Fibromyalgia - Interview with Dr. I. Jon Russell

n the interview below, Special Topics correspondent Myrna Watanabe talks with Dr. I. Jon Russell about his highly cited fibromyalgia research. In our analysis of this field, Dr. Russell’s work ranks at #5, with 26 applicable papers cited a total of 610 times. Three of these papers are included on the lists of the most-cited papers in this field over the past decade and over the past two years.
Dr. Russell is an associate professor of medicine in the Department of Medicine, Division of Clinical Immunology at the University of Texas Health Science Center in San Antonio. He also is director of the University Clinical Research Center in San Antonio. He trained as a biochemist and earned his Master’s and Ph.D. degrees in biochemistry from University of Nebraska in Lincoln, later attending medical school at Loma Linda University in Loma Linda, California, from which he received his M.D. degree.

Dr. Russell is an internist with a subspecialty in rheumatology. His research interest is the fibromyalgia syndrome, which he helped to classify, along with his long-time collaborator Dr. Fred Wolfe. Dr. Russell’s background in biochemistry has been helpful in identifying several chemical abnormalities in fibromyalgia. He notes that despite his highly cited papers, as indicated in Essential Science Indicators, fibromyalgia has been a controversial diagnosis.

His research on fibromyalgia has ranged from early characterization of fibromyalgia syndrome patients, research classification of the condition, its epidemiology, its biochemical pathogenesis, and, more recently, its pharmacological management. Dr. Russell is a consultant to many pharmaceutical and investment companies, including Pfizer, Eli Lilly, Society of Industry Leaders, Shearson-Lehman, and many others.

Your most-cited paper in the last 10 years, which had been cited 109 times at the time of our analysis, is, "Health status and disease severity in fibromyalgia—Results of a six-center longitudinal study," (Arthritis and Rheumatism 40:1571-9, 1997). Why has this paper been cited so often?

Fred Wolfe (from the Arthritis Research Center in Wichita, Kansas, and the University of Kansas School of Medicine) was the mastermind of this project, but five other investigators across the country submitted fibromyalgia syndrome patients to be monitored every six months for many years. The essence of this paper was a comparative analysis of a cross-section of fibromyalgia syndrome patients all across the United States using the same assessment instruments for all. It was coupled with a study of national costs associated with the syndrome. Together, these papers have provided the knowledge base upon which national and international decisions could be made regarding how to plan for and deal with this condition.

Our 1990 paper on the research classification of the fibromyalgia syndrome (Wolfe F, et al., "The American College of Rheumatology 1990 criteria for the classification of fibromyalgia," Arthritis and Rheumatism 33[2]:160-72, 1990) would probably be our most cited work because it provided a uniform framework upon which international research about this condition could be based. This paper allowed investigators around the world to be confident of their fibromyalgia syndrome diagnosis so patients entered into research studies would be uniform. Every research paper that reports an investigation about the fibromyalgia syndrome would be expected to quote this paper.

Acceptance of the fibromyalgia syndrome by physicians is growing in proportion to the large numbers of published studies that provide objective support for allodynia, central sensitization, neurochemical abnormalities, and well-tolerated, effective therapy.

Through the years, Fred Wolfe and I have had many papers together. Another important paper in this series reported on the prevalence of the fibromyalgia syndrome in the general population of the United States (Wolfe F, et al., "The prevalence and characteristics of fibromyalgia in the general population." Arthritis and Rheumatism, Volume 38[1]:19-28, 1995). I think this paper has been critical to progress regarding the fibromyalgia syndrome because it paved the way for estimating the magnitude of the problem in the United States and the cost of the disorder to the national economy. With these data it was possible to project the potential benefits to the pharmaceutical industry if companies were to invest in the development of medications with known mechanisms of action that would really improve the quality of patients’ lives. Many exploratory market surveys were conducted during this time.

Your highly cited papers seem to be moving from description of the syndrome to biochemical mechanisms of the disease and potential drugs to treat the condition. Is this a natural progression of your interest or are there specific reasons for these changes?

Before we knew how to consistently diagnose the fibromyalgia syndrome, it was impossible to conduct meaningful biochemical research studies. Therefore, I assisted with clinical presentation studies, epidemiology studies, and cost-of-care studies. Whenever time and financial support allowed, I would conduct a biochemical study. In most of those studies, we were fortunate to have chosen directions that were fruitful. Much of this occurred and was published before 1996, prior to the time frame for this Special Topics analysis.

Together, the classification criteria and the study to determine the prevalence of the disorder in the general population prepared the way for biochemical studies. For several years, I had studied the levels of serotonin and its metabolites in the blood and urine from people with fibromyalgia and normal controls. One day, Fred Wolfe asked, "Why don’t you do serotonin levels on the serum samples that I’ve collected from fibromyalgia syndrome patients?" (Wolfe F, et al., "Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. Journal of Rheumatology 24[3]:555-9, 1997).

Our transition to the study of spinal fluids is an interesting story. I proposed to our Institutional Review Board that I draw spinal fluid from fibromyalgia syndrome and healthy normal controls to examine the levels of selected neurochemicals known to be involved in the process of nociception. The answer was no. The explanation was that it is inappropriate to perform a test with potential adverse effects on patients who have nothing wrong with them.

I changed my approach and wrote to a friend, Dr. Henning Vaerøy in Norway, who had already done a study of spinal fluid substance P in fibromyalgia syndrome. I proposed that he come on a speaking tour to San Antonio but his "ticket" was to be an aliquot of each of his spinal fluids that we could analyze in our laboratory. The resultant study was successful in documenting low levels of biogenic amines in people with the fibromyalgia syndrome (Russell IJ, et al., "Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis," Arthritis and Rheumatism 35[5]:550-6, 1992). With that finding in hand, I again approached the Institutional Review Board, and this time, they approved both a spinal fluid collection and a sample bank for the long-term storage of samples collected from fibromyalgia syndrome patients and appropriate controls.

Back in about 1994, our San Antonio group published our second paper on examination of spinal fluid in fibromyalgia syndrome (Russell IJ, et al., "Elevated cerebrospinal fluid levels of substance P in patients with fibromyalgia syndrome," Arthritis and Rheumatism 37[11]:1593-1601, 1994). We confirmed and expanded upon the earlier finding by Vaerøy that spinal fluid substance P levels are dramatically elevated in people with the fibromyalgia syndrome. This finding has now been confirmed by two other research groups studying three different ethnic groups.

So then, our question was, "Why do we have elevated substance P levels in the spinal fluid of fibromyalgia syndrome patients?" I recruited a world-class neuroscientist, Dr. Alice Larson, from the veterinary school in Saint Paul, Minnesota. We talked about this problem of how substance P was produced and she proposed that nerve growth factor might be responsible. I sent her spinal fluids, and Dr. Susan Giovengo, who was working in Dr. Larson’s laboratory, assayed them for nerve growth factor. We already knew that substance P levels were high in patients with primary fibromyalgia syndrome, but were numerically less so in secondary fibromyalgia syndrome when it was associated with rheumatoid arthritis. Dr. Giovengo’s assay of nerve growth factor demonstrated that it was very high in people with primary fibromyalgia syndrome but was not elevated in those with secondary fibromyalgia syndrome (Giovengo SL, Russell IJ, Larson AA, "Increased concentrations of nerve growth factor (NGF) in cerebrospinal fluid of patients with fibromyalgia," J. Rheumatol. 26[7]:1564-9, 1999).

The next step was to ask about the excitatory amino acids, such as glutamate and aspartate, which are released in the dorsal horn of the spinal cord in the process of afferent pronociception. Again it was Dr. Alice Larson who did the measurements on our San Antonio spinal fluids (Larson AA, et al., "Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways," Pain 87[2]:201-11, 2000). The result was that the levels in the fibromyalgia syndrome spinal fluids were not significantly different from normal controls but that there were intercorrelations between neurochemicals that suggested an active pain process in the patients with fibromyalgia.

Together, these findings set the stage for interpretation of the fibromyalgia syndrome as an objective disorder in which the patients’ perception of pain and allodynia appeared to be correct.

Probably the next most important piece of information comes from our more recent directions. In collaboration with several other centers under funding from the National Institutes of Health, we explored the genetic basis of the fibromyalgia syndrome among people in families who had at least two affected immediate family members. There were two chromosomal loci that related highly [Lod score] with two separate subgroups of fibromyalgia syndrome patients (Iyengar SK, et al., "Genetic linkage of fibromyalgia syndrome to the serotonin receptor 2A region on chromosome 13 and the HLA region on chromosome 6," Submitted to Genes and Immunity, in review, 2005). A full genome scan is underway using the samples from this study.

Is there any one study, paper, or group of related papers you have written or co-authored that you believe have been most influential in your field? If so, which?

I think the aforementioned substance P paper was probably the most influential, but it probably should have been paralleled by the one on biogenic amines in the spinal fluid of fibromyalgia syndrome patients.

Were there problems in convincing your colleagues that fibromyalgia was a real condition?

Over the past 10 years, people have been "discovering" the fibromyalgia syndrome. Suddenly, drug companies, insurance companies, government agencies, and a variety of investigators have been concluding that fibromyalgia is here to stay and that it can be very expensive. It was then that the fibromyalgia syndrome acquired a very powerful foe, the insurance industry in the United States and Canada, who were loath to pay for claims of injuries sustained during falls or motor vehicle accidents that seemed to be temporally related to the onset of the fibromyalgia syndrome symptoms.

Some of our medical colleagues are also hesitant to espouse the disorder, but that is changing. Acceptance of the fibromyalgia syndrome by physicians is growing in proportion to the large numbers of published studies that provide objective support for allodynia, central sensitization, neurochemical abnormalities, and well-tolerated, effective therapy.

What other contributions have you made to the field?

Considering all of this, I felt that the important contribution for me to offer was to find objective evidence from the laboratory that the fibromyalgia syndrome is a biologic disorder. That has been the impetus for many of our other papers. It is gratifying, therefore, to observe that many of the medicinal agents that have proven beneficial for managing the symptoms are known to fix abnormalities that we have described. For these reasons, I have also felt good about my efforts to assist the pharmaceutical industry in studying promising new medications. It is satisfying to administer a medication that has a known mechanism of action that would be predicted to help the fibromyalgia syndrome symptoms and see the benefit come to life.

For example, the drug tramadol (Ultram) was the first neurochemical therapeutic agent to achieve a statistic of p=0.001 for the management of pain in the fibromyalgia syndrome. I was pleased to lead the research team in writing the manuscript for that study (Russell IJ, et al., "Efficacy of tramadol in treatment of fibromyalgia," J. Clin. Rheumatol. 6[5]:250-7, 2000).

Over a period of about seven years, I worked on clinical studies to test the anticonvulsant drug pregabalin (eventually released as Lyrica), and helped to author the first published manuscript on this topic (Crofford LJ, et al., "Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial," Arthritis Rheum. 52[4]:1264-73, 2005).

I also worked for about three years on another worthy agent, duloxetine (Cymbalta), which is the first real member of the serotonin-norepinephrine reuptake inhibitors. I predict that there will be others in this class before long. (I was an investigator, but not an author, on the key publications.)

Another agent that I have been pleased to study has been sodium oxybate, which I class as a strong sedative and inducer of restorative sleep. I am helping to prepare the manuscript for that agent’s debut in the field of fibromyalgia syndrome studies (Russell IJ, Perkins T, Michalek JE, Xyrem^® for Fibromyalgia Syndrome Research Group, "Sodium oxybate [Xyrem^®] relieves pain and improves sleep in patients with the fibromyalgia syndrome: a randomized, double-blind, placebo-controlled, multi-center clinical trial," in preparation).

What I want to portray here is this: even though I think of myself as a biochemist with clinical training, the clinical studies were critical. They helped to prepare the way to finding biochemical mechanisms for which medications could be developed to help the patients.

What else are you involved in?

I felt that it was important for us to develop an educational program for patients and physicians. We started with what we called the "Primer for Fibromyalgia." It was a six-page brochure explaining the syndrome and listing other resources. We gave it away free to anyone who requested it. The Arthritis Foundation listed our "Primer" among its approved resources for fibromyalgia syndrome patients. We were printing about 1,000 copies of the "Primer" per quarter for at least three years. Since there was no specific funding for that effort, it got so we could no longer afford to support it.

I then helped to write a book for a lay audience that was published and has sold over 150,000 copies (Fransen J, Russell IJ, The Fibromyalgia Help Book: Practical Guide to Living Better with Fibromyalgia, St. Paul, MN: Smith House Press, 1996).

With funding from the RGK Foundation of Austin, Texas, we produced a Nova-like video production to educate patients and help clinicians and patients understand the disorder better. Between 3,000 and 4,000 copies of that video were distributed to patients and support groups.

Then there was the issue that physicians wanted to learn about the fibromyalgia syndrome. In 1993, I started a journal for physicians who are interested in this field, the Journal of Musculoskeletal Pain, for which I continue to serve as the editor. The journal is now finishing its 15^th year of continuous publication.

We worked with others of like interests to start a series of meetings that were eventually named MYOPAIN. In 1995, we started the International MYOPAIN Society. I helped develop the bylaws and served as its first president. The organization has now grown to over 700 members in about 40 countries and has an international meeting every three years, alternating between the U.S. and a European country. That, I think, is quite a successful effort because physicians who were involved in this field felt they were isolated, and this society has given them a way to maintain their social and academic ties with active research in the field.

What are you working on now?

We just submitted a paper—Kuan TS, et al., "Discrimination of fibromyalgia patients from normal controls using the levels of cerebrospinal chemicals," (submitted to Pain, 2006)—in which we show that we can identify spinal fluid from people with the fibromyalgia syndrome based on three biochemical tests for substance P, nerve growth factor, and 5-hydroxyindole acetic acid. When we plug the concentrations of the three neurochemicals into a formula we developed, it distinguishes fibromyalgia syndrome spinal fluid from that of healthy normal controls with an accuracy of 90%.

This year, we presented an abstract at the American Pain Society which reports that there is a G protein-coupled receptor that is dysfunctional in fibromyalgia. The interesting thing about this was that this measurement was made on peripheral blood lymphocytes. The most important impact should have been on the central nervous system, but it seems to have affected all the cells of the body. There is a dysfunctional G protein complex on the surface of cells, and that could be an important reason why fibromyalgia syndrome patients have so many symptoms.

Is there anything about your papers or your career that you think would be important for our readers?

The concept that I would most want to get across is that all of my efforts in this regard have been intended to provide a variety of kinds of support for fibromyalgia syndrome patients and to educate physicians so they are better prepared to help the patients.

Since 1982, I have lectured about the fibromyalgia syndrome to physicians at least once in nearly every state of the union and at least once in 15 countries. I’ve given about 300 continuing medical education lectures to physicians and patient groups with the goal of providing information resources about the disorder. With regard to the patients, these lectures have helped them to regain confidence in themselves. When patients are repeatedly told that there is nothing wrong with them, they begin to doubt themselves. The information provided in the lectures about objective abnormalities documented in the fibromyalgia syndrome give them support for their own psyches.

Back in the 1980s, at the American College of Rheumatology national meetings, there were only five or six of us meeting together each year to talk about the fibromyalgia syndrome. Sometimes, our wives came along to fill a few more chairs. There are lots of good advocates now. In 1990, we were fortunate to come up with 20 people who believed enough in the fibromyalgia syndrome to participate in the criteria study. If you look at the number of publications on fibromyalgia, there were about 15 a year until 1990, when the American College of Rheumatology criteria paper was published. Thereafter, the number of papers went up to about 120 a year, and has stayed at that level or higher ever since. Based on the temporal relationship of the criteria to change in publications, I would conclude either that the 1990 ACR classification criteria paper was a critical publication, or that a critical time was reached, or both.

I have been grateful in the last five years to be invited to write the fibromyalgia syndrome chapters in both of the world’s main textbooks of pain (Loeser JD, et al., Bonica's Management of Pain, 3^rd edit., Philadelphia: Lippincott Williams & Wilkins, 2001 and McMahon S, Koltzenburg M, Wall and Melzack’s Textbook of Pain, 5^th edit., Oxford: Churchill Livingstone, 2005). In addition, I was asked by David Simons, M.D., who bears the legacy of Janet Travell, M.D., in advocating for the myofascial pain syndrome, to write a fibromyalgia syndrome chapter in his Trigger Point Manual and in another book called Muscle Pain with David Simons, M.D., and Sigfried Mense, M.D., Ph.D., in each case to facilitate having the reader make comparisons with the myofascial pain syndrome.

It is clear now that the movement to recognize, research, and manage the fibromyalgia syndrome is well grounded and will continue to progress with many young people taking the lead from those of us who now have limited time to contribute.

I. Jon Russell, Ph.D., M.D.
University of Texas Health Science Center
San Antonio, TX, USA

Related Links:

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Read an interview with the coauthor of this paper: Dr. M.B. Yunus

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http://www.myopain.org

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ESI Special Topics: October 2006
Citing URL: http://esi-topics.com/fibro/interviews/IJonRussell.html