New Developments in Fibromyalgia

Grand Rounds


Graciela Alarcon, MD
Jean Knight Lowe Professor of Medicine in Rheumatology
University of Alabama at Birmingham


  1. Fibromyalgia and Its Prevalence
  2. Diagnosing and Studying Fibromyalgia
  3. Pathogenesis
  4. Treating Fibromyalgia
  5. Fibromyalgia vs. Chiari Malformation
  6. Challenging the Existence of Fibromyalgia
  7. Diagnosing Fibromyalgia with Other Rheumatic Conditions
  8. The Role of Serotonin in Fibromyalgia
  9. Fibromyalgia and Chronic Fatigue

 

Stephen A. Paget, MD: It's a pleasure today to introduce Graciela Alarcon, who is the Jane Knight-Lowe Professor of Medicine and Rheumatology at the University of Alabama. She and her group at the University of Alabama have really given us excellent information about diagnostic tools, clinical aspects, and also therapeutic aspects of this very common disorder, fibromyalgia. However, she could just as well be talking about her long- term studies on undifferentiated connective tissue diseases, systemic lupus erythematosus in Latino women, rheumatoid arthritis treatment with Minocycline and other tetracycline type medications, and her over 240 publications. She has really touched every area of rheumatology, and has done it in a methodologically sound and high quality way, and she is respected by the whole international community. It is a pleasure to welcome Graciela here to talk about fibromyalgia.

Graciela S. Alarcon, MD: Thank you Steve for this nice introduction. As I was talking with Steve before the talk, when I trained in rheumatology, I was taught that fibrositis, which is what we call fibromyalgia, actually didn't exist. It only happened at Cleveland Clinic, but not at Hopkins. Over the years, however, we have accepted the fact that this is a condition that we rheumatologists see, and see quite often.

Fibromyalgia and Its Prevalence

To prepare for this talk, I went ahead and reviewed the literature. Just to give you an idea of the number of publications that we have now in the area of fibromyalgia, this is a number of publications over 30 years and this is the number of publications over the last six years. We can see, in rheumatology journals, roughly half the literature has appeared over the last six years. If you stand them up, it's just about half and half over the last six years. The same happens with the medicine journals, and if we combine them, we can see that we have really an avalanche of information coming from different centers around the world.

When this happens, there are two things that we need to be very careful about, because obviously not everything that is written is actually true. We have to try not to over interpret the literature and apply those kinds of interpretations before they are actually proven.

It's impossible to discuss the 1000+ papers that have appeared over the last six years. I will just limit my presentation, then, to some general comments. Then I will emphasize some of the aspects of our research program at UAB, and then I will go to the pathogenesis, from which I will bring data from other investigators. And finally, I will give you my words of wisdom, if any, about the treatment of these patients.

We actually see more fibromyalgia now, more frequently, and any time that rheumatologists have this number of patients flocking to our clinics, the question is "Is it real, is it more frequent, or it is just an artifact, due to the fact that it is recognized and accepted". The patients seem to come more often.

What are he attributes of fibromyalgia? It is more frequent in adults; it is much more frequent in women. There is literature to suggest that it is more frequent in Caucasians than non-Caucasians. Part of that could be just access to medical care. As the word goes around about this, we are seeing more and more non-Caucasian patients.

In terms of place, it seems to be more concentrated in urban areas. But we are starting to see people coming from the rural areas. In terms of frequency, the condition is far more frequent than rheumatoid arthritis, and depending on the survey, it can go up to about even 10% of the population. Probably the figure is much lower than that, but still higher than rheumatoid arthritis.

Perhaps the birth certificate for fibromyalgia was issued in 1990, endorsed by a committee from the ACR, which published the criteria of classification of this disorder. Patients with fibromyalgia could be called such if they had generalized pain in at least 11 of 18 tender points, which are very specific in anatomical sites. The question is whether this criterion is useful in a clinical setting, and whether you can make a diagnosis of fibromyalgia with fewer tender points, which, of course, you can, and if there may be alternative criteria such as when the patient presents with other typical manifestations, sleep disturbances etc.

These are the manifestations that I am referring to. Patients that may not have 11 of 18 tender points may have generalized pain, the myalgias and arthralgias and particularly the fatigue and insomnia. In terms of minor clinical manifestations, many of our patients complain of joint swelling that we can really not see. It's subjective, and that is one of the reasons that we become so skeptical about those patients. Patients complain of dysesthesias, muscle spasms, or morning stiffness, usually lasting less than required for the diagnosis of classification of patients with rheumatoid arthritis.

In younger individuals, and especially in children, we see a lot of hypermobility. Here we have a picture showing that we have seen these symptoms even in the pre-Inca times. This is a self- portrait of Frida Kahlo, a woman who had a very terrible accident when she was very young, depicting herself with chronic pain and multiple dysesthesias. The patient is saying she hurts everywhere, and she is depicting herself with pins and needles even on her forehead.

Now patients with fibromyalgia are really seekers of medical care. We can see here that they don't just to go to rheumatologists. They go everywhere with a variety of complaints. We physicians tend to sometimes overdo it, and order more studies than we need to, and reinforce a negative behavior, so patients are subjected to cystoscopies and different imaging studies. And it is clearly shown in the literature that they undergo surgical procedures at a higher rate than non-fibromyalgia patients.

Diagnosing and Studying Fibromyalgia

This is how they come to us, and in many cases they come with a "rule out lupus" diagnosis, based on the fact that they have a positive ANA. We have to study those individuals -- "fibromyalgia-like ANA positive patients" -- and if they don't have all the manifestations of lupus, there is really no point of doing exhaustive serological studies.

Many other patients come in with the diagnosis of fibromyalgia fundamentally seeking better care. We have a pain researcher. I'm the rheumatologist on the team. We have a psychologist, physiologist, and a neuroradiologist. Over the 12 years we have had a number of graduate students and post-graduate students helping us in our research. We couldn't have done it without them. We studied initially three groups of individuals. First, the patients are those meeting criteria and seeking medical care for these complaints. Second, we studied a group of individuals from the community that met the criteria but were not seeking medical care, and we called those non-patients. And third, there was a group of healthy controls.

More recently, we studied two groups of individuals. We had a group of chronic fatigue patients and a group of depressed patients. The way we have conducted our studies is that we have advertised, used newspapers, radio stations, the internal magazines at the University, etc., to put ads seeking, for example, individuals with aches and pains that are not under a doctor's care.

The first step after the ad is placed is to screen those individuals over the phone using validated interviews, and that would exclude whatever we want to exclude in those groups. And then, I review the records of the patients that pass the interview. Then they come to the UCRC, where they have another interview and physical exam to be sure that they don't have any other reason to be excluded. For example we would exclude individuals that have had CNS pathology, back surgery, neck surgery, head surgery, etc., so our subjects are really clean of co-morbidities, and, of course, any other impediments to the studies. The patients are withdrawn from their medications over time so that when they are actually entered into the study they are not taking any medicines.

This is the original data that we published, which shows the threshold of the tender points for the three subjects that we initially studied, the patients, the non-patients and the control. Half the controls have a threshold way above what is accepted as the mark for fibromyalgia, which is 4 kilograms, and the patients have much lower pain thresholds. Another thing that the graph clearly shows is that this data is stable over time. In other words, the patients are not getting any better as we continue our studies, suggesting that whatever we do is not really helping them. The thresholds just remain really very low.

This is the same data that now are the control points. Once more the graphs are really looking very much the same, however, the thresholds are a little bit higher. This suggests really that the control points are not truly control in the sense that the thresholds are going to be much higher. Another thing is that this perception in terms of painful stimuli is everywhere, not just in the defined anatomical sites.

This is an instrument in which we measure anxiety, and we see the reverse here. The fibromyalgia patients have higher levels of anxiety as compared to the non-patients and the controls, and this data is also very stable over time. This next graph shows the same graduation, and, in this case, the scores are for depression. So the patients seem to have higher scores in the Center for Epidemiologic Studies Depression Scale depression scores as measured here, compared to the non-patients and as compared to the normal individuals, who really score much lower. Once more, as with the painful points or the anxiety scores, this data is very stable over time.

So what we have shown with this data is that the ones that tend to seek medical care are those that are more emotionally troubled. So that what probably brings the subjects to the hospital or the tertiary care centers is not the pain, per se -- because we have individuals that have pain also in the community that are handling it very well -- but actually their degree of psychopathology and psychological stress.

Subsequently, what we did is try to get to the bottom of the pathogenesis of pain in these patients. So we went ahead and studied the CSF of a group of individuals with fibromyalgia, the non-patients as well as healthy controls. We can see over here the levels of substance P, one of the neurotransmitters involved in pain sensation are actually much higher, and this is true for both fibromyalgia groups, the patients as well as the non-patients. This suggests actually that they are not really too different from the point of view of the alteration and pain perception, and they are really different in the way they respond to this alteration.

Subsequently, our group was the first one to come back to study and try to understand what is really going on in patients with this disorder. And, as we can see, these are the images or the uptake of in the caudate nucleus both in the left, the right and the average. We can see that the patients and the non-patients behave very similarly in these imaging studies, where we see that there is a decrease in original cerebral blood flow to the caudate in patients and non-patients, and we can see that there are much higher levels in the control individuals. As we know, the caudate is involved in pain modulation. This is the data for the thalamus, where there are lower levels of blood flow to the thalamus as well, although the difference was not statistically significant.

Now, following some of these non-patients over time has allowed us to see something very interesting. Initially, I was very reluctant to bring more fibromyalgia subjects to the clinic. I felt that everybody was going to turn from being a non-patient into being a patient. However, this is a follow-up of these subjects over a 30- month period. What we are seeing is that the large majority remained as non-patients, where some of them convert, so to speak, to being a patient, seeking medical care. When we tried to see what the predictors for this conversion were, what we saw was that those that had more than one life time psychiatric diagnosis (and that is determined by a structured interview) were more likely to convert to the category of patient.

I must add that we did not take those as non-patients that could not be patients by virtue of, for example, the fact that they didn't have any insurance. Those were excluded because they weren't really non-patients; they just didn't have access to medical care. We can see that the number of lifetime psychiatric diagnoses is much higher among those that converted, and we called them new patients as compared to the ones that remained.

I don't have the graph, but we continued observing these individuals, and a large majority has remained as such. Thus we strongly believe that it is really the psychopathology or the distress that they have that brings them into the hospital or into the tertiary care center rather than pain per se.

Now some investigators, because of the psychopathology, have suggested that fibromyalgia patients belong to the spectrum of the affective disorders, and fibromyalgia should be along with dysthymia, bipolar disorders etc. Because of that, we wanted to include as a control group a group of patients with depression. The other reason is that we were told the abnormalities that we have shown are really not only seen in fibromyalgia, they can be seen also in depressions, so we wanted to prove whether or not that was the case.

Then there is the argument that chronic fatigue and fibromyalgia may be overlapping conditions. Many patients with fibromyalgia present with significant fatigue and vice-versa, and therefore we wanted also to include this group. And it is not easy to really review records of patients that have been diagnosed as having fibromyalgia. They may measure several inches in thickness to review those records, and really for an hour we met with those individuals.

Nevertheless, after meeting criteria, those individuals were accepted into the study. And, as we can see here, this is the pain threshold level as a function of the group. We can see really that our screening process discriminated pretty well. We see that only the fibromyalgia subjects were the ones with lower pain thresholds as compared to the other three groups, which were really above the 4 kilograms, which is the mark established by the ACR.

Likewise, we were able to separate pretty well in terms of depression. On this scale, the patients with depression were the ones with a score of higher in this instrument. So this actually validated the screening process that we developed over the years at our center. I must remind you that in these studies, like in the other studies, the patients were off medications and we exclude patients with depression that had significant reasons to have musculoskeletal pain, so, if anything, this is a very pure group of depressed individuals.

These were all right-handed women. We tried to do stimulation studies to see if there are any changes in the brain blood flow after stimulation. So we didn't study men, because the proportion of men in most series is about 10%, so that is going to give us a very small number to do it with statistically. And we eliminated anyone that was not right-handed, because that eliminated activation of the other side of the brain.

So in the resting state, the patients have to be screened and off medicines and were asked to rest for one hour and then the needle was injected. The tracer was injected and five minutes later the patients were taken to nuclear medicine to have their SPECT examined. Now, in the case of the stimulation studies, the difference was that after the individuals rested in a quiet room for one hour, then the stimulation began and to do that, each subject was stimulated in three tender areas, with three kilograms about the old threshold for that particular point.

That means that for the fibromyalgia patients, they were stimulated at a much lower level than the other subjects in the other three groups, so despite that, you are going to see the results. So the stimulation began. Each point was stimulated ten times, 30 times all together, so when that finished, the needle was retrieved. The subjects were asked to complete a pain questionnaire and they underwent the SPECT study.

This is to corroborate what I just said. These are the three tender areas that were examined. These are the four study groups, and as we can see, the fibromyalgia subjects were stimulated with much lower levels of pressure as compared to the patients with depression, chronic fatigue or the controls, and the differences were highly statistically significant. This reinforces the fact that much lower pressure was being used in those individuals.

This is how the individuals perceived pain at a sensory level after the stimulation. We can see the fibromyalgia patients were the ones experiencing higher levels of pain despite the fact that they were stimulated with much lower levels of pressure. The unpleasantness reaction of pain was greater among the fibromyalgia patients than among the other three study groups.

This is what is called a statistically parametric method. What it does, what you are doing here, you are comparing all the images for one group, so this is within subjects and between subjects, and what the computer is doing is calculating the T-value and the P-value of each one of the subjects. And for the difference, what you are getting is really areas that go from blue to red. The red is the area where there is the most significant difference. This is corrected for the number of comparisons made, so what we have is a summary image that represents all the healthy controls in the rest period to pain period.

So we are comparing the stimulation period to rest period in all the controls and this is the summary image that actually shows the areas with a lot of statistically different. We can see here the left hemisphere, and what we are seeing is an increased uptake in the contralateral side. So in the left hemisphere we are really seeing increased blood flow to the thalamus and to the ACC (anterior cingulate cortex) which is the one that deals with the unpleasantness of pain.

We are seeing in this other view, also the 25 healthy controls that we have studied so far, increased uptake in the left somatosensory cortex. So, if you go much higher in a normal subject and stimulate way above threshold level, you are going to see bilateral activation, but if you stimulate at the levels that we have used, you are only going to see unilateral activation. And because all the subjects were right- handed, what we are seeing here is activation in the left side of the brain.

Now this is what happened in our fibromyalgia subjects. We had 22 individuals. What we are seeing is that the activation occurs not just in the left side of the brain but also in the other side. So, despite the fact that we are using lower levels of pressure, we are achieving bilateral activation of the brain, and that is seen in the thalamus as well as the ACC (anterior cingulate cortex) and the somatosensory cord. So, in the three areas involved very much in pain unpleasantness, we are seeing bilateral activation.

Now in the case of the depressed patients, the numbers are not quite as robust. Nevertheless, the data seem to indicate so far that the activation is primarily in the left side in these right handed individuals, and we can see that in these views and here in the somatosensory cortex also. Primarily the activation is in the left side of the brain.

In patients with chronic fatigue, we have been able to study so far nine subjects. So we really have to increase our numbers to make conclusions, but it appears that the activation is also primarily in one side. And remember, these subjects were stimulated with much higher levels of pressure as compared to the patients with fibromyalgia.

So obviously, we have not studied everything in fibromyalgia or I could not present everything that we have studied because of time constraints. However, I think that our group has contributed significantly to make the point that fibromyalgia is a condition in which there is a disorder of pain regulation. And that is expressed as allodynia, meaning that the pain is spread beyond the area where the pain actually occurs, or the stimulus is applied and hyperalgesia -- which means that something that is not painful is perceived as painful -- occurs.

Pathogenesis

There are many ways in which you can end up coming to the doctor seeking medical care. We strongly believe that you have individuals that have this disorder of pain regulation that live with it. And that normal pain behavior, which is really aggravated by psychopathology or psychological distress, is what takes these individuals to the tertiary care center. In many cases, when they come to us they already have altered physical and mental function, and very much altered social relations. They are seeking disability; they are really in very poor shape.

You can end up here in this allodynia and hyperalgesia many ways. The end point of the level of the central nervous system appears to be an increased excitability of the dorsal horn and that is mediated in MDA receptors. Now we can get there by starting up here, for example, by saying that the individuals have genetic susceptibility. That has been a study already, and at the present time we are doing family studies to try to understand whether the increased incidence of fibromyalgia in families is due to genetic predisposition or simply to nerve behavior, which can be a combination of the two, which is probably the case.

It can start by having an infection and then end with a pain syndrome. That has been described in Lyme disease for example. Many of our subjects have sleep abnormalities that alter the growth hormone, and that contributes to a defect that may contribute to pain. So there are many ways that you can end up over here and this is what we actually see. Many groups are in the study. In our study at the present time, for the most part we have concentrated in this area. Actually we wrote a review paper not too long ago for one of the neurology journals that says that there is enough evidence from our work and that of others to suggest that there is altered pain regulation in patients with fibromyalgia, and that probably the contribution of the periphery is really minimal as compared to the contribution of the central nervous system.

So I just want to make a few comments. Doing research in fibromyalgia is fun. We see the patients, we screen them. Our study does not involve treatment. We tell them that we don't yet have a treatment protocol to get them into anything that is really scientific.

Treating Fibromyalgia

So the best we can do is provide general guidelines in terms of what is good and what is bad. I think that patients benefit from exercise, in a structured program, if they are willing to do it. It is preferred to do an aquatic program. Pharmacological agents should be used very judiciously. The support groups can be very helpful, but sometimes but they really reinforce negative behavior.

Over the weekend, just for fun, I tried to see how many web sites for fibromyalgia are up now, and they go over half a million. So obviously, there is a lot of misinformation and perhaps our goal is to try to make that better understood to our patients, and to dissuade them from using unregulated information.

In the clinic, I have a list in my mind of what makes the patient have a good prognosis and a poor prognosis. Those with a poor prognosis are very sedentary, don't sleep well, are grossly overweight, are on sick disability, litigation, pending litigation, and already on a significant number of medications. Very likely they are going to continue doing poorly and they are going to continue shopping for doctors and no doctor is going to satisfy them. It is going to be very hard to get any better.

After I review my patients and examine them, I apply this little instrument that I took from one of the instruments we use in the research. It has 10 negative and 10 positive attributes that really are mixed, and we ask the patient to describe his or her attitude. Then we sum up all the negatives, like the stress, upset, guilt, etc. and the closer they come to 50, the more negative their coping styles are and the less likely the rheumatologists are going to do anything to have an impact on them. Those patients are better served by being referred to psychology or psychiatry for a comprehensive approach.

I'm not sure that psychologists or psychiatrists are going to be very effective in changing these coping styles, but they have the tools that we don't have to try to do it. In general, the treatment maneuvers that we have are really pharmacological agents, behavior interventions, and other maneuvers that I will review briefly.

Among the drugs we use are the antidepressants and SSRIs and other centrally active agents, such as new antagonists of NMDA receptors. Other psychotropics have been used, including anticonvulsants, and the success has been variable.

There is controversy about the use of narcotics with patients with fibromyalgia. There are other accepted methods that keep popping up in the literature, for example, the antiviral agents. I have seen patients come in and be prescribed Amantadine, and I ask why and someone finds a paper that somebody used it on three patients, and because of that, the doctors are actually prescribing it.

This paper that was published a few weeks ago in the American Journal of Medicine has made headlines in the New York Times. I'm sure it has some benefit, although more directly on the company, but has benefited somebody. However, I have to say that with the all the publicity given it, the study was only 12 weeks in duration. And you know that 12 weeks in duration really is nothing in terms of fibromyalgia, which is a lifetime condition.

So I think this study is not convincing at all and it doesn't have a follow-up in the long term, so you have to take it more than with a grain of salt. Different studies regarding this are conflicting. This is a figure from a study published in the American Journal of Medicine and we see this is as the fibromyalgia type questionnaire. It was much lower than in the study where patients treated with fluoxetine were compared with those that were treated with placebo.

The details about NMDA receptor antagonists is promising, but it is actually premature. We cannot use it in any clinical arena yet, because it is very short lasting, so you can produce an effect, but it is only very short lasting. And it's still, for the most part, intravenous administration, so they are not there yet for our patients, although they may be promising.

Most relaxants can be used or should be used in fibromyalgia patients who have some acute exacerbation which seems to be clearly muscle spasm or muscle sprain, but not in a chronic way, because they really lose their effect. However, if you look at the number of medications the patients are on, many of them are taking muscle relaxants on a very long-term basis and probably are taking them three times a day for a long time.

The use of nonsteroidals is also controversial. In reality, there is no proof the patients have inflammation in the peripheral tissue, so these medications are being used for their symptom effect and not for their peripheral effect. Once more, in a situation where the patient with fibromyalgia comes with a clearly localized pain in the shoulder over the trochanteric bursa, it makes more sense to use it, but not in the long term.

The data show that 90% of patients with fibromyalgia are taking nonsteroidals, and the question is whether we need to prescribe more expensive medications for pain control -- why not use an analgesic. Going to analgesics, the question is whether we should resort to narcotics for the control of pain. The problem with using narcotics is that, just like the NMDA receptors, they are activated when there is an increase in nociception to the spinal cord. The opioid receptors are also activated and probably what happens is that there is also some degree of tolerance, and therefore they may not be very useful in patients with fibromyalgia.

If you ask them whether they help, most patients say they are not strong enough, no matter what you give them. The one thing in their favor is that the data suggests that patients taking opioids in a controlled manner are able to work better, to have stronger relations with families, and have normal sexual activity. However, there is opioid resistance and therefore, these patients are very likely to escalate the use of the narcotic. Or use other drugs.

If they are going to be used, however, -- and I have very few patients with fibromyalgia that are really on narcotics -- this has to be an individualized decision and it has to be a signed contract. The patients cannot be calling the office after hours to get the fellow on call to refill the narcotic. That is totally unacceptable. One physician and one pharmacy should be the only one dispensing the prescriptions. If this contract is broken, then you have no reason to continue prescribing. The contract is terminated and the patient doesn't get any more prescriptions from you. Now that doesn't mean they are not going to get the prescription, but it means that you are not going to be responsible for that kind of prescription.

Do I inject trigger points? In the early 1980's, we did it all the time. As we went more and more into understanding what is the pathogen of pain in fibromyalgia, I'm not sure that that makes any sense. However, I have to admit that I have patients that are legacies of the 1980's and they are still coming for their injections and it's hard to tell them I don't believe it. They believe it, so they continue receiving them. But I don't start anyone, because I really don't think that they make a big difference.

Other maneuvers on the topical level can be used as well. There is a mountain of other maneuvers that have been described in the literature. For the majority the literature is really very scanty, no control, etc. Acupuncture -- I don't know if it really works, if it works as a placebo or works as a central factor.

Fibromyalgia vs. Chiari Malformation

One last comment, and it's the one that has been on the Internet so much, the New York Times and every other place that I can think of. It's whether or not patients with fibromyalgia should be screened for Chiari malformation. There is no question that some patients with Chiari (malformation) may have manifestations that look like fibromyalgia, but that is far from saying that every patient with fibromyalgia should be screened with an MRI for Chiari. Much less that you need to take certain views and measure them a certain way if you are going to really diagnose Chiari. That is really stretching the diagnosis of Chiari. If you cannot see it, it's not there.

Moreover, the number of complications that have been seen for operating on "Chiari" patients is tremendous. So the compressive surgery should be left for those patients that clearly have Chiari that produces compression of the spinal cord, and not for any other one that may have a very minimal abnormality.

So what is the challenge for the 21st Century? Obviously it is going to be very hard to treat our patients unless we better understand the pathogenesis of this disorder. We need to be able, not just from the clinical experience, but from the clinical studies done in a controlled fashion, to see what are the risk factors for a poor and good prognosis. We need to develop programs that will treat patients in a more successful way than we are doing at the present time. Thank you very much.

Challenging the Existence of Fibromyalgia

Dr. Paget: Graciela, that was a wonderful presentation. A few questions. What do you say to people in the audience and people on the web site to the concept that prominent rheumatologists don't believe that this exists, or that rheumatologists, if it exists, should deal with these patients?

Dr. Alarcon: I think it's sad that the overwhelming literature over the last ten years at least, that clearly indicates that this condition is real, is not taken seriously by a large proportion of the ACR members. You cannot change adult behavior. We are skeptical people and we are more skeptical now.

The other problem is that because we don't understand it, we tend to believe that the pain is not real. I think that is the real difference between the Munchausen patient who is faking the symptoms and the fibromyalgia patient who is really having pain. I'm sure some of you in the audience have had back pain occasionally. It's part of life and it's unpleasant. Well, imagine that pain being present all the time in every part of your body. The fact is that it is there. You really don't understand it, but that doesn't mean it's not there. And you should really listen to the patient.

Now having said that, I think that we are at least in the position of screening them for other diagnoses to be sure that that is all they have, and then guide them through the principles so that they don't perpetrate their symptoms and the symptoms can be interrupted. If the sleeping improves, the pain diminishes, they start to exercise and lose weight, I think they are going to overall be better.

Unfortunately, many patients, by the time they come to us, are already at the end of their rope, meaning that they are taking ten different medicines. They are completely de-conditioned and there is nothing we can do. Even psychiatrists and psychologists are going to be able to very little. I think that the job starts with the primary care physician. Many cases are really coming already on narcotics provided by the primary care physician. In many cases they are very young individuals, I'm talking about 18 and 16 year-old kids who are coming in with fibromyalgia and already taking narcotics. You look ahead to 60 years of life like that -- it is miserable.

Diagnosing Fibromyalgia with Other Rheumatic Conditions

Dr. Paget: That was a wonderful exposition. I'm going to take a different part of your life. I know that you see a lot of lupus patients and the part that I've never understood and maybe you can add to this, is the idea of simultaneously diagnosing lupus and fibromyalgia or some other disease and fibromyalgia. From an intellectual point of view does that have validity? And from a pragmatic point of view does that have validity?

Dr. Alarcon: We have to study fibromyalgia patients who also have another rheumatic disorder in our fibromyalgia studies. However, in lupus studies, we didn't start looking for it, but as the literature started coming in more and more, and as we were clearly seeing and following more patients, it became clear that some lupus patients do have secondary to concomitant fibromyalgia. In many cases it's that fibromyalgia or fibromyalgia-like complex symptomatology that makes them so hard to treat. About 10% of lupus patients in the SELENA study have features of fibromyalgia by standardized methods of ascertaining the tender points and generalized pain.

Now there is another group, one that I do not really think has lupus. They have myalgias, arthralgias, they had a little ulcer and a positive ANA. They don't have lupus, they have fibromyalgia with ANA positivity, and that is all they have.

My other fellow is writing the paper. She has followed 25 subjects with fibromyalgia ANA positivity to see what proportion will evolve into lupus over time and the lupus is not being seen like overt CNS, renal, nothing like that. It is being seen as primarily arthritis, skin type of lupus. She is also following another group of lupus patients, not meeting the clinical definition of lupus, such as simple renal disease, to see if they will involve into full blown lupus, and for the most part, they also stayed like that. So we are going to have these subsets until we understand this disease better.

Question: Graciela, just to follow up on Dr.Paget's comments, I was going to ask the same thing. I thought fibromyalgia was a wonderful disease because it is something you were going to diagnose the patient with, no abnormalities on x-ray, no abnormalities in the lab, was perfectly normal physically, but had this definition by the ACR. Then they came out with the fibromyalgia plus other illnesses and I started thinking why if they have rheumatoid arthritis and lupus did you need to look for another reason for pain. But some of the studies you did are very interesting because you were able to show a group of patients that they have a lower threshold to pain. It might be interesting now to go back to the rheumatoid population and to the lupus population with those same studies and see if you can differentiate two groups that have lower threshold to pain and do they end up with secondary fibromyalgia? Because without that, I find it almost impossible to use. It's interesting, because there is a lot of data in the cancer literature where they have applied some psychological tests to patients with cancer pain, which all of us treat with the most potent medicine. And they can definitely demonstrate in two groups that those that score poorly in emotional and psychological testing have lower thresholds for pain than the other cancer group. You can actually split them out. It may be interesting to do that. But I find fibromyalgia plus another disease to be a ridiculous diagnosis.

Dr. Alarcon: Well, I don't think it is, and the reason it's not is because those patients do not respond to your anti-rheumatic medications. I have patients with fibromyalgia and rheumatoid arthritis that went on Enbrel. I was very clear, I said that is going to help your joints, but I don't think it's going to help the pain that you feel overall. That was exactly what happened. I think that it is very clear that patients with rheumatoid arthritis or lupus that also have fibromyalgia have the typical tender areas that do not seem to be responsive to anti-inflammatory therapy period. Even though we haven't done the studies, since we have examined the patient systematically, I have no doubt that those patients are going to have lower pain thresholds. So we haven't gone through the motions, but it is very clear that they have very low pain thresholds; that is not lupus.

The Role of Serotonin in Fibromyalgia

Question: I have two questions. What is the role of serotonin in the pathogenesis in fibromyalgia? And what is your impression of the fibromyalgia clubs that are around, where people seem to go and commiserate with each other and come out with more symptoms than they went in with?

Serotonin is one of the neurotransmitters that is antinociceptive. So in that big figure of the boxes, that is what it is. So the patient with fibromyalgia seems to be depressed, so the antinociception doesn't occur. Now as to the support groups, it's clearly indicated that some of the support groups reinforce negative behavior. When a patient asks me about going to a support group, I say I need to know which one, because I know very well from some of the ones in our area, the patients come out worse than they were before. So I think that if you are starting your own support group that you have some degree of control over, that is good, or tell the patients to stay away from the negative ones.

Fibromyalgia and Chronic Fatigue

Question: You have patients with chronic fatigue syndrome, which seems significantly different from those patients who have fibromyalgia. How does that translate into the way you approach the treatment of those two groups of patients?

I don't think anyone has any clue as to how to effectively treat patients with chronic fatigue. If those patients have pain, you can treat the pain, but I don't think anyone has really and truly made any difference in the treatment of fatigue. It is another poorly understood symptom that we tend to stay away from because we don't understand. I don't have any clues as to how to treat those patients.

Question: It is very clear that patients with fibromyalgia are tender all over, costochondral area, and other areas outside of the "tender points". What do you think, conceptually, the tender points represent centrally? Do they have a central representation as to why they are more prominent than others or do they have a peripheral tissue representation?

I would think this is a totally unsettling issue. It starts from the past. I mean the 70's and 80's suggested that there were local abnormalities that, really and truly, if you going to make a microscopic examination, the tissue is normal. There are some metabolic abnormalities that have been described. However, whether or not they are real or there was a fluke in those studies I'm not sure. I think primarily they are central and they represent areas of nociception that have been enlarged. So really, the concept of allodynia from the pain really spread beyond the area of where it started. In children with hypermobility or younger adults, we see, for example, that trauma starts the process. They may have sprained an ankle, which is very common in hypermobility, and from then on they start having significant pain. I think that you can start peripheral with the tissue injury and then have a generalized pain syndrome that has to be produced on a central level.


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