific structural defect or polymorphism occurs in the regulatory region of the serotonin transporter gene among the participants in the study. Two previous reports, one from Germany and the other from Israel, have shown that this polymorphism is found more frequently in women with FMS than in healthy women. However, we do not know to what extent the polymorphism is found in the family members of these women. Due to a limit on the budget we could propose to the NIH, we could not request funds that would allow us to generate and store renewable samples of genetic DNA from our consenting study participants. Thanks to support from AFSA, however, we now have the funding to support this important aim. This will allow us to identify the extent to which the family members may differ with regard to the presence of this gene polymorphism as well as other polymorphisms relevant to FMS that are identified in future research. Thus, the support from AFSA will positively impact our current and future research efforts. We hope that it increases the speed with which investigators learn about genetic influences on the pain sensitivity associated with FMS, thereby benefiting patients as well as their family members."

References

1. Salemi S, et al. Detection of IL-1b, IL-6, and TNF-alpha in Skin of Patients with FMS. J Rheumatol 30(1):146-50, 2003.
2. Watkins LR, Maier SF: Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82(4):981-1011, 2002.
3. Wallace DJ, et al. Cytokines play an aetiopathogenetic role in FMS. Rheumatology 40:743-749, 2001.
4. Gur A, et al. Regional cerebral blood flow and cytokines in young females with FMS. Clin Exp Rheumat 20:753-60, 2002.
5. Gur A, et al. Cytokines and Depression in Cases with FMS. J Rheumatol 29(2):358-61, 2002.
6. Milligan ED, et al. Systemic Administration of CNI-1493, a p38 MAP Kinase Inhibitor. J of Pain 2(6):326-333, 2001.

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Treatment Trials

Investigating therapies that appear promising but are not ordinarily prescribed for FMS/CFS patients is a high priority for AFSA funding. This goal may seem straightforward, but it is complicated by the multifaceted nature of the syndrome. Medications that work for pain don't usually help with sleep. Those that help keep patients alert and cognitively functional during the day don't mitigate the pain or sleep problems, and in some cases, they might hinder sleep. Then there are all of the other symptoms of FMS/CFS that often require specific treatments (both drug and nondrug), such as headaches, irritable bowel, jaw pain and dysfunction, and exercise intolerance. This means that the gold standard of treatment trials, which dictates that one group of patients be tested on a single medication while the other group takes a placebo, can present many problems when studying FMS/CFS therapies. Still, AFSA has funded four exceptional treatment trials on FMS/CFS patients to help open the door to treatments that may be underutilized. They also offer an understanding about why the prescribed therapies might work better in some patients as opposed to others.

As Dr. Leslie Crofford states in the "Neuroendocrine" section, the pharmaceutical industry is finally looking into therapies for FMS/CFS. This major accomplishment is essential for the future well-being of patients, but the drug company trials will take time and they will not involve inexpensive, unpatented medications that are currently available to patients. This is where AFSA funding can play an essential role in researching treatments. Our funding enables researchers to investigate drugs that are available to patients now!

Clonazepam

Many clinicians say that when they add clonazepam to their patient's treatment regimen, they find it very helpful. Although clonazepam is not under a patent (and therefore is relatively cheap), it is a benzodiazepine. Benzodiazepines are scheduled drugs, and because of this, physicians may avoid prescribing clonazepam to their FMS/CFS patients. Given the reluctance of many physicians to prescribe this readily available drug, Don L. Goldenberg, M.D., Professor of Medicine at Tufts University and Chief of Rheumatology at Newton-Wellesley Hospital, was awarded a grant to look at the efficacy of low-dose clonazepam in patients with FMS. Goldenberg, like many other clinicians, had found this drug to be very safe and free of most adverse side effects but its actual benefit to patients remained unknown. Does it work to improve sleep? Does it reduce anxiety as many benzodiazepines do? Does it impact pain in patients with FMS? These and many other questions needed to be answered.

Below, Dr. Goldenberg summarizes his study design (as illustrated in the diagram), his findings and their significance for patients with FMS ... and most likely for patients diagnosed with CFS:

"From January 21, 2000 until December 1, 2000, we enrolled 16 patients in a randomized trial of clonazepam versus placebo in fibromyalgia. This was designed as a crossover study and each patient received 0.5 mg of clonazepam and an identical looking placebo—each for a 12-week period. There was a washout period during which no medications were taken between the two 12-week sessions. In this crossover design, each patient functioned as their own control. The patients were examined at six points during the study. We evaluated each patient's tender points as well as each patient's assessment of global well-being, pain, sleep, and fatigue at six different time intervals.

"For each of these parameters, we found no significant difference in clonazepam versus the placebo. Although clonazepam improved sleep and fatigue significantly, the placebo response was just as robust. There was more of a homogeneity (consistency) in the response to clonazepam, whereas the placebo response varied dramatically. Some patients got much worse on placebo, but some surprisingly got much better.

"I do believe that clonazepam is a useful medication for FMS despite these results. However, it is not appropriate as a single medication since its primary effect is in regard to the sleep disturbances. It probably works best in patients who also have restless legs syndrome or periodic limb movements during sleep, and we did not assess these conditions during the study because it would have required expensive overnight sleep lab testing. We also might have obtained better results if we had used a slightly higher dose, such as 1.0 mg of clonazepam at bedtime. Finally, this randomized clinical trial demonstrates the importance of doing medication studies with a placebo and demonstrates the well-know, powerful effects that a placebo can have in the short-term."

Goldenberg did not encounter noticeable side effects with the use of clonazepam, nor did he observe any habituation problems after the 12 weeks that patients were placed on this drug. A simple one-week washout period was both safe and adequate. This study was designed to test the efficacy of clonazepam alone, despite the fact that most patients use multiple therapies for their many symptoms. If you are having sleeping problems similar to restless legs or uncontrollable limb movements, clonazepam may be a viable, safe option that may be "added on" to your other therapies to improve your quality of life. A reasonable starting dose is 0.5 mg, and based on Dr. Goldenberg's comments, you and your doctor may consider increasing your dose to 1.0 mg before deciding whether this line of therapy is helpful.

Bromocriptine and Melatonin

The numerous hormonal (endocrine) and neurotransmitter abnormalities in FMS patients present a treatment challenge. Serotonin in the blood and central nervous system appears to be low in FMS, and this could cause problems in the body's production of many hormones. In turn, these hormones may have a diverse impact on the symptoms of FMS, including pain and disturbed sleep. The breakdown product of dopamine (homovanillic acid) is also reported to be low in the spinal fluid of patients with FMS and represents yet another neurotransmitter that has a diverse impact on the way the body's neuroendocrine system's function.¹ For example, low dopamine levels are associated with higher than normal production of prolactin from the pituitary, which is known to increase anxiety. It's also believed to be low in patients with certain sleep disorders that are fairly common in FMS: restless legs syndrome (RLS) and periodic limb movements during sleep (PLMS).

Therapeutic manipulation of serotonin and dopamine levels in patients with FMS should lead to symptom improvements. This is what Robert McMurray, M.D., Chief of Medicine at the VA Hospital in Jackson, MS, proposed in his application to AFSA. McMurray evaluated the treatment of 16 patients in a double-blinded, placebo-controlled study of two different therapies taken at night for FMS: 6 mg of melatonin or 2.5 mg of bromocriptine. Melatonin works to increase brain serotonin levels, and has hypnotic effects that may aid sleep as well. Bromocriptine acts like dopamine and it also produces an anti-anxiety/anti-stress effect. McMurray figured that both therapies used together would work better than either one individually, but the purpose of the study was to tease out the specific effects of melatonin and bromocriptine.

The cross-over design, as illustrated in the diagram above, took 16 months for each participant to complete. Patients spent four months on placebo, four months on melatonin, four months on placebo, and then four months on bromocriptine. All patients were analyzed every four months of the study for the number of tender points, dolorimeter scores (estimate of pain tolerance), sleep, fatigue, pain, and morning stiffness. In addition to symptom parameters, McMurray also measured blood hormone levels of melatonin, prolactin, and cortisol. Cortisol was measured to estimate each person's stress level (stress activates the HPA-axis, which should then produce higher levels of cortisol). According to McMurray, initial analysis of the data suggest that each of the two medications may be useful for a subgroup of FMS patients.

On the whole, there was a 26% reduction of subjective pain in patients on bromocriptine compared to placebo (preliminary assessment). Some patients had dramatic improvements, however, that were hidden by statistical analysis, so McMurray looked at individual responses in the 16 subjects. He also compared the hormonal changes in patients who exhibited a positive response to determine if there were any trends that could predict a response to either drug.

Six of sixteen patients (38%) had a significant decrease in tender point number during treatment (4 with melatonin; 1 with bromocriptine; 1 with either drug) compared to their respective placebo phases. The average reduction in the number of tender points was 47% (14 tender points to 7.2 tender points) for melatonin. Similarly, six of sixteen patients (38%) had an increase in pain tolerance as measured by dolorimetry (2 with melatonin; 2 with bromocriptine; 2 with either drug) compared to placebo phases. Pain tolerance increased 68% in melatonin responders and 95% in bromocriptine responders. Melatonin improved sleep an average of 56% for the three patients responding to this drug. Neither drug produced any changes in fatigue or morning stiffness values. On average, it took close to three months to achieve the maximum benefits from either drug, and only one patient was identified as a "placebo responder."

Click here to see a table summarizing McMurray's results (PDF)

Overall, there were no differences in serum hormone concentrations of melatonin and prolactin during any of the phases. However, in patients responding to either drug, serum melatonin concentrations during treatment doubled. From this preliminary data, it appears that when either melatonin or bromocriptine produces a positive effect in FMS patients, it corresponds with a dramatic increase in their serum levels of melatonin (unpublished observation).

In contrast to the elevation of melatonin, there were no significant differences in serum prolactin concentrations between responders and nonresponders. This occurred despite the administration of the bromocriptine, a known prolactin suppressive drug. This suggests that either prolactin does not play a substantial role in the pathogenesis of FMS or that a 2.5 mg dose of bromocriptine was not sufficient to cause a reduction in prolactin levels and a higher dose may have been more effective. Similarly, there was no significant abnormality in serum cortisol concentrations or in the results of the dexamethasone suppression tests (used to look at the production of cortisol from the adrenal glands).

Preliminary analysis of study participants revealed subsets of FMS patients (20-40%) responding to neuroendocrine manipulation with either melatonin or bromocriptine, characterized by a decrease in tender points, an increase in dolorimetry, or sleep improvement. The average time to maximal response was approximately three months for either drug and improvement was associated with increased serum melatonin concentrations during the response period. McMurray cautions that the above information is only a preliminary analysis of his study and that formal publication of his data may provide more definitive conclusions. Also, further studies will be required to elucidate the significance of the above observations.

In an article published in August of 2001, Dr. McMurray reviews the use of bromocriptine for treating rheumatic and autoimmune diseases, including lupus, rheumatoid arthritis, FMS, migraine headaches, premenstrual syndrome, and fatigue.² He says that bromocriptine may be a nonstandard or add-on therapy for these conditions when they are unresponsive to traditional approaches. How does a drug that acts like dopamine work in these diseases that have such different physiologic causes? McMurray indicates that bromocriptine has many possible modes of action in addition to lowering prolactin levels, such as suppressing cytokine production (especially IL-6) or reducing nitric oxide. Elevated cytokines and nitric oxide production have both been found in patients with FMS.

A newer drug that works like bromocriptine, called Mirapex, was recently shown at the 2002 American College of Rheumatology meeting to be helpful for a subset of FMS patients. The purpose of the study (yet to be published), conducted by Andrew Holman, M.D., of Renton, WA, was to show that by adding a small dose of Mirapex onto the existing treatment regimen for 27 FMS patients, that their painful symptoms would be significantly reduced.3 The trial was not blinded or placebo-controlled, nor were any neuroendocrine measures taken to determine how the drug was producing its benefits in those patients who responded to the drug. However, the results indicate the need to better understand how dopamine-like drugs might ease the symptoms of FMS.

Dextromethorphan plus Ultram

Dextromethorphan is an NMDA receptor antagonist. Based on studies by Roland Staud, M.D.,^4,5 and others, there is strong objective evidence that the NMDA receptors in the spinal cord and brain are amplifying the painful impulses in FMS patients. Dextromethorphan has few side effects and is a common ingredient in over-the-counter cough syrups. Ultram has already been documented in the medical journals by I. Jon Russell, M.D., Ph.D., and Robert Bennett, M.D., as being effective in reducing the pain in many patients with FMS.⁶

Robert Bennett, M.D., of Oregon Health Sciences University in Portland, was awarded a grant in 1997 by AFSA to look at the ability of dextromethorphan to boost the action of Ultram, thereby providing better pain relief than Ultram by itself. At the 2000 American College of Rheumatology meeting, Bennett and his co-investigator, Sharon Clark, Ph.D., FNP, presented the preliminary results of their study. The preliminary ACR abstract is posted on AFSA's Web site. The study is now complete and has been submitted for publication in a peer-reviewed medical journal. It is hoped that this report will become available to treating physicians worldwide before the end of 2003 or early 2004.

What is the significance of this project to you, a contributor to AFSA? To help you evaluate the answer to this question, Dr. Bennett kindly answered a few questions posed to him regarding his award and the value of this project:

What did the AFSA award mean to you?
Receiving a research grant is always an ego booster to a researcher as it means that my peers have reviewed the proposal and found it worthy of support. Due to the competitiveness of research, the majority of grant proposals do not get funded; this is a fact of life for all researchers. This particular proposal was modest in its scope and had little chance of being funded by larger agencies such as the NIH. Much drug research in FMS is funded by pharmaceutical companies; however this is not available for drugs such as dextromethorphan which are not patentable and as such offer no financial incentives to industry. Furthermore funding by AFSA enables one to have more freedom in study design, with none of the "strings attached" to industry sponsored studies.

What did the project enable you to accomplish?
The notion that NMDA inhibitors may benefit FMS patients has only been shown previously in short term studies of intravenous ketamine. This current study was able to demonstrate that the orally available NMDA inhibitor, dextromethorphan, when added to a weak opioid (in this case tramadol) was of benefit to a subset of FMS patients in terms of improved pain relief.

How will patients benefit from the study?
Hopefully the results of this study will encourage other physicians to use therapeutic trials of dextromethorphan as a supplemental agent for pain management in FMS.

What new avenues of research have resulted from this AFSA award?
I do not consider that this study has opened up any major new avenues of research, but rather pointed to the relevance of considering an "enrichment design" in some FMS studies. (By "enrichment," Dr. Bennett refers to looking at the benefits of adding a new therapy onto a person's existing treatment regimen. This enables study participants to stay on stable doses of their current therapies, while the affects of a new add-on therapy are evaluated. When a condition being studied generates a multitude of symptoms and the underlying physiology is complex, such as it is with FMS, the "enrichment design" enables researchers to look at the added effect of a single therapy based on its suspected physiologic role. In this case, the dextromethorphan was hypothesized to interact with the NMDA receptors in patients to reduce pain amplification, and thus further reduce the overall sensation of pain.)

Effexor's Impact on Pain Inhibition

Effexor-ER is the brand name for the drug venlafaxine. It works primarily to increase serotonin in the central nervous system, but its secondary mode of action is to increase noradrenaline as well. However, Effexor's ability to raise noradrenaline is not as potent as its primary action to raise serotonin. As you have already read in "Objective Tests To Validate Your Pain," Serge Marchand, Ph.D., received an AFSA award in 2000 to conduct several different related projects. First, it was essential to determine if the diffuse noxious inhibitory control system (DNIC) could be accurately tested in humans to develop a database by which FMS and regional pain patients could be compared. As it turns out, the DNIC system does not appear to be operating well in patients with FMS (although it works well in regional low back pain syndrome patients) ... the manuscript for this study is being prepared for publication.

Naturally, if researchers find that a pain control system is not functioning up to par in patients with FMS, the next step ought to be to look at pharmacological agents that might help the system work better. This is the aim of the second part of Marchand's study: to test the effectiveness of Effexor-ER in 25 FMS patients during an eight-week crossover trial. Marchand measured the ability of each patient's DNIC system before and at the conclusion of the study so that he could learn more about how the drug might work. In most drug trials, medications are judged as helpful in a patient subgroup (mostly based on subjective measures), but "how" the drug operates in the body is rarely investigated. In the AFSA-funded trial on Effexor, Marchand hopes to shed more light on explaining "how" a drug that increases serotonin (and norepinephrine to some extent) may work to modify the function of an important pain-inhibitory system in the body.

Studies that look beyond the question of whether a given drug is helpful generate lots of data. Marchand was a key presenter at the 2001 American Pain Society's session on fibromyalgia treatments, where he briefly described preliminary findings pertaining to a portion of patients in the Effexor trial. However, the job of compiling the large amount of data that was generated by the study has taken considerable time. As soon as the Effexor study appears in the medical journals, we will provide you with more details of the study findings, along with feedback from Marchand regarding his interpretation of the project outcome.

References

1. Russell IJ, Vaeroy H, Javors M, Nyberg F: Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis & Rheum 35(5):550-6, 1992.
2. McMurray RW: Bromocriptine in rheumatic and autoimmune diseases. Seminars in Arthritis and Rheumatism 31(1):21-32, 2001.
3. Holman AJ: Pramipexole for fibromyalgia: the first open label, multicenter experience. Arthritis & Rheumatism 46(9, suppl):S108, abs#189, 2002.
4. Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD: Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. PAIN 91(1-2):165-175, 2001.
5. Staud R, Robinson ME, Vierck CJ, Price DD: Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. PAIN 101:167-174, 2003.
6. Russell IJ, Kamin M, Bennett RM, Schnitzer TJ, Green JA, Katz WA: Efficacy of tramadol in treatment of pain in fibromyalgia. J Clin Rheumatology 6(5):250-7, 2000.

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